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Nicholson WK, Wilson LM, Witkop CT, et al. Therapeutic Management, Delivery, and Postpartum Risk Assessment and Screening in Gestational Diabetes. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Mar. (Evidence Reports/Technology Assessments, No. 162.)
This publication is provided for historical reference only and the information may be out of date.
Therapeutic Management, Delivery, and Postpartum Risk Assessment and Screening in Gestational Diabetes.
Show detailsWe present the findings of our review using a standard format for each of the four key questions. First, we present the conceptual framework for each question, incorporating relevant background information and potential implications for clinical practice. Next, we summarize the population characteristics of each study. We then summarize the findings, emphasizing those results that are most relevant to our conceptual framework. We outline the methodological issues related to the heterogeneity of study design and outcome analyses and then summarize our assessment of the quality of each study using established quality criteria published in the literature. Finally, we assign a grade to the overall body of evidence on each question or sub-question.
Search Results
A summary of the search results for the primary literature review is presented in Figure 2. From the search, we retrieved 11,400 unique citations. After a review of the titles and abstracts, 552 were deemed eligible for further review, and the full articles were retrieved. A total of 45 articles were included in this review.
Key Question 1
What is the evidence for the risks and benefits of oral diabetes agents (e.g., second-generation sulfonylureas and metformin), as compared to all types of insulin, for both the mother and neonate in the treatment of women with gestational diabetes?
- a.
How does maternal outcome vary based on the level of glucose at the initiation of a medication?
- b.
How does neonatal outcome vary based on the level of glucose at the initiation of a medication?
Background and Conceptual Framework
Understanding the risks and benefits of the use of insulins or oral diabetes agents during pregnancy for both maternal and neonatal outcomes is essential to the care of women with gestational diabetes and their offspring.28 29 As shown in the conceptual framework (see Figure 3), our objective for Key Question 1 was to review RCTs and observational studies to compare the risks and benefits of medical treatment for the management of glucose levels in women with gestational diabetes. As previously highlighted, pregnancies with gestational diabetes are often characterized by many maternal and neonatal complications, including poor maternal glucose control, cesarean delivery, and neonatal hypoglycemia. Our primary goal was to summarize the maternal and neonatal outcomes across treatment modalities, to derive pooled estimates where possible, and to summarize the relevant conclusions based on the available literature.
Results
Overview and population characteristics of eight RCTs comparing insulins, insulin analogues, and oral diabetes medications. We identified eight RCTs with a total of 845 participants that met our inclusion criteria for review.30–37 Evidence Table 1 describes the primary characteristics of each of the trials. Four of the studies reported study durations of 8 months to 4 years,30 34 35 37 while the other four studies did not report a study duration.31–33 36 The studies were published between 1990 and 2006. For the four studies that reported the starting year of the study,30 34 35 37 the earliest starting year was 1985. The trials were conducted in diverse countries and populations: Three trials were conducted in the United States,30 32 36 one in Italy,34 one in Finland,31 one in India,33 one in Brazil,37 and one in Israel.35 The trials also compared different treatment interventions: Two clinical trials32 33 compared insulin to glyburide; one trial37 compared insulin, glyburide, and acarbose; two studies34 36 compared regular human insulin and insulin lispro; one study31 compared long-acting and short-acting insulins; one study38 compared insulin administered two-times-daily and four-times-daily; and one study30 compared diet and insulin.
The average maternal age ranged from 25 to 34 years and did not substantially differ across groups. Only three studies reported the racial distribution of the study participants:33 34 36 Anjalakshi et al.33 reported that 100 percent of the study participants were Indian. Most participants (95 percent) in the study by Jovanovic et al.36 were reported as Hispanic. All of the participants in the study by Mecacci et al.34 were reported as Caucasian.
In the studies that reported maternal weight, the weight measures were similar between groups. Five studies30 34–37 reported gravidity, and three studies30 32 36 reported the parity of study participants, which ranged from nulliparity to 2.5 prior births.
Consistent with our study selection criteria, each of the eight RCTs reported the test used to diagnose gestational diabetes. Three studies31 33 37 used the 75-gm OGTT World Health Organization (WHO) criterion. Two studies30 35 used the National Diabetes Data Group (NDDG) criterion, and three studies32 34 36 used the 3-hr, 100-gm OGTT with threshold values based on the Carpenter and Coustan criterion. Langer et al.32 used the FBG threshold of 95 mg/deciliter (dL) based on the 100-gm OGTT Carpenter and Coustan criteria to determine eligibility and as the threshold value for treatment with insulin or glyburide. Bertini et al. used a FBG greater than 90 mg/dL or a 2-hr PPG greater than 100 mg/dL as threshold values for initiation of treatment with glyburide or insulin. Anjalakshi et al.33 initiated medical therapy if the 2-hr PPG was 120 mg/dL or greater after two weeks of nutritional therapy. The average gestational age at screening and diagnosis of gestational diabetes varied across studies from 22 to 28 gestational weeks. Mecacci et al.34 reported a median gestational age at diagnosis of 28 weeks (range: 25 to 32). Polyhonen-Alho31 reported a gestational age range of 24 to 28 weeks.
Maternal and neonatal outcomes in eight RCTs of insulin, insulin analogues, and oral diabetes medications. Data were available for abstraction for five of the eight maternal outcomes of interest and 11 of the 13 neonatal outcomes in Key Question 1. As shown in Table 2, data were abstracted on several maternal outcomes, including: (1) average glycemic control (mg/dL), (2) episodes of maternal hypoglycemia, (3) mean difference in maternal weight; (4) cesarean delivery, and (5) episodes of pre-eclampsia. Neonatal outcomes included: 1) infant birth weight, (2) macrosomia, (3) LGA, (4) SGA, (5) hypoglycemia, (6) hyperbilirubinemia, (7) perinatal mortality, (8) respiratory distress syndrome, (9) congenital malformations, (10) birth trauma, and (11) neonatal intensive care admissions.
Insulin versus glyburide
Maternal outcomes. Three RCTs32 33 37 compared the effects of insulin and glyburide on five different maternal outcomes (see Appendix F, Evidence Table 2). Because of the sparseness of the data and diversity of outcomes, we were unable to combine any of the studies in meta-analyses; therefore, we have described the results qualitatively here.
Two RCTs32 33 evaluated maternal glycemic control. Langer et al.32 randomized 404 women to receive insulin (n=203) or glyburide (n=201). The insulin regimen was based on maternal weight, with two-thirds of the units administered as neutral protamine Hagedorn (NPH) and one-third of the units as regular insulin. In the study by Langer, glyburide was initiated at a dose of 5.0 milligrams (mg) or 2.5 mg and increased to a maximum dose of 20 mg/day. In the study by Anjalakshi,33 glyburide was initiated at a dose of 0.625 mg. No maximum or average dose was reported. Langer et al.32 reported no statistically significant differences in average final FBG or 2-hr PPG levels between those receiving insulin and those on glyburide. The average (mean ± standard deviation [SD]) FBG levels were 96 ± 16 for insulin and 98 ± 13 for glyburide (p = 0.17). The average 2-hr PPG levels were 112 ± 15 for insulin and 113 ± 22 for glyburide (p = 0.6).
A smaller randomized trial33 of 26 participants comparing glyburide to insulin also reported no statistically significant differences in mean 2-hr PPG levels during pregnancy in the insulin versus the glyburide group.
The two larger RCTs32 37 compared the percentage of women undergoing cesarean delivery in each group. Langer32 reported that 49 (24 percent) of the women on insulin underwent cesarean delivery, as compared to 46 (23 percent) of the women on glyburide (p > 0.05). Bertini et al.37 reported no significant differences in the rate of cesarean delivery among three groups of women receiving insulin (44 percent), glyburide (50 percent), or acarbose (52 percent).
Bertini37 and Langer32 both reported on maternal hypoglycemia. Bertini defined maternal hypoglycemia based on the need for hospitalization and reported no episodes of hospitalization in any of the three treatment groups. Langer did not define maternal hypoglycemia but reported a significantly higher percentage of women with a blood glucose level under 40 mg/dL in the insulin group than in the glyburide group (20 percent versus 4 percent; p = 0.03).
Bertini37 also compared the mean difference in maternal weight at delivery to the baseline value in each treatment group and found no significant differences.
We have concluded that maternal outcomes did not differ significantly between insulin and glyburide. However, two33 37 of the three studies presented were limited by their small sample size and limited power to detect significant differences in some outcomes. Furthermore, we were unable to fully assess other relevant outcomes, such as maternal hypoglycemia, because of inconsistencies in the definition of outcomes. Taking into consideration the quantity, quality, and consistency of the studies comparing the effects of glyburide versus insulin on maternal outcomes, we graded the strength of evidence as very low (see Appendix F, Evidence Table 3).
Neonatal outcomes. Three RCTs reported on nine different neonatal outcomes (see Appendix F, Evidence Table 4). We have described most of the results qualitatively because of the sparseness of the data and the diversity of the outcomes (see Table 2). Three studies with relatively similar populations and interventions reported data on the mean differences in infant birth weight between the insulin and glyburide groups. As shown in Table 3, all three RCTs32 33 37 reported lower mean birth weights for the infants in the insulin group than for the infants in the glyburide group. In the three RCTs, infants in the insulin group were reported as being 120 gm, 244 gm, and 62 gm smaller, respectively, than the infants in the glyburide group. We performed a meta-analysis using a random effects model, combining data from the Anjalakshi 2006 RCT33 with data from the Bertini 200537 and Langer 200032 RCTs. We report the results as the weighted mean difference in infant birth weight in the insulin group as compared to the glyburide group. These three RCTs, with a total of 478 infants, provided a weighted mean infant birth weight difference of 93 gm (95 percent confidence interval (CI): -191 to 5 gm). Infants in the insulin group were on average 93 gm smaller than infants in the glyburide group (see Table 3 and Figure 4). This finding is not statistically significant, and the clinical relevance of such a small difference is unclear. While exclusion of any one study's results would not have markedly altered our results, the largest study by Langer et al. contributed the most to the overall mean difference in birth weight.
Langer et al. reported no significant differences between treatment groups in the percentage of infants with hypoglycemia. Among the 201 women on glyburide, 9 percent of the infants experienced hypoglycemia, as compared to 6 percent of those with mothers on insulin (p = 0.25). Bertini et al. reported a higher percentage of infants with macrosomia (birth weight greater than 4,000 gm) and LGA among the women on glyburide than among those on insulin or acarbose. A significantly higher percentage of infants had hypoglycemia in the glyburide group than in the insulin or acarbose groups (33 percent compared to 4 percent and 5 percent, respectively; p = 0.006). However, Bertini reported no difference in SGA infants or in perinatal mortality between the group on insulin and the group on glyburide.
We concluded that the use of insulin may be associated with an average 93-gm lower infant birth weight when compared to glyburide. However, this difference was not statistically significant. It is unlikely that this finding has substantial clinical relevance, given the small difference in infant size. We graded the strength of the evidence as very low (see Appendix F, Evidence Table 3) for studies comparing the effects of glyburide and insulin on neonatal outcomes. While there was consistent evidence on infant birth weight from the three RCTs, the lack of consistency in the reporting of other relevant neonatal outcomes across the three studies made it difficult to draw firm conclusions. The large trial by Langer and colleagues32 certainly provided credible estimates for several neonatal comparisons, but the findings were limited to one sample of women and had limited generalizability.
Regular insulin versus insulin lispro
Maternal outcomes. Two RCTs34 36 compared the effects of regular insulin and insulin lispro on at least one of three maternal outcomes: cesarean delivery, average blood glucose level, and maternal hypoglycemia (see Appendix F, Evidence Table 2). Jovanovic36 and Mecacci34 recruited 42 and 49 participants, respectively, in two trials comparing regular insulin to insulin lispro. In the trial by Jovanovic, the initial dose of both regular insulin and insulin lispro was 0.7 units/kilogram (kg) combined with NPH two times per day and adjusted weekly. In the trial by Mecacci and colleagues, regular insulin and insulin lispro were started at a dosage of 1 unit/10 gm of carbohydrates in meals three times per day. The mean dosage was 34.3 units/day in the regular insulin group and 35.1 units/day in the lispro group.
The mean decrease in glycosylated hemoglobin from the time of entry into the study until delivery was greater in the women on lispro (mean difference from baseline -0.35 percent) than in those on regular insulin (mean difference from baseline -0.07 percent; p = 0.002).36 Maternal hypoglycemia, reported as the mean (standard error [SE]) percentage of all blood determinations in the hypoglycemic range, was not significantly different in the insulin lispro group and the group receiving regular insulin (0.88 percent ± 0.25 percent versus 2.2 percent ± 0.86 percent; p > 0.05).36 Mecacci reported significantly higher maternal 1-hr PPG levels in the insulin lispro group than in the regular insulin group (108 mg/dL ± 11 versus 88 mg/dL ± 11, respectively; p < 0.001).34 However, both pre-prandial and 2-hr PPG levels were similar in the two groups (p > 0.05 for pre-prandial and 2-hr PPG). Both Jovanovic and Mecacci reported no significant differences in the proportion of women undergoing cesarean delivery; Jovanovic reported no differences across all cesarean deliveries,36 and Mecacci reported no differences between groups for cesarean delivery specifically for cephalopelvic disproportion.34
We concluded that maternal glucose control, as measured by glycosylated hemoglobin or 1-hr glucose levels, did not differ between women treated with insulin lispro and those receiving regular insulin. The rate of cesarean delivery in the two groups was also similar. However, taking into consideration the quantity, quality, and consistency of the studies comparing the effects of regular insulin and insulin lispro on maternal outcomes, we graded the overall body of evidence as very low (see Appendix F, Evidence Table 3). There were only a limited number of maternal outcome measures reported in either RCT: Only cesarean delivery and maternal glucose control were reported by both studies. While there was consistency in the findings reported across both studies, the available data were limited to two RCTs with small sample sizes (total N = 92). Also, there was only a limited ability to detect differences in outcomes. The absence of a difference in the rate of cesarean delivery, for example, was likely a reflection of the small number of participants in each RCT and the limited power to detect clinically or statistically significant differences.
Neonatal outcomes. While Jovanovic and colleagues did not provide actual data, they reported no difference in the proportion of infants with macrosomia or neonatal hypoglycemia who were born to women receiving regular insulin, as compared to women receiving insulin lispro (see Appendix F, Evidence Table 4).36 Mecacci et al. reported no difference in mean infant birth weight or the number of LGA or SGA infants born to women receiving regular insulin and those receiving insulin lispro.34
Based on limited evidence from these two studies, we concluded that neonatal outcomes do not differ substantially between regular insulin and insulin lispro. Taking into consideration the quantity, quality, and consistency of the studies comparing the effects of regular insulin versus insulin lispro on neonatal outcomes, we graded the strength of the evidence as very low (see Appendix F, Evidence Table 3).
Long-acting insulin versus short-acting insulin
Maternal outcomes. Polyhonen-Alho et al. randomized 23 participants to short-acting or long-acting insulin (see Appendix F, Evidence Table 2).31 Three doses of short-acting insulinwere given before breakfast (4 international units [IU]), lunch (6 IU), and dinner (4 IU). Long-acting insulin was administered at 14 IU each morning. There were no reported maternal outcomes in the study by Poyhonen-Alho et al. Therefore, for this comparison, we graded the strength of the evidence regarding maternal outcomes as insufficient (see Appendix F, Evidence Table 3).
Neonatal outcomes. In their comparison of long-acting to short-acting insulin, Poyhonen-Alho et al.31 reported a higher percentage of infants with macrosomia in the group receiving long-acting insulin than in the group receiving short-acting insulin (see Appendix F, Evidence Table 4). They reported no statistically significant differences in the occurrence of nerve palsy or infant metabolic abnormalities between the two groups. We concluded that long-acting insulin may be associated with a greater risk of macrosomia than is short-acting insulin. We graded the strength of evidence on neonatal outcomes for this comparison as very low (see Appendix F, Evidence Table 3) because of the sparseness of the data, the limited sample size, and the fact that the available data came from only one study.
Twice-daily versus four-times-daily insulin
Maternal outcomes. Nachum et al. compared outcomes in 136 women randomized to receive regular insulin twice-daily with those in 138 women randomized to receive regular insulin four-times-daily.35 The exact units of insulin were not reported. There was no risk difference in cesarean delivery between the two groups (see Appendix F, Evidence Table 2). Maternal weight gain during pregnancy was also similar between the two groups, and the average maternal glucose levels were similar. Both groups reported one participant with hypoglycemia. We concluded that no evidence exists to suggest a difference in maternal outcomes between twice-daily and four-times-daily use of insulin. For this comparison, we graded the strength of the evidence on maternal outcomes as very low (see Appendix F, Evidence Table 3).
Neonatal outcomes. In contrast to their findings for maternal hypoglycemia, Nachum et al. reported a higher proportion of neonatal hypoglycemia in infants born to women on twice-daily insulin, as compared to four-times-daily insulin (6 percent versus 1 percent; p = 0.02) (see Appendix F, Evidence Table 4).35 The proportion of infants with hyperbilirubinemia was also higher in the group treated with twice-daily dosing, as compared to four-times-daily dosing (21 percent versus 11 percent; p = 0.02). The proportion of infants with macrosomia (birth weight > 4,000 gm) was similar in the twice-daily and four-times-daily insulin groups (19 percent versus 16 percent, respectively). The proportion of LGA infants (30 percent versus 26 percent) was also similar in the two groups. There was no difference in the proportion of infants with congenital abnormalities, birth trauma, or respiratory distress syndrome. Average infant birth weight was not reported. Based on this single study, we concluded that twice-daily use of insulin may be associated with worse neonatal outcomes than four-times-daily use, but we graded the strength of the evidence on neonatal outcomes as very low (see Appendix F, Evidence Table 3).
Diet versus insulin
Maternal outcomes. Thompson30 randomized 95 women to dietary management or insulin plus dietary management. The diet regimen was 35 kilocalories per kg of ideal body weight. A fixed dose of 20 units NPH and 10 units regular insulin was administered daily. There was no reported difference in the proportion of women undergoing cesarean delivery (see Appendix F, Evidence Table 2). Baseline and FBG levels during the study were also similar between the two treatment groups.
Taking into consideration the quantity, quality, and consistency of the evidence comparing the effects of diet versus insulin on maternal outcomes, we graded the strength of the evidence as very low (see Appendix F, Evidence Table 3). Thus, the strength of evidence was too low to allow us to draw a meaningful conclusion about whether maternal outcomes differ for the two treatments.
Neonatal outcomes. In that same study, there were significant differences in the proportion of infants with macrosomia (> 4,000 gm) and in mean birth weight (see Appendix F, Evidence Table 4).30 For example, only 5.9 percent of the infants in the diet and insulin group met the criteria for macrosomia (≥ 4,000 gm), as compared to 26.5 percent of infants in the group treated with diet alone. Similarly, infant birth weight was higher in the diet-alone group than in the diet and insulin group (p = 0.002). There was no difference in neonatal hypoglycemia or hyperbilirubinemia. Although this one study suggested that neonatal outcomes might be better with the use of insulin plus dietary management as compared to diet alone, we graded the strength of the evidence as very low (see Appendix F, Evidence Table 3). Additional studies in diverse samples of gestational diabetics with well-defined measures of neonatal outcomes are needed to make it possible to draw meaningful conclusions regarding these outcomes.
Metformin versus insulin. There is no currently published evidence on maternal and neonatal outcomes in women with gestational diabetes who have been treated with metformin versus insulin.39 Recently published data on metformin treatment in pregnancy are primarily based on small cohort studies in women with PCOS, in whom it has been used to treat infertility.40–43 Women with PCOS and women with type 2 diabetes who continue to receive metformin through the first trimester of pregnancy have demonstrated few adverse pregnancy events. An ongoing prospective RCT (the Metformin in Gestational Diabetes [MiG] trial) comparing metformin with insulin in women with gestational diabetes is currently underway in New Zealand and Australia.44 The goal of the trial is to recruit 750 women over a 2-year period, collecting data on multiple maternal and neonatal outcomes. The primary outcome is a composite of neonatal morbidity, including hypoglycemia, respiratory distress, phototherapy, birth trauma, low 5-minute Apgar score, and prematurity. The secondary outcomes include maternal glycemic control, neonatal body composition, and markers of neonatal insulin sensitivity. An interim report of 453 participants showed no adverse events.44 We anticipate that the results of this trial will provide meaningful insight into the potential risks and benefits of metformin therapy. The results of the MiG trial are likely to provide further evidence on the short-term (e.g., congenital anomalies) and as yet potentially unrecognized long-term effects of placental transfer and in utero fetal exposure to metformin.
Adverse drug events. We found little data concerning the potential risks of oral diabetic agents, insulin analogues, or insulin. Table 4 summarizes the potential adverse drug events for the newborn, which include: (1) congenital anomalies, (2) hyperbilirubinemia, (3) perinatal mortality, (4) birth trauma, (5) respiratory distress syndrome, and (6) neonatal hypoglycemia. As shown in Table 4, Langer32 reported no difference in the number of infants with hyperbilirubinemia in the glyburide group compared to the insulin group (4 percent versus 6 percent, respectively; p = 0.36). Langer32 also reported essentially no difference in the number of infants with a congenital anomaly between pregnant women treated with glyburide and those treated with insulin. There were five infants with a congenital anomaly in the glyburide group and four infants in the insulin group (p = 0.74). Nachum,35 in a comparison of twice-daily insulin versus four-times-daily insulin, found no difference in the number of infants with a congenital anomaly (2 percent versus 1 percent, respectively) or birth trauma (2 percent versus 1 percent, respectively) in either group (see Table 4). Although the data were limited, there was no evidence of differences in neonatal intensive care admission with twice-daily or four-times-daily insulin (p = 0.68). Further investigations with sufficient power to detect meaningful differences will provide much needed evidence regarding potentially adverse neonatal and early childhood effects of medical treatments. While there is currently little evidence on metformin, long-term followup of infants will provide evidence on the downstream consequences of placental transport and intrauterine exposure to metformin.
There were few reports of maternal hypoglycemia. Bertini37reported none; Langer32 reported a higher number of women with FBG less than 40 mg/dL in the glyburide than in the insulin group. Maternal hypoglycemia was not significantly different in the insulin lispro group and the group receiving regular insulin (0.88 percent ± 0.25 percent versus 2.2 percent ± 0.86 percent; p > 0.05).36 The twice-daily insulin and four-times-daily insulin groups each had one case of maternal hypoglycemia.35
Quality assessment of the RCTs. We assessed five parameters of quality for each of the RCTs. Participants were randomized in each of the eight RCTs, with five of the studies30 32 35–37 describing the randomization scheme (see Appendix F, Evidence Table 5). None of the trials were blinded. Only half of the trials30 34 36 37 reported and described participant withdrawals and the reasons for losses to followup.
Limitations. There are specific limitations of the RCTs that deserve further comment. First, as outlined in Table 2, maternal and neonatal outcomes were not consistent across studies. Few of the same outcome measures were included in two or more studies. Furthermore, the definitions of outcomes varied across studies. For example, among the three trials of the effects of insulin and glyburide, the diagnosis of maternal hypoglycemia was based on three different measures (< 40 mg/dL; < 40 mg/dL on two or more occasions; hypoglycemia requiring hospitalization). The small number of the trials comparing medical treatments also limited our ability to draw substantial conclusions. None of the trials included a power analysis or effect size estimation for various outcome measures. None of the trials included an intention-to-treat analysis (see Appendix F, Evidence Table 2).
Observational studies of the effect of insulin and oral diabetes medications on maternal and neonatal outcomes
Overview and population characteristics of five observational studies. We identified five observational studies that examined a total of 911 patients with gestational diabetes and met our inclusion criteria for review.45–49 Evidence Table 6 (see Appendix F) describes the characteristics of each study. Each of the five studies was conducted in the United States between 1999 and 2005. The study duration ranged from 2 to 3 years across the five studies. Two studies46 48 compared maternal and neonatal outcomes in women treated with insulin and women treated with glyburide. Two studies45 47 examined factors related to glyburide success or glyburide failure. Glyburide “successes” were women with gestational diabetes who maintained target glucose levels on glyburide alone. Glyburide “failures” were those who were switched to insulin or for whom insulin was added to the glyburide therapy. One study49 compared maternal and neonatal outcomes in women treated with insulin and women treated with glyburide and also reported on factors related to glyburide failure.
Four studies45–47 49 used the 100-gm Carpenter and Coustan criterion (2003 ADA criterion), and one study48 used the NDDG criterion to diagnose gestational diabetes. Four studies45 47–49 reported the percentage of participants with prior gestational diabetes. All five studies reported the gestational age of pregnancies at the time of diagnosis of gestational diabetes; these ages ranged from 18 to 33 weeks of gestation.
All five studies reported the average maternal age at gestational diabetes diagnosis, which ranged from 26.4 to 32.8 years. Three studies reported the racial distribution of the participants.46 48 49 The majority of the participants (87 percent) in the study by Chmait et al.45 were of Hispanic origin. Jacobson and Rochon reported a racially diverse cohort of African-American, Caucasian, Asian, and Hispanic women (see Appendix F, Evidence Table 6). Three studies47–49 reported baseline measures of body weight in terms of the mean pre-pregnancy BMI (ranging from 26 to 33.9 kg/m2). One study47 did not report the actual BMI but also reported no significant differences in BMI between study groups. The proportion of nulliparous women ranged from 7.7 percent to 33 percent across the five studies.
The initial glyburide dose was 2.5 mg daily in three of the four studies. Two studies reported an initial dose between 2.5 mg and 5 mg per day. Dosages were escalated on the basis of glucose control to a maximum of 20 mg/day in each study.45–49 The initial insulin dose in three45–47of the four studies was 0.7 units/kg. One study49 reported a standard regimen consisting of a combination of NPH and regular insulin injected subcutaneously three times daily. One study48 did not report the initial insulin dose. Insulin levels were adjusted, with four studies reporting no maximum dose. Jacobson48 reported a mean dose of 34.4 units per day in 249 of the 268 women treated with insulin.
Observational studies. Because of the differences in study design, the use of non-comparable groups, and the differences in outcome measures, we chose not to conduct a meta-analysis of the five observational studies included in our review. We offer a summary of the relevant findings and study conclusions and discuss their potential relevance for future research. We include the data on 5 maternal and 11 neonatal outcomes from the observational studies. The maternal outcomes were: (1) operative vaginal delivery, (2) pre-eclampsia, (3) cesarean delivery, (4) glucose control, and (5) maternal hypoglycemia. The neonatal outcomes were: (1) hypoglycemia, (2) hyperbilirubinemia, (3) macrosomia, (4) LGA, (5) SGA, (6) perinatal mortality, (7) infant birth weight, (8) neonatal intensive care admissions, (9) birth trauma, (10) congenital malformations, and (11) shoulder dystocia.
Summary of the observational studies of maternal and neonatal outcomes. Jacobson et al.48 retrospectively compared 268 women treated with insulin between 1999 and 2000 to 236 women treated with glyburide between 2001 and 2002. Their study also included 80 women treated with insulin from 2001 to 2002. Sociodemographic data were collected from clinical databases and a retrospective chart review. Jacobson reported a higher final average FBG (97.7 mg/dL ± 12.2 [standard deviation (SD)] versus 90.2 ± 12.7; p < 0.001), 1-hr PPG (137.8 mg/dL ± 23.6 [SD] vs 131.4 ± 23.3; p < 0.001) and 2-hr PPG (118.8 mg/dL ± 19.6 versus 117.6 ± 23.2; p < 0.05) in the insulin group than in the glyburide group (see Appendix F, Evidence Table 7). Conversely, the average number of FBG levels that met the criterion for maternal hypoglycemia was significantly higher in the glyburide group than in the insulin group (p < 0.001). Also, in multivariate analysis, women treated with glyburide had a higher likelihood of developing pre-eclampsia (odds ratio [OR] = 2.32; 95 percent CI: 1.17 to 4.63) than did women on insulin therapy. There were no differences in cesarean delivery (p = 0.7) or operative vaginal delivery (p = 0.8) rates between the two groups.
In multivariate analysis, after adjustment for race/ethnicity, FBG on OGTT, BMI, and gestational age at diagnosis of gestational diabetes, the use of glyburide therapy was not statistically associated with neonatal hypoglycemia, hyperbilirubinemia, macrosomia, or delivery of LGA or SGA infants when compared to insulin therapy (see Appendix F, Evidence Table 8).48 As shown in Evidence Table 8, the 95 percent CI for each outcome included 1. However, glyburide therapy was significantly associated with a lower likelihood of neonatal intensive care admission (OR = 0.5; 95 percent CI: 0.34 to 0.93). While Jacobson concluded that glyburide was as effective as insulin in the management of gestational diabetes, baseline differences between the two treatment groups suggested that the women on glyburide may have been healthier or had less underlying insulin resistance than those in the insulin group. Women in the original insulin group (1999 - 2000), for example, had a higher average BMI (31.9 kg/m2 ± 6.8 versus 30.6 ± 7.0; p = 0.04) and higher FBG on the baseline OGTT (105.4 mg/dL ± 12.9 versus 102.4 ± 14.2; p = 0.005) than did women in the glyburide group. While Jacobson et al. adjusted for several important covariates, they did not adjust for prior gestational diabetes status, which might also indicate underlying insulin resistance.
Conway et al.47 followed 75 women who elected to be treated with glyburide after failing to achieve adequate glucose control with diet alone.47 The study compared pregnancy outcomes in 12 women with glyburide failure who were converted to insulin therapy to the outcomes in 63 women who were successfully treated with glyburide until delivery. The initial glyburide dose was 2.5 mg/day and was escalated on the basis of glucose control to a maximum of 20 mg/day. There was no difference in the proportion of macrosomic infants in the glyburide failure group and the glyburide success group (8 percent versus 11 percent; p = 1.0) (see Appendix F, Evidence Table 8). Also, there was no difference in average infant birth weight (3267 gm ± 815 in the failure group versus 3327 gm ± 634 in the success group; p = 0.78). The absence of significant differences may be due in part to the limited power of the study to detect a small difference between groups.
Chmait45 conducted a prospective, cohort study of 69 women with gestational diabetes who failed diet alone and elected to proceed with glyburide therapy. Of the 69 participants, 13 participants were started on glyburide therapy but later required the addition of insulin or were transitioned from glyburide to insulin therapy because of inadequate glucose control. Fifty-six (81 percent) of the participants achieved adequate glucose control on glyburide.
While the mean FBG and 1-hr PPG levels on the diagnostic OGTT were similar for the glyburide failure group (105 mg/dL and 206 mg/dL, respectively) and the glyburide success group (94 mg/dL and 199 mg/dL respectively; p > 0.1 for both measures), there were significant differences in glucose values during treatment (see Appendix F, Evidence Table 7).45 The mean FBG levels during treatment with glyburide (114 mg/dL) and the mean 1-hr PPG levels (145 mg/dL) were both significantly greater for the glyburide failure group than for the glyburide success group (FBG 88 mg/dL; 1-hr PPG 124 mg/dL; p < 0.001 for both measures). There was no difference in the proportion of cesarean deliveries between the two groups (38 percent in failure group versus 34 percent in success group; p > 0.05). Also, there were no differences in the proportion of macrosomic infants (10 percent in the failure group versus 18 percent in the success group; p = 1.0) or average infant birth weight (3608 gm ± 398 in the failure group versus 3430 gm ± 714 in the success group; p = 0.78) (see Appendix F, Evidence Table 8). There were no differences in hyperbilirubinemia or neonatal intensive care admissions.
Chmait concluded that women with gestational diabetes with FBG levels under 110 mg/dL and 1-hr PPG levels under 140 mg/dL were more likely to successfully continue glyburide therapy throughout pregnancy. However, these findings were based on a small sample size without any reported adjustment for confounders. Also, because the majority of participants were Hispanic, the findings may not apply to other populations.
Yogev et al.46 conducted a prospective study of 82 participants recruited from a diabetes clinic in which they sought to determine the rate of asymptomatic maternal hypoglycemia in women treated with diet, insulin, or glyburide. Of these 82 participants, 27 were treated with diet alone, 25 with glyburide, and 30 with insulin. As compared to the women on glyburide, the women on insulin had a 4.4-fold higher likelihood of having an episode of asymptomatic hypoglycemia (OR = 4.4; 95 percent CI: 1.4 to 13.9) (see Appendix F, Evidence Table 7). There were no episodes of hypoglycemia among the participants treated with diet alone.
Finally, Rochon et al. conducted a retrospective study of 101 participants recruited from a prenatal diabetes clinic in order to identify characteristics that might predict failure of glyburide therapy and to evaluate whether those women who had failed glyburide were more likely to undergo adverse pregnancy outcomes.49 These gestational diabetics, who had undergone a 1-week trial of diet but were not meeting glycemic goals (FBG between 60 and 90 mg/dL and 2-hr PPG of 120 mg/dL or less), were then started on glyburide. Those who were consistently 15 percent to 25 percent above the FBS or 2-hr PPG target values were switched to insulin therapy. Eighty (79 percent) of the 101 participants were identified as glyburide “successes” compared to 21 (21 percent) who were categorized as glyburide “failures.” Rochon and colleagues reported few statically significant differences in the maternal or neonatal outcomes for the success and failure groups. The rate of neonatal intensive care admissions was higher in the glyburide success group than in the glyburide failure group (33 percent versus 10 percent; p = 0.04). Infant birth weight was similar between the success and failure groups (3,415 gm ± 620 compared to 3,319 ± 559; p = 0.5). The absence of significant differences in birth weight may reflect, at least in part, the limited power of the study to detect a small difference between groups.
There was no difference in the percentage of cesarean deliveries (38 percent versus 43 percent) between the success and failure groups. The rate of shoulder dystocia (10 percent versus 11 percent) was also similar in both groups. Although congenital anomalies were not included as one of the outcomes, Rochon and colleagues reported two neonatal intensive care admissions in the glyburide success group that were due to a congenital anomaly. Also, most admissions to the neonatal intensive care unit were related to neonatal hypoglycemia (10 infants in the success group and 2 in the failure group). The authors concluded that there are few adverse maternal or neonatal outcomes in pregnancies in which glyburide therapy has failed and insulin is required. They also concluded that the rate of neonatal intensive care admissions was higher in the glyburide success group than in the glyburide failure group, primarily because of neonatal hypoglycemia.
Quality assessment of cohort studies. The quality of each of the five cohort studies was assessed using a modified version of the STROBE criteria.23 Each study reported reproducible inclusion and exclusion criteria and recruited participants using a consecutive sample of participants (see Appendix F, Evidence Table 9). Only two of the five studies had a prespecified, clearly presented hypothesis.46 48 None reported power analyses to estimate effect size. As previously stated, insufficient power may have accounted for the absence of detectable differences in infant birth weight in the studies by Conway47 and Rochon.49 While the loss-to-followup rate was reported in four45–47 49 of the five studies, only one study45 described the characteristics of those lost to followup. Two studies reported the actual percentage of missing data,45 46 but only one of these two studies45 described how the missing data were handled in the analysis.
Limitations. In addition to the quality assessment outlined above, two additional limitations deserve further comment: First, only one study48 adjusted for potential confounders. Jacobson adjusted for several relevant covariates, including race/ethnicity, FBG, BMI, and gestational age at diagnosis of gestational diabetes. Additional adjustment for relevant labor complications, such as maternal hypertension or intrapartum infection, might help to elucidate the association of insulin therapy with maternal and neonatal outcomes. Second, there was no discussion of potential selection bias in the conduct of the observational study or the potential influence of this bias on the associations reported. Because of the observational design and lack of adjustment for confounders, it is difficult to draw conclusions with confidence.
Given the limitations of the observational studies, we based our conclusions on the available RCTs. None of the observational studies was strong enough to justify a modification of the conclusions drawn from the RCTs.
Key Question 1a. How does maternal outcome vary based on the level of glucose at the initiation of a medication?
Key Question 1b. How does neonatal outcome vary based on the level of glucose at the initiation of a medication?
Maternal glycemia and maternal and neonatal outcomes. We found no evidence for variation in maternal or neonatal outcomes on the basis of the glucose level at the initiation of treatment with an oral agent or insulin. One ongoing study may provide evidence to address this important clinical question. We look forward to the publication of the findings from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study.50 The HAPO Study is a 5-year, prospective, observational study designed to examine the association of various levels of maternal glycemia in the third trimester with adverse pregnancy outcomes in a multi-national, multicultural, ethnically diverse cohort of women. This investigator-initiated observational study has recruited 23,325 pregnant women from nine countries. All participants undergo glucose tolerance testing. Those participants with levels below the pre-defined threshold are provided with standard obstetrical care, and their providers are blinded to their glucose levels. Maternal blood is obtained for measurement of serum C-peptide and hemoglobin A1c (HbA1c) and cord blood for serum C-peptide and plasma glucose; a capillary specimen is obtained between 1 and 2 hr after delivery for measurement of neonatal plasma glucose. Neonatal anthropometrics are obtained, and followup data are collected at 4–6 weeks post-delivery. The primary outcomes are cesarean delivery, increased fetal size (macrosomia/LGA/obesity), neonatal morbidity (hypoglycemia), and fetal hyperinsulinemia. Preliminary findings, presented at the 67th Annual Scientific Session of the ADA,51 suggest a linear association between rising maternal glucose levels in the third trimester and the likelihood of cesarean delivery. Large babies (defined as being in the largest 10 percent of the newborn population) were born to only 5 percent of women with the lowest fasting plasma glucose levels (less than 75 mg/dL) but to 27 percent of those with the highest levels (greater than 100 mg/dL). Women with the highest glucose levels had a 6.6 times greater risk of delivering an infant with macrosomia than did women with the lowest glucose levels (OR = 6.6; 95 percent CI: 4.6 to 9.6). Rising glucose levels were also associated with a linearly higher likelihood that the newborn would be above the 90th percentile for total skinfold thickness (5.4 percent at the lowest glucose levels versus 28 percent at the highest, OR = 1.52, 95 percent CI: 1.40 to 1.59). These findings suggest that the likelihood of adverse outcomes increases linearly with rising maternal glucose levels even when the range of maternal glucose levels is considered normal. These findings should provide further information on the level of glycemia at which adverse events may occur, although the glucose levels may be below the threshold values for gestational diabetes. Also, these findings may provide insight into the level of glucose at which therapy with an oral agent or insulin should be added to diet therapy.
Conclusions
We found limited evidence on the risks and benefits of oral diabetes agents, insulin analogues, and insulin. The available evidence, to date, suggested little difference in maternal or neonatal outcomes for treatment with oral agents versus any type of insulin, but inconsistencies in clinical outcomes measures across studies and lack of data make it difficult to draw firm conclusions. No studies compared metformin to insulin or other oral agents. Our meta-analysis showed a small, non-significant lower infant birth weight in pregnant women treated with insulin as compared with those treated with glyburide. This small difference of 93 gm is unlikely to have significant clinical relevance. Further studies are needed to determine whether there is a consistent and clinically definable difference in infant birth weight. There appeared to be little difference in various reported measures of maternal glucose control in women treated with glyburide versus insulin (FBG and 2-hr PPG) or in women treated with insulin lispro versus regular insulin (glycosylated hemoglobin and 1-hr PPG). It is unclear whether differences in maternal hypoglycemia are associated with different treatment regimens: Only one study of glyburide and insulin37 defined threshold values for maternal hypoglycemia as part of the study protocol. In one study comparing insulin lispro to regular insulin, maternal hypoglycemia was based on the need for hospitalization rather than threshold glucose values. No available evidence met our inclusion criteria for variations in maternal or neonatal outcomes being based on glucose levels at the initiation of oral agents or insulin. However, as we have indicated above, ongoing investigations, such as the HAPO Study, may provide evidence to suggest threshold values at which clinicians should add oral diabetic agents, insulin analogues, or insulin to diet therapy. The results of the MiG trial should provide evidence regarding the relative benefits and harms of treatment with metformin versus insulin. Finally, additional data regarding congenital anomalies, the long-term consequences of glyburide use, and the effects of metformin transport across the placenta should inform clinical practice and clinical guidelines for the use of oral diabetic agents in pregnancy.
Key Question 2
What is the evidence that elective cesarean delivery or the choice of timing of induction in women with gestational diabetes results in beneficial or harmful maternal and neonatal outcomes?
- a.
What is the evidence for elective cesarean delivery at term, as compared to an attempt at vaginal delivery (spontaneous or induced) at term, with regard to beneficial or harmful maternal and neonatal outcomes in gestational diabetes?
- i.
cesarean versus spontaneous labor and vaginal delivery
- ii.
cesarean versus induced labor and vaginal delivery
- iii.
cesarean versus any attempt at vaginal delivery at term
- b.
What is the evidence for labor induction at 40 weeks, as compared to labor induction at an earlier gestational age (less than 40 weeks) or spontaneous labor, with regard to beneficial or harmful maternal and neonatal outcomes in gestational diabetes?
- i.
labor induction at less than 40 weeks versus labor induction at 40 weeks
- ii.
labor induction at 40 weeks versus spontaneous labor
- iii.
labor induction at less than 40 weeks versus spontaneous labor
- c.
How is the EFW related to outcomes of management of gestational diabetes with elective cesarean delivery or the timing (i.e., gestational age range) of labor induction?
- d.
How is gestational age related to outcomes of management of gestational diabetes with elective cesarean delivery or the choice of timing (i.e., gestational age range) of labor induction?
Maternal outcomes - cesarean delivery
- hemorrhage
- infection
- operative vaginal delivery
- perineal tears
Neonatal outcomes - anoxia
- birth trauma
- birth weight
- congenital malformations
- hyperbilirubinemia
- hypoglycemia
- LGA
- macrosomia
- mortality
- neonatal intensive care admissions
- respiratory distress syndrome
- shoulder dystocia
- SGA
Background and Conceptual Framework
Clinicians use a variety of clinical parameters in their clinical decisionmaking for intrapartum management. Estimates of fetal weight, gestational age, and maternal glucose control are measures of particular importance in pregnancies complicated by gestational diabetes. Clinical management can also be influenced by patient preference and provider perception. Management options include expectant management, labor induction, or “elective” cesarean delivery. In the context of diabetic pregnancies, we refer to “elective” cesarean delivery as a procedure performed following discussion between the patient and clinician, with the goal of avoiding adverse neonatal outcomes such as shoulder dystocia, nerve palsy, or fracture.
Medical institutions have traditionally developed protocols for labor management of women with gestational diabetes, incorporating a combination of anecdotal experience, published literature, and recommendations by national clinical organizations. Both the ACOG and the ADA7 13 have provided guidance with regard to labor management of pregnancies complicated by gestational diabetes. The current guidelines, however, are based primarily on retrospective studies that summarize individual hospitals' experiences with maternal and neonatal outcomes. Limitations in the available literature on the management of women with gestational diabetes may have contributed to delays in the development of broadly accepted guidelines for clinical management and to the current variation in practice patterns and clinical outcomes.
Our objective was to conduct a systematic review of the available literature on the effect of EFW and gestational age on maternal and neonatal outcomes in pregnancies involving gestational diabetes. We also focused on the effect of delivery options (i.e., expectant management, induction, and elective cesarean delivery). We developed a conceptual framework to guide the review of Key Question 2, incorporating the key steps in clinical decisionmaking for labor management (see Figure 5). We focused on gestational age and EFW and the potential influence of these measures on options for delivery. Although they are outside the scope of this review, we include contributing maternal and metabolic factors in the conceptual framework, since these are key elements in the broader context of labor management of women with gestational diabetes.
Results
Overview and population characteristics of studies of the effect of labor management on outcomes. Evidence Table 10 describes the characteristics of each of the eight studies that met our criteria for review (see Appendix F). Five studies were conducted in the United States52–56 and three in Israel.57–59 The studies were conducted between 1983 and 2004, and the study periods ranged from 4 to 19 years. We identified one RCT that compared the effect of two labor induction protocols on maternal and perinatal outcomes.55 We also identified four observational studies that examined the effect of EFW and/or gestational age on delivery management and outcomes.53 57–59 One observational study56 compared the effect of labor induction in a class A2 gestational diabetes sample at 38 weeks of gestation to expectant management of a class A1 sample. Gestational diabetes class A1 is managed with diet alone, while gestational diabetes class A2 requires insulin or glyburide in addition to diet to manage glucose levels. One retrospective cohort study compared a trial of labor to repeat cesarean delivery in a sample of women with gestational diabetes and a prior cesarean delivery.52 Another study54 examined the risk of shoulder dystocia in gestational diabetes patients undergoing a trial of labor.
Outcomes from eight studies. The eight studies identified for this review were heterogeneous with regard to methodology, comparison groups, the time period in which the study was conducted, the length of the study period, the populations included, and the outcome measures of maternal and infant well-being (see Table 5 and Appendix F, Evidence Table 10). Because of the extent of this heterogeneity, we were unable to provide any quantitative synthesis of the literature. We have summarized each study individually, incorporating a summary of the objectives, study design, results, and conclusions presented by the authors. Also, we identify methodological issues that might influence these conclusions. We have categorized our summary of the studies first in terms of study design (RCTs followed by observational studies) and then in terms of the primary exposure (i.e., fetal weight, gestational age, delivery method) under study. The categories we considered were: (1) gestational age and timing of induction, (2) EFW and elective cesarean or timing of labor induction, (3) gestational age or EFW and timing of labor induction, (4) gestational age at delivery, and (5) gestational age and/or EFW and timing of labor induction and/or elective cesarean delivery.
Impact of gestational age on the timing of labor induction. We identified one RCT that addressed the impact of labor induction at term, as compared to expectant management, on maternal and neonatal outcomes in gestational diabetes.55 Kjos 1993 recruited 200 women from one tertiary care center. The study sample included 187 women with class A2 gestational diabetes and 13 women with pre-existing (class B non-insulin-requiring) diabetes. Inclusion criteria were clearly stated: good glucose control in at least 90 percent of measured levels, 38 completed weeks of gestation, good compliance with clinic appointments and home glucose monitoring, no antepartum testing abnormalities, singleton gestation with cephalic presentation, EFW less than 3800 gm at 38 weeks with no evidence of fetal growth restriction, no other medical or obstetrical complications, and no more than two previous cesarean deliveries. Women who met the inclusion criteria, agreed to randomization, and had an established diagnosis of diabetes were eligible to participate in the study. Women were randomized to either expectant management or induction of labor at 38 weeks. Of those with pre-existing diabetes, nine were in the active induction group and four were in the expectant management group. The two treatment groups did not differ significantly in terms of maternal age, gravidity, parity, maternal weight, or gestational age at entry into the study. The racial distribution of the study participants was not reported. Gestational age was calculated from the first day of the last menstrual period and adjusted if ultrasound estimation (before 22 weeks) differed from the menstrual age by 10 days or more. Amniocentesis and measurement of the lecithin-to-sphingomyelin (L/S ratio) was used if gestational age could not be accurately determined. Labor was induced with intravenous oxytocin at 38 weeks or in the presence of fetal lung maturity. Vaginal prostaglandin was used for cervical ripening if indicated (Bishop's score less than four) and if the patient had no contraindications to therapy.
Maternal outcomes. Thirty of 100 women in the active induction group had spontaneous labor or cesarean delivery prior to scheduled induction, and 56 of 100 women in the expectant management group required induction or cesarean delivery prior to the onset of labor for medical indications (see Appendix F, Evidence Table 11).55
In the final intention-to-treat analysis, there was no difference in cesarean delivery rates between the two groups (25 percent in the active induction group versus 31 percent in the expectant management group; p = 0.43). The average gestational age at delivery in the induction group was 1 week less than the gestational age in the expectant management group (39 weeks versus 40 weeks; p < 0.05).
Neonatal outcomes. Even after adjustment for gestational age at delivery, maternal weight, and maternal age, the average infant birth weight in the expectant management group (3,672 gm; 95 percent CI: 3,595 to 3,749 gm) was significantly greater than that in the active induction group (3,446 gm; 95 percent CI: 3,368 to 3,522 gm; p < 0.01) (see Appendix F, Evidence Table 12).55 The proportion of infants with macrosomia, defined as a birth weight of 4,000 gm or more, was higher in the expectant management than in the active induction group (27 percent versus 15 percent; p = 0.05). When defined as a birth weight greater than the 90th percentile, the proportion of infants with macrosomia was also higher in the expectant management than in the induction group (23 percent versus 10 percent; p = 0.02). There was no significant difference in the number of cases of shoulder dystocia or in the average 5-minute Apgar score between the two groups. Also, there were no episodes of neonatal hypoglycemia requiring treatment and no perinatal deaths in either treatment group.
The findings of this RCT suggested that infants born to women undergoing induction at 38 weeks have significantly lower average birth weights and perhaps a lower risk of macrosomia than do those born to women treated with expectant management. The absence of any difference in cesarean delivery rates suggested that maternal morbidity among women undergoing 38-week induction is similar to that of women undergoing expectant management. The similarity in demographics of the two groups suggested appropriate randomization. Adjustment for key covariates, including gestational at delivery, maternal weight, and age strengthened our confidence in the observed associations.
Impact of EFW on elective cesarean delivery and timing of labor induction. We identified one observational study on the effect of EFW on maternal and neonatal outcomes related to elective cesarean delivery and the timing of induction of labor.53 Conway et al. prospectively followed diabetic women (91.4 percent with gestational diabetes) who were delivered at a tertiary care institution between 1993 and 1995 according to an institutional protocol. Based on this protocol, women with diabetes underwent ultrasonographic estimates of fetal weight between 37 and 38 weeks of gestation. Women whose EFW was greater than or equal to 4,250 gm underwent cesarean delivery; those in whom the EFW was estimated at less than 4,250 gm but considered LGA (defined as 90th percentile or greater for the gestational age in their population) underwent labor induction. We will refer to this group who delivered between 1993 and 1995 as the study group. Outcomes for this study group were compared to those of a historical control group of diabetic women who delivered between 1990 and 1992, prior to the implementation of the new protocol. The study and control groups did not differ significantly in terms of their mean maternal age, racial composition, gestational age at delivery, or proportion of women with gestational diabetes or pre-gestational diabetes. Twenty-seven percent of the patients in the study group did not undergo ultrasound evaluation.
Maternal outcomes. As shown in Evidence Table 10 (see Appendix F), the authors reported that the average gestational age at delivery was similar for the study group and the historical control group (39.2 weeks versus 39.3 weeks; p > 0.05).53 The cesarean delivery rate, however, was significantly higher in the study group (25.1 percent versus 21.7 percent; p < 0.04) (see Appendix F, Evidence Table 11). The authors suggested that the higher proportion of cesarean deliveries in the study group could be attributed to the implementation of the new protocol. When the elective cesarean deliveries for EFW of 4,250 gm or more (53/343) and cesarean deliveries for failed induction for LGA (7/343) were excluded from the study group, there was no difference in cesarean delivery rate between groups.
Neonatal outcomes. There were significantly fewer macrosomic infants (defined as weighing 4,000 gm or more) in the study group than in the control group (8.9 percent versus 11.6 percent; p = 0.04) (see Appendix F, Evidence Table 12). There was a greater likelihood of shoulder dystocia in the control group (OR = 1.9, 95 percent CI: 1.0 to 3.5) than in the study group. In a subgroup analysis of the macrosomic infants delivered vaginally, there was also a statistically significant greater likelihood (OR = 2.9, 95 percent CI: 1.0 to 8.4) of shoulder dystocia in the control than in the study group.
Based on this prospective, observational study, it appears that in women with gestational diabetes, a protocol involving elective cesarean delivery for macrosomia and induction at 38 weeks for LGA may reduce the number of macrosomic infants and the risk of shoulder dystocia, but it may also be associated with an increase in the number of cesarean deliveries. However, the lack of adjustment for the severity of the diabetes or other potentially confounding variables in this study may have resulted in an overestimate of the effect of the protocol on outcomes. Furthermore, temporal changes in the management of women with gestational diabetes may have also influenced the outcomes reported.
Relationship of gestational age and fetal weight to the timing of labor induction. We identified one cohort study58 that examined the relationship of gestational age and EFW to the timing of induction. Lurie et al58 prospectively followed a sample of women and compared outcomes with a historical control group in order to determine whether labor induction at 38 to 39 weeks of gestation might reduce the incidence of shoulder dystocia in women with gestational diabetes class A2. The study group (n = 96) was induced at 38 weeks or, if the EFW was greater than 4,500 gm, underwent elective cesarean delivery. The study group was compared to a historical cohort of women (n = 164) who delivered between 1983 and 1989 and in whom labor was induced only if the EFW was greater than 4,000 gm or, if the EFW was greater than 4,500 gm, underwent elective cesarean delivery. This historical cohort was the same study population described by Lurie et al. in an earlier paper,57 which will be discussed subsequently. Gestational age was based on the first day of the last menstrual period and serial crown rump measurements in the first trimester. Amniocentesis was performed to assess fetal lung maturity, using the L/S ratio prior to induction. Baseline participant characteristics, including maternal age and parity, were similar between the two groups. There were no reported data on maternal race, weight, or glucose control.
Maternal outcomes. Women in the study group delivered significantly earlier than did women in the control group (38.4 weeks versus 39.2 weeks; p < 0.001) (see Appendix F; Evidence Table 11). A slightly higher proportion of women in the study group than in the control group underwent cesarean delivery, but the difference was not statistically significant (23 percent versus 19 percent; p > 0.05). The rates of vacuum-assisted delivery were similar for the two groups (5.2 percent versus 5.5 percent; p > 0.05).58
Neonatal outcomes. Neither infant birth weight nor the proportion of macrosomic infants was significantly different between the two groups (see Appendix F, Evidence Table 12). The proportion of infants with shoulder dystocia was lower in the elective induction group than in the historic control group, but the difference did not reach statistical significance (1.4 percent versus 5.3 percent; p > 0.05). Clavicular fractures, nerve palsies, mortality, and respiratory distress were rare events overall, and their incidence was not significantly different between groups.
Additional analysis. The authors conducted a second analysis in which the outcomes in the study group were compared to those in a subset of the historical cohort of women who delivered after 40 weeks of gestation (n = 62). The proportion of deliveries complicated by shoulder dystocia was significantly reduced (from 10.2 percent to 1.4 percent; p < 0.05) in the study group when compared to this subset of the historical control group. Also, only nine percent of the infants in the study group had a weight greater than 4,000 gm, as compared to 24 percent in the historical control group (p < 0.05).
In summary, the authors of this paper found that the decrease in shoulder dystocia in the study group was only statistically significant if the study group was compared to the subgroup of control patients that delivered after 40 weeks. In addition to a lack of adjustment for severity of diabetes and a consideration of the temporal changes that had occurred in the management of patients with gestational diabetes, this study was further limited by its small population size.
Impact of gestational age at delivery. In their 1992 paper, Lurie et al57 conducted a retrospective chart review of all gestational diabetic women who delivered over a 5-year period, examining maternal and neonatal outcomes for women with gestational diabetes class A1 and A2 who delivered after 40 weeks of gestation or prior to 40 weeks. The groups were matched with regard to age, parity, and fetal presentation. Gestational age was based on the date of the last menstrual period and ultrasound measurements of crown rump lengths in the first trimester. Outcomes were reported separately for gestational diabetes classes A1 and A2.
Maternal outcomes. Among women with gestational diabetes class A1 (diet-controlled gestational diabetes), the mean gestational age at delivery was 40.9 weeks for those who delivered after 40 weeks and 38.2 weeks for those who delivered before 40 weeks (p not reported). There were no differences in the numbers of vacuum-assisted vaginal deliveries (0/65 versus 4/65) or cesarean deliveries (7/65 versus 9/65; p = 0.0997) between women delivering after 40 weeks of gestation and those delivering prior to 40 weeks of gestation (see Appendix F, Evidence Table 11).
Similar findings were obtained for the women with gestational diabetes class A2 (insulin-requiring gestational diabetes). The mean gestational age at delivery was 40.5 weeks in the group delivering after 40 weeks and 37.5 weeks in the group delivering before 40 weeks (p not reported). There were no differences in the number of vacuum-assisted deliveries (1/59 versus 4/59) or cesarean deliveries (15/59 versus 13/59; p = 0.6216).
Neonatal outcomes. For women with either class A1 or A2 gestational diabetes, the rate of macrosomia (defined as birth weight greater than 4,000 gm) was higher in the group of women delivering after 40 weeks than in those delivering prior to 40 weeks, but the difference was not statistically significant: for gestational diabetes A1, 24.6 percent in the group delivering after 40 weeks versus 15.4 percent for those delivering before 40 weeks (p = 0.1853); for gestational diabetes A2, 20.3 percent in the group delivering after 40 weeks versus 6.8 percent for those delivering before 40 weeks (p = 0.057) (see Appendix F, Evidence Table 12). The mean birth weights in the two groups were not significantly different in the case of gestational diabetes A1 patients (3,439.00 gm versus 3,617.85 gm; p = 0.0619). However, infants of gestational diabetes A2 patients who delivered after 40 weeks had a significantly higher mean birth weight (3,639 gm) than did infants born to those who delivered before 40 weeks (3,275 gm) (p = 0.0003). There was no significant difference in the rate of shoulder dystocia, birth trauma, neonatal metabolic complications, respiratory distress syndrome, or mortality between the two groups in either population.
In this retrospective cohort study, the only significant difference between patients delivering after 40 weeks and those delivering before 40 weeks was a higher mean birth weight in the subset of class A2 gestational diabetes patients, which was to be expected, given that gestational age is a strong predictor of birth weight. The authors concluded that the timing of delivery does not have a significant impact on clinically important maternal or neonatal outcomes. However, although the authors did perform a stratified analysis for class of gestational diabetes, the study did not adjust for other potential confounders or for delivery management in the groups.
Impact of gestational age and/or EFW on the timing of labor induction and/or elective cesarean delivery. Peled59 conducted a protocol-based chart review to evaluate the effect of gestational age and EFW on labor management. In this study, the charts of 2,060 patients with gestational diabetes treated over a 19-year period were abstracted for maternal and neonatal outcomes. The investigators compared four time periods, each with a distinct management protocol for the timing of labor induction or elective cesarean delivery, based on EFW and gestational age and target thresholds for maternal glycemia (Period A: 1980-1989; Period B: 1990-1992; Period C: 1993-1995; Period D: 1996-1999). Gestational age was calculated from the first day of the last menstrual period and confirmed by first trimester ultrasound when possible. EFW was estimated either clinically or by ultrasound. Outcomes among women in Period D (the study group) were compared with outcomes among women in the three prior periods (historical control groups). Women in the study group were induced at 38 weeks of gestation if the EFW was consistent with LGA (defined as greater than 90th percentile) or underwent elective cesarean if the EFW was greater than 4,000 gm. In Period A, patients underwent elective cesarean if the EFW was greater than 4,500 gm; otherwise, they were induced at 42 weeks. In both Periods B and C, patients underwent elective cesarean delivery if the EFW was greater than 4,000 gm, and they were induced at 40 weeks if LGA was diagnosed. It is noteworthy that the groups differed in terms of the level of glycemic control in the institution's protocol. For patients in Periods C and D, insulin was started at lower fasting glucose levels (> 5.3 mmol/L) and 2-hr postprandial levels (> 6.6 mmol/L) than in Periods A and B (> 5.8 mmol/L and > 7.8 mmol/L, respectively). Furthermore, patients had lower glycemic goals in Periods C and D (< 5.3 mmol/L) than in Period B (< 5.8 mmol/L) or Period A (no goal set). Thus, although glycemic control did not alter decisions regarding delivery, it is important to keep in mind that patients in the four periods differed in terms of their level of glucose control. Prostaglandin E2 gel or tablets was used for labor inductions over the 19-year period of the study. The authors also included both class A1 and A2 gestational diabetes patients but did not report outcomes separately for the two groups. The proportions of women treated with insulin during the four study periods were variable: 13 percent in Period A, 16.4 percent in Period B, 28 percent in Period C, and 32 percent in Period D. There was no other comparison of baseline characteristics (e.g., age, race, parity) in the four groups.
Maternal outcomes. The mean gestational age at delivery was similar for all four groups (between 38 and 39 weeks). The cesarean delivery rate decreased over time, from 21 percent in Period A to 18 percent in Period B and 16 percent in Period C, but it increased to 34 percent in Period D (see Appendix F, Evidence Table 11). A similar increase in the cesarean delivery rate was noted by the author in a concurrent non-gestational diabetes population included in the same study.59
Neonatal outcomes. There was a reduction in the proportion of infants with birth weights greater than 4,000 gm (3.86 percent in the study group versus 20.6 percent in Period A, 16.3 percent in Period B, and 11.7 percent in Period C). The proportion of deliveries complicated by shoulder dystocia (none in Period D, versus 1.5 percent in Period A, 1.2 percent in Period B, and 0.6 percent in Period C) also decreased over the study period. Perinatal mortality rates also decreased from 8 percent in Period A to 3 percent in Period B, to 0 percent in Period C, and 0.77 percent in Period D. While p values were reported for comparisons between the gestational diabetes population and the non-gestational diabetes population, they were not reported for comparisons between time periods (the relevant comparison groups for this analysis).
Although this study provides data on a large population of patients with gestational diabetes, the lack of information on baseline characteristics (e.g., age, race, parity, severity of disease) in the four groups and the lack of adjustment for any differences between groups severely limited our ability to draw any substantial conclusions from this study. Also, the authors did not adjust for or discuss the influence of other potential obstetrical management patterns over the 19-year period. Clinical management of diabetic patients had changed substantially over the 19-year period of the study. Modifications in practice patterns have likely influenced the outcomes reported in these investigations. While examining trends in outcomes is useful, it is not possible to fully adjust for changes in practice patterns, leading to some level of bias in the reported associations.
Additional studies. We identified three additional studies that met our initial inclusion criteria but which focused on aspects of labor management that are outside our primary area of evidence review for Key Question 2. Nevertheless, given the paucity of data addressing labor management among women with gestational diabetes, we believe the findings of these studies and their relevance to delivery management deserve limited discussion.
Impact of gestational age on the timing of induction of labor in patients with different levels of disease severity. In a retrospective cohort study, Rayburn examined maternal and neonatal outcomes under an institutional protocol in which class A2 gestational diabetes patients were routinely induced at 38 weeks and class A1 gestational diabetes patients were managed expectantly.56 It is important to note that the control group, the gestational diabetes A1 patients who were managed expectantly (n = 137), underwent induction if there were any obstetrical indications for delivery, including pre-eclampsia, gestational hypertension, or poor glucose control; if the cervix was “favorable” at 40 weeks; or if the patient reached 42 weeks of gestation. The authors reported that only 53 percent of patients in the control group required induction, a rate that was significantly different from that in the study group (90 percent, p < 0.001). The gestational age at delivery was significantly different between groups (38.1 weeks in the study group as compared to 39 weeks in the control group, p < 0.001). The study found no differences in the rates of cesarean delivery or shoulder dystocia, macrosomia, respiratory difficulties in the neonate, or neonatal intensive care admissions.
The significant limitation of this investigation is that the study and control groups by definition had different severity levels of disease (class A1 versus class A2). There were also significant differences in the racial composition (the study group was 70 percent Hispanic, versus 60 percent in the control group; p < 0.01) and parity in each group (18 percent were nulliparous in the study group, versus 31 percent in the control group, p = 0.01).56
Impact of elective cesarean delivery versus a trial of labor in patients with previous cesarean delivery. Marchiano conducted a retrospective cohort study to examine outcomes related to elective repeat cesarean delivery versus a trial of labor in a population of women with gestational diabetes;52 423 women with class A1 gestational diabetes and singleton pregnancy who had undergone one previous cesarean delivery were included in the study.
The repeat cesarean delivery rate was 30 percent for those who attempted a trial of labor. The rate of macrosomia (defined as infant birth weight > 4,000 gm) for those who attempted a trial of labor was 18 percent, as compared to 33 percent for those who underwent elective cesarean (p < 0.0001) delivery. A sub-group analysis of women who attempted a trial of labor indicated a cesarean delivery rate of 43 percent for those whose infants weighed 4,000 gm or more, as compared to 28 percent for those with infants weighing less than 4,000 gm.
Although these results are relevant to the management of women with gestational diabetes, the results are only generalizable to those with prior cesarean delivery. Furthermore, the authors used actual infant birth weight rather than EFW in the analysis. Because EFW can vary from actual weight at delivery, it is difficult to draw useful conclusions from these results in terms of clinical decisionmaking for elective cesarean delivery versus an attempt at vaginal delivery.
Shoulder dystocia in patients with gestational diabetes. Keller 199154 performed a retrospective chart review of 210 patients with gestational diabetes from a tertiary care center in Chicago. Of the 210 patients, 173 underwent a trial of labor, 34 had elective repeat cesarean delivery, and 3 had an elective cesarean delivery for EFW greater than 4,000 gm (individual patient/provider decision). In those who underwent a trial of labor, the rate of cesarean delivery was 30.6 percent and the rate of forceps use was 4.6 percent. When birth weight categories were examined, the cesarean delivery rate was 33 percent in the greater than 4,500 gm group, 34 percent in the 4,000 to 4,499 gm group, and 29 percent in the 3,500 to 3,999 gm group.
The risk of shoulder dystocia in those patients who delivered vaginally was 12.5 percent overall and ranged from 9 percent in the lowest birth weight group to 14 percent in those weighing 4,000 to 4,499 gm and 38 percent in those infants weighing over 4,500 gm. Fractures and nerve injuries were rare (seven total) and were not related to birth weight category. The study also reported that the risk of shoulder dystocia in patients with class A1 gestational diabetes was not significantly different (OR = 0.78, 95 percent CI: 0.25 to 2.27) from that in patients with class A2 gestational diabetes.54
These findings by Keller offer a descriptive analysis of labor outcomes in women with gestational diabetes. Given the lack of a comparison group and any adjustment for confounders, as well as the limited sociodemographic and clinical information on the study sample, it is difficult to draw any reasonable conclusions from this study regarding labor management in women with gestational diabetes.
Quality assessment. We assessed the quality of the single RCT55 identified for this review using the Jadad criteria.22 The study reported pre-specified hypotheses, the inclusion criteria were clearly stated, power calculations were presented with effect sizes, the outcomes were clearly described, and adjustment was performed for several potential confounders. However, the methods for randomization, including sequence generation and assurance of allocation concealment, were not clearly described (see Appendix F, Evidence Table 13).
No observational studies met all of our quality criteria (see Appendix F, Evidence Table 13). Of the seven observational studies, only two had pre-specified hypotheses.53 58 Of the eight studies, all but one59 reported inclusion and/or exclusion criteria, and sampling was consecutive in all eight studies. Outcomes were not clearly defined in two of the studies.56 57 Power calculations were only performed in two studies.56 58 The analysis was adjusted for potential confounders in two studies.52 56
Limitations. Several limitations to these studies deserve further comment. First, there was heterogeneity in the severity of the gestational diabetes reported in the one RCT and four primary observational studies, making it difficult to assess the magnitude and direction of any association of the effect of gestational age or EFW with labor management. All four of the primary observational studies included women with gestational diabetes A1 and gestational diabetes A2, but only one reported outcomes stratified by insulin requirement.57 Furthermore, the RCT55 and one of the observational studies53 included pre-gestational diabetics, even though this condition represented only a small proportion of the sample (less than 10 percent). The results of these studies might have varied substantially if the study population had been limited to women with gestational diabetes class A1 or A2 or if the outcomes were stratified by severity.
Second, the four primary observational studies were conducted over a wide timeframe. It is difficult to account for the rise in the prevalence of gestational diabetes during this timeframe or the modifications in physician practice patterns and obstetrical technology that have certainly influenced maternal and neonatal outcomes. For example, while the intention of the study by Peled59 was to assess the impact of different management approaches over the 19-year period, it was impossible to discern the potential contribution of changes in glycemic target levels to delivery management over the four time periods.
Third, none of the four primary observational studies adjusted for potential confounders. Therefore, the magnitude of the associations between gestational age or EFW and outcomes may have been overestimated.
Fourth, the high rates of induction of labor in the expectant management group (49 percent) and of cesarean delivery in both groups in the RCT by Kjos et al55 illustrate the low threshold for intervention in current practice for patients with diabetes. They also highlight the potential role of medical liability in the design of studies of labor management. Physicians' concerns regarding medical liability, provider perception of risk, and maternal demand for cesarean delivery may limit the ability to conduct well-designed clinical trials of labor management.
Conclusions
One experimental study in this field suggested that active induction of labor at 38 weeks of gestation reduces birth weight, macrosomia, and LGA without increasing the rate of cesarean section. It was difficult to fully assess these outcomes, however, on the basis of a single clinical trial of only 200 patients. The current body of observational studies also suggested a potential reduction in macrosomia and shoulder dystocia with elective labor induction and elective cesarean delivery for macrosomia or LGA infants. We systematically searched the literature for evidence that the choice of timing of induction or elective cesarean delivery resulted in beneficial or harmful maternal or neonatal outcomes, as described in detail in the Key Question. Given the substantial heterogeneity in the studies reviewed and the serious limitations in study design and analysis of the existing literature, we were unable to draw any firm conclusions about the role of elective induction or cesarean delivery in the management of gestational diabetes.
Taking into consideration the quantity, quality, and consistency of the studies comparing the effects of labor management on maternal and neonatal outcomes, we graded the strength of evidence as very low (see Appendix F, Evidence Table 14).
Key Question 3
What risk factors, including but not limited to family history, physical activity, pre-pregnancy weight, and gestational weight gain, are associated with short-term and long-term development of type 2 diabetes following a pregnancy with gestational diabetes?
Background and Conceptual Framework
We conducted our systematic review of this question according to the framework outlined in Figure 6. Our objective was to include a range of risk factors that incorporated sociodemographics and pre-pregnancy measures as well as antenatal and delivery factors in both the immediate and long-term postpartum periods. The risk factors included were based on (1) traditional, established epidemiologic and physiologic risk factors for type 2 diabetes and (2) risk factors identified in the literature during our initial review of titles and abstracts.
We identified a number of studies that examined the risk factors for type 2 diabetes among women with previous gestational diabetes. These studies varied widely in terms of their design, population, measurement of risk factors, and method of analysis. No single study included all the risk factors we enumerated. Although longitudinal studies and well-done case-control studies that use multiple regression methods provide the best evidence about the independent contribution of risk factors, we also included studies that used univariate analytic methods if they reported a relative measure of association.
Based on our conceptual model in Figure 6, we grouped the risk factors into the following nine categories:
- 1.
Anthropometry
- 2.
Pregnancy-related factors
- 3.
Postpartum factors
- 4.
Parity
- 5.
Family history of type 2 diabetes
- 6.
Maternal lifestyle factors
- 7.
Sociodemographics
- 8.
Oral contraceptive use
- 9.
Physiologic factors
Results
Overview and population characteristics of 16 observational studies of risk factors for the development of type 2 diabetes. We identified 16 prospective or retrospective/non-concurrent cohort studies that evaluated at least one risk factor in our categories (see Appendix F, Evidence Table 15). However, none of the studies addressed the lifestyle factors depicted in our conceptual model. The studies were conducted in diverse populations and included 10 studies in North America; three studies were conducted in Asia, two in Europe, and one in Australia. Patients were recruited from a hospital or hospital-based clinic in all cases. The followup time for the studies ranged from 6 weeks to 12 years (see Appendix F, Evidence Table 16).
The studies varied with respect to quality (see Appendix F, Evidence Table 17). All of the studies reported inclusion and exclusion criteria, and most stated how the outcome of type 2 diabetes was defined (93.3 percent). Most reported loss to followup (75 percent), with 75 percent of these having a loss to followup of greater than 20 percent. Comparisons between those participants who were successfully followed up and those who were lost to followup were reported in 33 percent of the studies. Only 50 percent of the studies stated pre-specified hypotheses. None of the studies reported power or sample size calculations or the strategy used to handle missing data.
Studies varied in terms of their reporting of the baseline characteristics of the participants. Fifty-six percent of the studies reported the racial makeup of the population, 75 percent reported parity status, and all of them reported the ages of the participants (see Appendix F, Evidence Table 16).
Family history of type 2 diabetes. We identified five studies that evaluated family history of type 2 diabetes as a risk factor for the development of type 2 diabetes in women with previous gestational diabetes (see Appendix F, Evidence Table 18).60–64 The duration of followup for 102 to 909 participants ranged from 6 weeks to 8 years. All five studies conducted multivariate analyses, but only one study reported a relative measure of association.61 Cho et al. reported that after adjusting for age, gestational age at diagnosis, pre-pregnancy BMI, FBG at diagnosis, and homocysteine level, women with a family history of type 2 diabetes were more likely to develop type 2 diabetes than were women without such a history (RR = 1.7; 95 percent CI: 0.6 to 4.6), but the relative risk was not statistically significant. Because of the limited data, we were unable to draw firm conclusions regarding the magnitude of the association between a family history of diabetes and the risk of type 2 diabetes in women with gestational diabetes.
Sociodemographics. We identified six studies that evaluated a total of four sociodemographic factors as risk factors for the development of type 2 diabetes in women with previous gestational diabetes (see Appendix F, Evidence Table 19).60–63 65 66 The four sociodemographic factors examined were age, race, working status, and hospital. The duration of followup for the six samples of 100 to 909 participants ranged from 6 weeks to 11 years.
Age. Six studies60–63 65 66 assessed age as a risk factor; five of the six studies used multivariate analysis.60–63 66 Only one study reported the relative measure of association resulting from the multivariate analysis: Cho et al. reported that after adjustment for gestational age at the time of diagnosis, pre-pregnancy BMI, family history of type 2 diabetes, FBG at diagnosis, and homocysteine level, women greater than 30 years of age had a two-fold increased likelihood of developing type 2 diabetes (RR = 2.0; 95 percent CI: 0.68 to 6.0), but this association was not statistically significant, as evidenced by the 95 percent CI that included one.61 In one univariate analysis, Dacus et al. observed that older age did not appear to be associated with the risk of type 2 diabetes (RR = 0.68; 95 percent CI: 0.24 to 1.9).65
Hospital location. Cheung et al. were able to evaluate the hospital attended for antenatal clinic visits as a risk factor for the development of type 2 diabetes in women with previous gestational diabetes, since they had recruited women from two hospitals.60 Although they included age, parity, FBG at gestational diabetes diagnosis, BMI during pregnancy, 2-hr OGTT, number of prior gestational diabetes pregnancies, method of glucose control, and family history of type 2 diabetes, these investigators did not report a relative measure of association for the hospital attended and type of diabetes.
Work status. Cho et al. evaluated working status as a risk factor for the development of type 2 diabetes in eight multivariate models, including age, parity, family history of type 2 diabetes, working status, blood pressure, lipid profile, and one of eight measures of adiposity (postpartum BMI, waist circumference, weight, subscapular skin fold thickness, suprailiac skin fold thickness, tricep skin fold thickness, body fat weight, or waist-to-hip ratio).62 However, the relative measure of association was not reported for the association between working status and development of type 2 diabetes for any of the eight models.
Race. In a univariate analysis, Dacus et al. evaluated race as a risk factor for the development of type 2 diabetes in women with previous gestational diabetes. They reported that as compared to other race groups, blacks had a 50 percent increased risk of developing type 2 diabetes, but this association was not statistically significant (RR = 1.5; 95 percent CI: 0.45 to 5.0).65
We concluded that there are only limited data on which to base any meaningful conclusions regarding sociodemographic factors and the short- or long-term risk of type 2 diabetes among women with gestational diabetes.
Maternal lifestyle factors. We did not identify any studies that examined the relationship between lifestyle factors, such as physical activity and diet, and the development of type 2 diabetes in women with prior gestational diabetes. We therefore concluded that no evidence exists to determine whether maternal lifestyle affects the risk of developing type 2 diabetes after having gestational diabetes.
Parity. We identified four studies that evaluated parity as a risk factor for the development of type 2 diabetes in women with previous gestational diabetes (see Appendix F, Evidence Table 20).60 62 66 67 The duration of followup for the samples of 102 to 909 participants ranged from 6 weeks to 11 years. All four studies conducted multivariate analyses, but only two studies reported a relative measure of association for parity with type 2 diabetes.66 67 After adjustment for GAD and insulinoma antigen-2 (IA-2) antibody status, method of glucose control, BMI, age, and serum C-reactive protein (CRP) at 9 months, Lobner et al. found that compared to gestational diabetics who were nulliparous, gestational diabetics with more than two previous births had an almost three-fold increased risk of developing type 2 diabetes (relative hazard [RH] = 2.5; 95 percent CI: 1.1 to 5.3).66 There was a 20 percent increased risk of developing type 2 diabetes associated with having had one to two previous births, as compared to nulliparity, but this association was not statistically significant (RH = 1.2; 95 percent CI: 0.8 to 1.7).66 Metzger et al. evaluated parity as a continuous variable and reported that for each unit increase in parity, there was no statistically significant change in the log odds of developing type 2 diabetes (β = 0.19; p = 0.09).67 We concluded that higher parity may be associated with an increased risk for type 2 diabetes among women with gestational diabetes, but further evidence is needed to draw firm conclusions regarding this potential association.
Pregnancy-related factors. We identified nine studies that evaluated seven pregnancy-related factors as risk factors for the development of type 2 diabetes in women with previous gestational diabetes (see Appendix F, Evidence Table 21).60 61 63 65 66 68–71 These factors were: gestational age at diagnosis, method of glucose control, dosage of bedtime intermediate-acting insulin required, class A2 gestational diabetes (defined as any FBG ≥ 105 mg/dL), previous gestational diabetes, number of prior gestational diabetes pregnancies, 50-gm glucose challenge test (GCT), and spontaneous abortions. The duration of followup for the 88 to 1,636 participants ranged from 6 weeks to 12 years.
Gestational age at diagnosis of gestational diabetes. Five studies61 63 65 68 70 assessed gestational age at diagnosis of gestational diabetes as a risk factor, and four of the five studies used multivariate analysis.61 63 68 70 The studies varied in terms of their categorization of gestational age at gestational diabetes diagnosis: Two studies divided gestational age at gestational diabetes diagnosis into quartiles and used the first quartile as the reference:68 70 Both Kjos et al.68 and Schaefer-Graf et al.70 reported a protective effect of gestational age at gestational diabetes diagnosis in the fourth quartile as compared to gestational age at gestational diabetes diagnosis in the first quartile, with the effect ranging from a 52 percent to a 65 percent reduction in the likelihood of developing type 2 diabetes (RH = 0.48; 95 percent CI: 0.29 to 0.82; and OR = 0.35; 95 percent CI: 0.23 to 0.54) respectively. Both studies varied with respect to the covariates included in the multivariate model, and they did not share any common covariates. Schaefer-Graf et al.70 included FBG at gestational diabetes diagnosis, class A2 gestational diabetes, area under the glucose curve of pregnancy OGTT, previous gestational diabetes and 50-gm GCT, while Kjos et al.68 included postpartum OGTT glucose area under the curve, antepartum OGTT glucose area under the curve, and highest antepartum FBG. When third-quartile gestational age at gestational diabetes diagnosis was compared to the first quartile, a smaller protective effect was observed in both studies. Schaefer-Graf et al. reported a 55 percent reduction in the likelihood of developing type 2 diabetes (OR = 0.45; 95 percent CI: 0.27 to 0.76).70 Kjos et al. reported a 27 percent reduction in the likelihood of developing diabetes, but this association was not statistically significant (RH = 0.73; 95 percent CI: 0.45 to 1.2).68 For both studies, when second-quartile gestational age at gestational diabetes diagnosis was compared to the first quartile, no significant difference in the development of type 2 diabetes was found (Schaefer-Graf et al., OR = 1.1; 95 percent CI: 0.72 to 1.7; and Kjos et al., RH = 0.66; 95 percent CI: 0.39 – 1.1).
Cho et al. categorized gestational age at gestational diabetes diagnosis into two groups, women who were diagnosed with gestational diabetes at greater than or equal to 26 weeks and women who were diagnosed at less than 26 weeks. There was no significant difference in the development of type 2 diabetes between the two groups after adjusting for age, pre-pregnancy BMI, family history of type 2 diabetes, FBG at diagnosis, and homocysteine level (RR = 2.4; 95 percent CI: 0.88 to 6.6).61
Jang et al. assessed gestational age at gestational diabetes diagnosis as a continuous variable and found that for each week of increase in gestational age at gestational diabetes diagnosis, there was a 0.01 decrease in the log odds of developing type 2 diabetes (β = -0.01; SE = 0.05; p = 0.008).63
In a univariate analysis, Dacus et al. categorized gestational age at gestational diabetes diagnosis into two groups, comparing women who were diagnosed with gestational diabetes at less than 24 weeks and those diagnosed with gestational diabetes greater than or equal to 24 weeks. No significant difference was observed between the two groups in terms of the development of type 2 diabetes (RR = 2.5; 95 percent CI: 0.9 to 6.9).65
Method of glucose control. Five studies evaluated the method of glucose control during pregnancy as a risk factor for the development of type 2 diabetes.60 65 66 69 71 Three of these studies60 66 69 included a multivariate analysis, but only two of them60 66 reported a relative measure of association for this risk factor. These two studies varied considerably. Cheung et al. found that as compared to women who did not use insulin, those that did use insulin during pregnancy had a three-fold higher risk of developing type 2 diabetes after adjusting for age, parity, FBG at diagnosis, BMI at index pregnancy, 2-hr OGTT, number of prior pregnancies complicated by gestational diabetes, family history of type 2 diabetes, and hospital location (RR = 3.2; 95 percent CI: 1.6 to 7.0).60 Lobner et al. reported that as compared to women who were diet-controlled, women who received insulin during pregnancy had an almost five-fold increased risk of developing type 2 diabetes after adjustment for age, parity, GAD and IA-2 antibody status, BMI during pregnancy, and serum CRP (RH = 4.7; 95 percent CI: 3.2 to 7.1; p < 0.0001).66
Two studies included a univariate analysis, but only Steinhart et al. reported a relative measure of association for the method of glucose control. This study reported an almost three-fold increased likelihood of developing type 2 diabetes in women requiring insulin as compared to those not on insulin, but this association was not statistically significant (OR = 2.8; 95 percent CI: 0.8 to 11.2).71
One study by Cheung et al. examined the required dosage of bedtime intermediate-acting insulin as a risk factor. For each unit (unspecified) increase in dosage, there was a 9 percent increased likelihood of developing type 2 diabetes after adjustment for FBG (RR = 1.1; 95 percent CI: 1.0 to 1.2).60 The clinical relevance of this finding, however, is unclear, given that it is based on data from one study and is of borderline statistical significance.
50-gm GCT. The 50-gm GCT is routinely performed during pregnancy as the baseline screening test for gestational diabetes. Only one study evaluated the results of the 50-gm GCT performed during pregnancy as a risk factor for the development of type 2 diabetes.70 Schaefer-Graf et al. categorized the GCT results into quartiles, using the first quartile as the reference. They reported that as compared to women with 50-gm GCT results in the first quartile, women with results in the second, third, and fourth quartiles had an increasingly higher risk of developing type 2 diabetes (OR = 2.9; 95 percent CI: 1.2 to 6.6; OR = 3.8; 95 percent CI: 1.7 to 8.5; and OR = 3.5; 95 percent CI: 1.6 to 7.6 for the second, third, and fourth quartiles, respectively), after adjusting for FBG at diagnosis, class A2 gestational diabetes, area under the glucose challenge curve of pregnancy OGTT, gestational age at diagnosis of gestational diabetes, and previous pregnancy complicated by gestational diabetes.
Class A-2 (insulin-requiring gestational diabetes). One study evaluated class A2 gestational diabetes, defined as requiring insulin therapy because of FBG levels greater than or equal to 105 mg/dL, as a risk factor for the development of type 2 diabetes.70 Schaefer-Graf et al. reported that as compared to women with gestational diabetes class A1, women with gestational diabetes class A2 were 2.4 times more likely to develop type 2 diabetes, after adjusting for FBG at diagnosis, 50-gm GCT, area under the curve for a pregnancy OGTT, gestational age at diagnosis of gestational diabetes, and previous pregnancy complicated by gestational diabetes (OR = 2.4; 95 percent CI: 1.2 to 4.7).
Previous pregnancies complicated by gestational diabetes. Two studies evaluated previous pregnancies complicated by gestational diabetes as a risk factor for the development of type 2 diabetes.60 70 These studies included multivariate analysis, but only one study reported a relative measure of association for this risk factor.70 Schaefer-Graf et al. reported that as compared to women without a previous pregnancy complicated by gestational diabetes, those with a such a pregnancy were 60 percent more likely to develop type 2 diabetes, after adjusting for FBG at diagnosis, 50-gm GCT, area under the glucose challenge curve of pregnancy OGTT, gestational age at gestational diabetes diagnosis, and previous pregnancy complicated by gestational diabetes (OR = 1.6; 95 percent CI: 1.1 to 2.5).
Spontaneous abortion. One study that included a univariate analysis examined spontaneous abortion as a risk factor for the development of type 2 diabetes in women with previous gestational diabetes.71 Steinhart et al. reported that as compared to women without spontaneous abortions, those with spontaneous abortions were 36 percent more likely to develop type 2 diabetes, but this association was not statistically significant (OR = 1.4; 95 percent CI: 0.5 to 3.5).
We concluded that the overall grade of evidence for pregnancy-related factors was moderate.
Postpartum factors. We identified five studies that evaluated a total of four postpartum factors as risk factors for the development of type 2 diabetes in women with previous gestational diabetes (see Appendix F, Evidence Table 22).62 64 69 71 72 The four postpartum factors examined were additional pregnancy, breastfeeding, duration of followup, and recurrent gestational diabetes. Duration of followup for the 88 to 909 participants ranged from 6 weeks to 12 years.
Additional pregnancy. Two studies assessed additional pregnancy as a risk factor for the development of type 2 diabetes in women with previous gestational diabetes, and both used multivariate analysis.69 72 However, only one study reported a relative measure of association for this risk factor.72 After adjusting for postpartum weight change (per 10 pounds), OGTT glucose area, postpartum BMI, and breastfeeding, Peters et al. found that as compared to women with no additional pregnancy, those with an additional pregnancy had a three-fold increased risk of developing type 2 diabetes (RH = 3.3; 95 percent CI: 1.8 to 6.2).72
Breastfeeding. Two studies assessed breastfeeding as a risk factor for the development of type 2 diabetes, and both constructed multivariate models.64 72 However, neither of these studies reported relative measures of association for this risk factor.
Duration of followup. One study evaluated the duration of followup as a risk factor for the development of type 2 diabetes in women with previous gestational diabetes and constructed eight multivariate models, involving age, parity, family history of type 2 diabetes, working status, blood pressure, lipid profile, and one of eight measures of adiposity (postpartum BMI, waist circumference, weight, subscapular skin fold thickness, suprailiac skin fold thickness, tricep skin fold thickness, body fat weight, or waist-to-hip ratio).62 However, the relative measure of association was not reported for the association between duration of followup and development of type 2 diabetes for any of the eight models.
Recurrent gestational diabetes. One study evaluated recurrent gestational diabetes as a risk factor for the development of type 2 diabetes in women with previous gestational diabetes and conducted a univariate analysis.71 Steinhart et al. reported that as compared to women without recurrent gestational diabetes, those with recurrent gestational diabetes had a 24-fold increased risk of developing type 2 diabetes (OR = 24.8; 95 percent CI: 3.0 to 1132.2). The width of this confidence interval, however, suggests substantial variability in the point estimate and makes it impossible for us to draw any firm conclusions from these data.
We concluded that the overall grade of the evidence for postpartum factors was very low.
Measures of anthropometry. We identified 11 cohort studies that evaluated a total of 11 different anthropometric measures: weight, height, BMI, body fat weight, subscapular skin fold thickness, suprailiac skin fold thickness, tricep skin fold thickness, waist circumference, waist-to-hip ratio, percent ideal body weight, and weight change (see Appendix F, Evidence Table 23).60–67 69 72 73 The number of participants ranged from 17061 to 909.62 Followup of participants ranged from 6 weeks to 12 years. Of the 11 studies, 9 reported a relative measure of association.60–63 65–67 72 73 Eight studies 60–63 66 67 72 73 reported an adjusted relative measure of association. We have included these adjusted relative measures in Figure 7. One study reported an unadjusted relative measure from a univariate model.65 The studies varied in terms of the time period in which the assessment of anthropometry was conducted.
Of the 11 studies, three used pre-pregnancy measures of obesity.61 63 73 Two of these studies reported a significant positive association between pre-pregnancy anthropometric measures and the development of type 2 diabetes.63 73 One study reported a protective effect of a higher anthropometric measure,61 and one study did not report the measure of association.63 Pallardo et al. found that as compared to women with a pre-pregnancy BMI less than or equal to 27 kg/m2, women with a BMI greater than 27 kg/m2 had an eight-fold increased risk of developing type 2 diabetes, after adjusting for the number of abnormal glucose results from the OGTT and C-peptide glucose score (OR = 8.7; 95 percent CI: 2.3 to 32.9).73 Jang et al. reported that for every 1-kg increase in pre-pregnancy weight, there was a 0.36 increase in the log odds of developing type 2 diabetes, although this relationship was not statistically significant (β = 0.36, SE = 0.10).63 One study61 reported a reduction in the likelihood of type 2 diabetes with higher BMI: Cho et al.61 reported that as compared to women with a pre-pregnancy BMI less than or equal to 23 kg/m2, women with a pre-pregnancy BMI greater than 23 kg/m2 were less likely (RR = 0.78; 95 percent CI: 0.27 to 2.2) to develop type 2 diabetes, after adjusting for age, gestational age at diagnosis of gestational diabetes, family history of type 2 diabetes, FBG at diagnosis, and homocysteine level. This reported association, however, was not statistically significant. We concluded that pre-pregnancy measures of obesity are associated with an increased likelihood of type 2 diabetes.
Three of the 11 studies used anthropometric measures during pregnancy. These studies reported a positive association between anthropometric measures and the development of type 2 diabetes.60 66 67 For example, Lobner et al. reported that women with a BMI greater than 30 kg/m2 were 50 percent more likely to develop type 2 diabetes than were women with a BMI less than 30 kg/m2, after adjusting for GAD and IA-2 antibody status, method of glucose control, parity, age, and serum CRP at 9 months (RH = 1.5; 95 percent CI: 1.0 to 2.2).66 In addition, Metzger et al. reported that as compared to women who were non-obese (<120 percent ideal body weight), women who were obese (≥ 120 percent ideal body weight) had an almost three-fold increased likelihood of developing type 2 diabetes, after adjusting for 3-hr integrated insulin level and parity.67 For each kg/m2 increase in BMI, Cheung et al. reported a 10 percent increase in the risk of developing type 2 diabetes (relative risk [RR] = 1.1; 95 percent CI: 1.0 to 1.2), after adjusting for age, parity, FBG at diagnosis, 2-hr OGTT, the number of prior pregnancies complicated by gestational diabetes, method of glucose control, family history of type 2 diabetes, and hospital location.60
Five studies62–65 72evaluated anthropometric measures assessed during the postpartum period, but only four studies62 64 65 72 reported a relative measure of association. As shown in Figure 7, Cho et al. assessed eight anthropometric measures, comparing women in the highest quartile to those in the lowest quartile.62 Each of the eight measures was positively associated with the development of type 2 diabetes, after adjusting for age, duration of followup, parity, family history of type 2 diabetes, working status, blood pressure, and lipid profile, including triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. As compared to women in the lowest quartile of postpartum BMI and weight, women in the highest quartile had a three-fold increased likelihood (OR = 3.3; 95 percent CI: 1.7 to 6.5 and OR = 3.1; 95 percent CI: 1.6 to 6.0, respectively) of developing type 2 diabetes. In the same sample, Cho et al. reported that women in the highest quartile were 3.8 times more likely to develop type 2 diabetes (OR = 3.8; 95 percent CI: 1.8 to 7.6) than were women in the lowest quartile of body fat weight. The direction and magnitude of the association with type 2 diabetes were similar across several additional anthropometric measures. As compared to women in the lowest quartile, women in the highest quartile of (1) subscapular skin fold thickness, (2) suprailiac skin fold thickness, and (3) tricep skin fold thickness had a 2.0- to 2.8-fold higher likelihood of developing type 2 diabetes. Women in the highest quartile were over two times more likely to develop type 2 diabetes (OR = 2.8; 95 percent CI: 1.4 to 5.6; OR = 2.1; 95 percent CI: 1.2 to 3.7; and OR = 2.0; 95 percent CI: 1.1 to 3.6, respectively). Also, Cho et al. reported that as compared to women in the lowest quartile of waist circumference and waist-to-hip ratio, women in the highest quartile were over three times as likely to develop type 2 diabetes (OR = 3.9; 95 percent CI: 1.8 to 8.2 and OR = 3.1; 95 percent CI: 1.7 to 5.6, respectively). Two additional studies (Peters et al. and Xiang et al.) assessed postpartum BMI64 72 and postpartum weight64 in multivariate models but did not report the measure of association. In an unadjusted analysis, Dacus et al. reported a four-fold increased risk (RR = 4.1; 95 percent CI: 0.6 – 29.8) in the development of type 2 diabetes in women with a BMI of 27 kg/m2 or greater as compared to women with a BMI of less than 27 kg/m2, but this difference was not statistically significant.65
Three studies evaluated anthropometric measures as time-dependent covariates, assessing the association of the change in these measures between delivery and followup with type 2 diabetes.64 69 72 Peters et al. showed that for every 10-pound change in weight, there was a 95 percent increase in the risk of developing type 2 diabetes, after adjusting for additional pregnancy, OGTT glucose area, postpartum BMI, and breastfeeding (RH = 2.0; 95 percent CI: 1.6 to 2.3).72 Although Kjos et al. and Xiang et al. included weight change in their multivariate analyses, the relative association of weight change with type 2 diabetes was not reported.64 69 Height was examined in one study, but the measure of association from the multivariate model was not reported.63 Because of multiple cohort studies and measures of association, we graded the overall evidence for anthropometric measures as moderate.
Oral contraceptive use. Two studies evaluated oral contraceptive use and the risk of type 2 diabetes in women with a prior history of gestational diabetes (see Appendix F, Evidence Table 24).64 69 Kjos et al. found that as compared to women using a combination oral contraceptive pill, those using a progestin-only pill had a greater than two-fold increased risk of developing type 2 diabetes, following adjustment for the area under the postpartum glucose tolerance test curve, prior oral contraceptive use, method of glucose control, completion of a second pregnancy, postpartum weight loss, and duration of oral contraceptive use (RH = 2.9; 95 percent CI: 1.6 to 5.3).69 In that same study, duration of oral contraceptive use was also a significant predictor of type 2 diabetes risk. Women using oral contraceptives for 4 to 8 months and more than 8 months had, respectively, a three-fold (RH = 3.0; 95 percent CI: 1.4 to 6.5) and nearly five-fold (RH = 4.9; 95 percent CI: 1.8 to 13.7) increased risk of developing type 2 diabetes when compared to those with lower-duration use, following multivariable adjustment for the same variables.69
Xiang et al. did not find that progesterone-based contraceptives were consistently associated with an increased risk of type 2 diabetes. As compared to women who used combination oral contraceptives, those using depo-medroxyprogesterone acetate did not have an increased risk of type 2 diabetes in the entire cohort, after adjusting for postpartum BMI, breastfeeding, family history of type 2 diabetes, HDL cholesterol, triglycerides, and weight gain during followup (RH = 1.1; 95 percent CI: 0.6 to 1.9).64 This association did not differ by breastfeeding status.64 However, after adjusting for postpartum BMI, family history of type 2 diabetes, breastfeeding, HDL cholesterol, and weight gain during followup, use of depo-medroxyprogesterone acetate in women with triglycerides above the median of the population was associated with a two-fold greater risk of developing type 2 diabetes when compared to the use of a combination oral contraceptive and triglyceride levels below the population median (RH = 2.3; 95 percent CI: 1.1 to 4.8).64 We concluded that the limited number of studies available and the overall very low grade of evidence made it difficult to draw any firm conclusions regarding the relationship between progestin-only contraception and the development of type 2 diabetes among women with gestational diabetes.
Metabolic risk factors
FBG: antepartum. Five studies examined antepartum FBG at gestational diabetes diagnosis as a risk factor, and in all of these studies, FBG was a significant predictor of type 2 diabetes (see Figure 8 and Appendix F, Evidence Table 25).60 61 68 70 71 Cheung et al. found that each increasing mmol/L increment in FBG was associated with a 37 percent increase in the risk of type 2 diabetes, after adjustment for the dose of bedtime intermediate-acting insulin (RR = 1.4; 95 percent CI: 1.1 to 1.7).60 In that same study, FBG at diagnosis was associated with a 1.5-fold increased risk of type 2 diabetes, after adjusting for age, parity, BMI at the index pregnancy, 2-hr OGTT result, number of prior pregnancies, method of glucose control, family history of type 2 diabetes, and hospital (RR = 1.5; 95 percent CI: 1.3 to 1.9).60
In unadjusted analyses, Steinhart et al. found that as compared to women with an FBG less than or equal to 5.83 mmol/L, those with an FBG greater than 5.83 mmol/L had an 11-fold increased risk of developing type 2 diabetes (OR = 11.1; 95 percent CI: 2.3 to 103.4).71 Cho et al. found that women with an FBG greater than 5.3 mmol/L had a four-fold increased risk of developing type 2 diabetes, after adjusting for age, gestational age at gestational diabetes diagnosis, pre-pregnancy BMI, family history of type 2 diabetes, and homocysteine level (RR = 4.0; 95 percent CI: 1.4 to 11.4).61 In another study, Schaefer-Graf et al. found an increased risk of type 2 diabetes with increasing quartiles of FBG, such that women in the highest quartile had a 21-fold increased risk of developing type 2 diabetes when compared to those in the lowest quartile (OR = 21.0; 95 percent CI: 4.6 to 96.3).70 Finally, Kjos et al. also found an increased risk of type 2 diabetes with increasing tertiles of FBG, with women in the highest tertile having a greater than two-fold increased risk when compared to those in the lowest tertile, after adjusting for postpartum OGTT glucose area under the curve, gestational age at gestational diabetes diagnosis, and antepartum OGTT glucose area under the curve (RH = 2.5; 95 percent CI: 1.3 to 4.9).68
Characteristics of the OGTT
Antepartum OGTT results
Number of abnormal OGTT results. One study examined the number of abnormal OGTT results as a risk factor for subsequent development of type 2 diabetes.73 In this study, there was a three-fold increased risk of type 2 diabetes with each increase in the number of abnormal OGTT results, after adjusting for pre-pregnancy BMI and C-peptide glucose score (OR = 3.0; 95 percent CI: 1.4 to 6.4).73
Glucose tolerance test total. One study examined the OGTT total as a risk factor for type 2 diabetes. As compared to women with OGTT totals less than or equal to 41.63 mmol/L, those with a GTT total greater than 41.63 mmol/L had a 15-fold greater risk of developing type 2 diabetes (OR = 15.5; 95 percent CI: 2 to 678).71
1-hr glucose during the diagnostic OGTT. One study examined the 1-hr glucose level during the diagnostic OGTT as a risk factor for the development of type 2 diabetes.74 Buchanan et al. found that as compared to women with the lowest tertile of 1-hr plasma glucose during the diagnostic OGTT, women in the highest tertile had a 15-fold greater risk of developing type 2 diabetes, after adjusting for beta-cell compensation index and basal production rate (OR = 15.2; 95 percent CI: 1.4 to 166.3), and a 22-fold higher risk of developing type 2 diabetes, after adjusting for the OGTT 30-min incremental insulin:glucose ratio, basal glucose production rate, and insulin sensitivity index (OR = 22; 95 percent CI: 1.5 to 328.5).74
2-hr glucose during the diagnostic OGTT. Three studies evaluated the 2-hr glucose level during the OGTT as a risk factor for subsequent development of type 2 diabetes and found it to be a significant predictor in multivariate analyses (see Figure 8).60 63 67 Jang et al. found that for every 1-point increase in 2-hr glucose level, there was a 2 percent increased risk of developing type 2 diabetes (OR = 1.02; 95 percent CI: 1.00 to 1.03; p = 0.04), after adjusting for pre-pregnancy weight, gestational age at gestational diabetes diagnosis, 3-hour insulin level on the diagnostic OGTT, age, height, pre-pregnancy BMI, family history of type 2 diabetes, and postpartum weight.63 Metzger et al. found a similar association after adjusting for 30-minute stimulated insulin secretion on the OGTT and basal insulin (OR = 1.03; 95 percent CI: 1.01 to 1.04).67 Cheung et al. found a stronger association, in that there was a 30 percent increased risk of developing type 2 diabetes for each 1-point increase in the 2-hr glucose level during the OGTT, after adjusting for age, parity, FBG at gestational diabetes diagnosis, BMI at the index pregnancy, number of prior gestational diabetic pregnancies, method of glucose control during the index pregnancy, family history of type 2 diabetes, and hospital (RR = 1.3; 95 percent CI: 1.1 to 1.4).60
3-hr insulin level during the diagnostic OGTT. One study63 examined 3-hr insulin levels and found an inverse association between the insulin level and the risk of developing type 2 diabetes, after adjusting for pre-pregnancy weight, gestational age at gestational diabetes diagnosis, 2-hr glucose level, age, height, pre-pregnancy BMI, family history of type 2 diabetes, and weight at postpartum testing. A second study measured 3-hr integrated insulin levels and found no association with the development of type 2 diabetes.
30-minute incremental insulin:glucose ratio. Two studies examined the 30-min incremental insulin:glucose ratio from the antepartum OGTT.74 75 Both studies found it to be a predictor of type 2 diabetes. One study showed a non-significant 90 percent lower risk of type 2 diabetes in the highest versus the lowest tertile, after adjusting for incremental glucose area, diagnostic OGTT, frequently sampled intravenous glucose tolerance acute insulin response, basal glucose production rate, and insulin sensitivity index (OR = 0.1; 95 percent CI: 0.01 to 2.2), and a 92 percent lower risk after adjusting for 1-hr plasma glucose level during the diagnostic OGTT, basal glucose production rate, and insulin sensitivity index (OR = 0.08; 95 percent CI; 0.01 to 1.1).74
Antepartum OGTT glucose area under the curve. Five studies examined the antepartum OGTT glucose area under the curve and the subsequent risk of type 2 diabetes (see Figure 8).68 70 72 74 75 Kjos et al. found a graded association between the glucose area under the curve and the risk of type 2 diabetes. As compared to those in the lowest quartile, those in the highest quartile had a two-fold increased risk, after adjusting for postpartum OGTT glucose area under the curve, gestational age at gestational diabetes diagnosis, and highest antepartum fasting glucose (RH = 2.1; 95 percent CI: 1.2 to 3.9).68 Similarly, Schaefer-Graf et al. found that women in the highest quartile of glucose area under the curve had a significantly increased risk of type 2 diabetes when compared to those in the lowest quartile, after adjusting for FBG at diagnosis, diabetes pregnancy class, gestational age at gestational diabetes diagnosis, previous gestational diabetes, and results of the 50-gm GCT (OR = 3.6; 95 percent CI: 1.9 to 6.8).70 Buchanan et al. also found that the OGTT glucose area under the curve was a significant predictor of type 2 diabetes, after adjusting for the antepartum 30-min incremental plasma insulin:glucose ratio.75 In another study, they also found that women in the highest tertile of incremental area under the glucose curve had a 15-fold increased risk of type 2 diabetes when compared to women in the lowest tertile, after adjusting for frequently sampled intravenous glucose tolerance acute insulin response, OGTT 30-min incremental insulin:glucose ratio, basal glucose production rate, and insulin sensitivity index (OR = 15; 95 percent CI: 1.1 to 207.9).74
We concluded that increasing FBS or 2-hr glucose values on the diagnostic OGTT may indicate a higher likelihood of development of type 2 diabetes in women with gestational diabetes.
Postpartum OGTT results
Area under the curve for postpartum OGTT. Two studies by the same author examined the postpartum OGTT area under the glucose curve and the risk of developing type 2 diabetes.68 69 In the one study in which measures of association were reported, the risk of type 2 diabetes increased with increasing quartiles of postpartum OGTT area under the glucose curve (p-value for trend < 0.0001), after adjusting for gestational age at gestational diabetes diagnosis, antepartum OGTT glucose area under the curve, and highest antepartum fasting glucose.68 As compared to those in the lowest quartile, those in the highest quartile had an 11-fold increased risk of type 2 diabetes (RH = 11.5; 95 percent CI: 4.5 to 29.1).68
We graded the overall body of evidence for metabolic risk factors as moderate. There was consistency in the association of 2-hr PPG and Antepartum OGTT glucose area under the curve.
Additional measures of glucose metabolism. One study by Buchanan et al. examined several additional measures of glucose metabolism as risk factors for type 2 diabetes, including basal glucose production rate, beta-cell compensation index, clamp insulin sensitivity, and frequently sampled intravenous glucose tolerance acute insulin response.74 A higher basal glucose production rate was associated with a non-significantly increased risk of type 2 diabetes in several multivariable models that included: (1) incremental glucose area on the diagnostic OGTT, frequently sampled intravenous glucose tolerance acute insulin response, OGTT 30-min incremental insulin:glucose ratio, and clamp insulin sensitivity (model 1); (2) 1-hr OGTT plasma glucose and beta-cell compensation index (model 2); and (3) 1-hr OGTT plasma glucose, OGTT 30-min incremental insulin:glucose ratio, and insulin sensitivity index (model 3).74
Greater beta-cell compensation index was associated with a 91 percent lower risk of developing type 2 diabetes, after adjusting for OGTT 1-hr plasma glucose level and basal glucose production rate. Greater clamp insulin sensitivity was associated with a non-significantly lower risk of developing type 2 diabetes, after adjusting for OGTT 1-hr glucose level, OGTT 30-min incremental insulin:glucose ratio, and basal glucose production rate in model 1 (OR = 0.2; 95 percent CI: 0.03 to 1.2) and after adjusting for diagnostic OGTT incremental glucose area, frequently sampled intravenous glucose tolerance acute insulin response, OGTT 30-min incremental insulin:glucose ratio, and basal glucose production rate in model 2 (OR = 0.15; 95 percent CI: 0.02 to 1.2).74 Finally, women in the highest tertile of frequently sampled intravenous glucose tolerance test acute insulin response had a 92 percent lower risk of developing type 2 diabetes than did those in the lowest tertile, after adjusting for diagnostic OGTT incremental glucose area, OGTT 30-min incremental insulin:glucose ratio, basal glucose production rate, and clamp insulin sensitivity (OR = 0.08; 95 percent CI: 0.01 to 1.0).74
One study examined C-peptide glucose score as a risk factor for type 2 diabetes.73 In this study, a higher C-peptide glucose score was associated with a 54 percent lower risk of developing type 2 diabetes, after adjusting for pre-pregnancy BMI and the number of abnormal OGTT results (OR = 0.46; 95 percent CI: 0.25 to 0.85).73 We included these additional measures of glucose metabolism in order to provide a comprehensive summary of potential risk factors for the development of type 2 diabetes. While we were unable to draw conclusions from this emerging area of investigation, this review provided insight into the physiologic pathways that are being studied to better define the risk of type 2 diabetes among women with gestational diabetes.
The grade of evidence for both anthropometric measures and metabolic risk factors was moderate (see Appendix F, Evidence Table 26). However, after considering the quantity, quality, and consistency of the reviewed literature on risk factors, we graded the overall body of evidence as very low.
Other potential risk factors for type 2 diabetes
Blood pressure. Cho et al. found postpartum blood pressure to be a predictor of type 2 diabetes, although a relative measure for blood pressure was not reported in their multivariate models.62
Lipids. Two studies examined postpartum lipid parameters as predictors of type 2 diabetes,62 64 and in both of these studies, HDL cholesterol and triglycerides were risk factors for the development of type 2 diabetes; however, a relative measure for the lipid parameters was not reported in the multivariate models.62 64
Homocysteine. One study assessed homocysteine levels 6 weeks postpartum and found that women with homocysteine levels greater than 6.38 mmol had a greater than three-fold increased risk of developing type 2 diabetes when compared to those with homocysteine levels below this level, after adjusting for age, gestational age at gestational diabetes diagnosis, pre-pregnancy BMI, family history of type 2 diabetes, and FBG at diagnosis (RR = 3.6; 95 percent CI: 1.1 to 11.9).61
Autoantibodies. One study examined GAD and IA-2 antibodies as risk factors for type 2 diabetes and found that women with positive GAD or IA-2 antibodies had a four-fold increased risk of type 2 diabetes when compared to women who were antibody negative, after adjusting for the method of glucose control, BMI, parity, age, and serum CRP (RH = 4.1; 95 percent CI: 2.6 to 6.7).66 We were unable to draw meaningful conclusions based on the available evidence, but we have included summaries of these traditional (i.e., lipids, blood pressure) and novel measures to provide a comprehensive review of available risk factors for the development of type 2 diabetes.
Additional studies of risk factors for type 2 diabetes. We identified 11 studies that investigated factors associated with incident type 2 diabetes following a pregnancy complicated by gestational diabetes, but these studies did not include relative measures of risk or multivariate models.76–86 While these studies are important for qualitatively identifying risk factors, we consider them to provide the lowest level of evidence because there was no adjustment for potential confounders or relative estimates. The evidence is briefly discussed below by risk factor category.
- 1.
Family history of type 2 diabetes: No additional studies.
- 2.
Sociodemographics: Two studies investigated maternal age. Greenberg et al.83 compared maternal ages according to diabetic status at followup and did not find any statistical differences, while Dalfra et al.80 did find an association. Two studies, Kousta et al. and Ali et al.,77 87 examined the incidence of type 2 diabetes as stratified by race. Both studies found a higher incidence among black and Asian-Indian women than in European women or women of mixed ethnicity.
- 3.
Maternal lifestyle factors: No additional studies.
- 4.
Parity: Only one study, Linne et al.,79 compared parity in women with and without type 2 diabetes at followup. No association was observed.
- 5.
Pregnancy-related factors: Younger gestational age at diagnosis was consistently associated with increased incidence of type 2 diabetes in three studies: Greenberg et al.,83 Bartha et al.,82 and Dalfra et al.80 Insulin use during pregnancy was consistently associated with increased type 2 diabetes in two studies: Greenberg et al.83 and Dalfra et al.80 Class A2 gestational diabetes was associated with increased type 2 diabetes in one study, that of Kjos et al.85 Greenberg et al.83 found that cesarean delivery, shoulder dystocia, and birthweight percentile did not differ between women who did and did not develop type 2 diabetes during followup.
- 6.
Postpartum factors: Kjos et al.84 compared women who did and did not breastfeed following a pregnancy complicated by gestational diabetes and found that women who breastfed had a decreased incidence of type 2 diabetes.
- 7.
Anthropometric measures: BMI was investigated in six studies: Bian et al.,81 Greenberg et al.,83 Pallardo et al.,78 Dalfraet et al.,80 Linne et al.,79 and Bartha.82 There was a significant relationship between higher BMI and increased type 2 diabetes in all but one study.83 Pallardo et al.78 found that women who had developed type 2 diabetes during followup had higher current weight but did not differ in pre-pregnancy weight, weight change, or body fat percentage from women without type 2 diabetes at followup. Waist circumference was found to be associated with type 2 diabetes by Pallardo et al.78 but was not found to be associated by Linne et al.79 Waist-to-hip ratio was also not associated with type 2 diabetes in the study by Linne et al.79
- 8.
Oral contraceptive use: Kjos et al.85 found no difference in the incidence of type 2 diabetes in women using non-oral contraceptives, ethinyl estradiol-norethindrone, or ethinyl estradiol-levonorgestrel.
- 9.
Metabolic risk factors: Increased fasting glucose was consistently higher in women developing type 2 diabetes during followup in four studies: Xiang et al.,76 Linne et al.,79 Dalfra et al.,80 and Greenberg et al.83 Higher HbA1c was consistently associated with increased type 2 diabetes in two studies: Linne et al.79 and Greenberg et al.83 Decreased beta-cell compensation was associated with higher risk of type 2 diabetes in one study, Xiang et al.76 Plasma glucose levels at 2- and 3-hr during the diagnostic OGTT were found to be associated with increased type 2 diabetes in one study, Dalfra et al.,80 but not associated in another, Greenberg et al.83 Greenberg et al.83 did find a difference in 1-hr OGTT between women developing type 2 diabetes during followup and those who remained normoglycemic. Dalfra et al.80 also found postprandial plasma glucose, plasma insulin at 30 min during the OGTT, and postpartum plasma glucose area under the curve to be associated with type 2 diabetes. While Linne et al.79 found blood pressure and lipids to be similar in women with and without type 2 diabetes at followup, Pallardo et al.78 found significant differences in triglycerides and diastolic blood pressure but not HDL cholesterol, total cholesterol, or systolic blood pressure in women with and without type 2 diabetes at followup.
Additional comments on multivariate models. While a multivariate analytic approach was used to evaluate most of the risk factors for the development of type 2 diabetes, the factors considered and adjusted for in the models differed between studies. For example, some studies focused on anthropometric measures, while others focused on physiologic measures. Still others included a broader range of key measures of interest. Studies varied with respect to the covariates included in the multivariate models (see Appendix F, Evidence Table 15). Some studies determined which variable to include in the multivariate models by identifying the most significant predictors from the univariate analysis. Other studies did not report how or why specific covariates were chosen to be included in the models. Most studies included a list of key covariates known to be associated with type 2 diabetes, including (1) age, (2) parity, (3) family history of type 2 diabetes, and (4) method of glucose control (diet versus insulin or oral medication). Age was included in all of the multivariate models. However, no one study included all of the other three key covariates. Also, no group of covariates common to all of the multivariate models was constructed for the evaluation of a given risk factor.
Two studies60 62 with well-defined approaches to the development of the multivariate models deserve further comment. In their investigation of the relationship of eight different obesity indices with onset of type 2 diabetes, Cho et al.62 followed 909 Korean women for a mean of 2.13 ± 1.75 years. The authors first stratified the study population into three groups (normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes) and performed a univariate analysis, examining the distribution of each of the seven obesity measures and relevant sociodemographic and clinical risk factors across the three groups of participants. Data were collected on risk factors that had been defined prior to the initiation of the study. Each obesity measure was then recategorized into quartiles (75th percentile compared to 25th percentile), and the association of each measure with type 2 diabetes was assessed using simple logistic regression. Correlations between obesity measures and other covariates were assessed. Only those factors that were statistically significantly associated with type 2 diabetes in the univariate analysis were included as covariates with the obesity measures in the final prediction model. These factors were blood pressure, lipid profile, age, duration of followup, parity, family history of type 2 diabetes, and working status. All eight of the obesity measures were associated with type 2 diabetes. Waist circumference was the strongest predictor (OR = 5.8; 95 percent CI: 2.0 to 11.8). After adjustment for covariates, the association of waist circumference with postpartum type 2 diabetes was moderately attenuated (OR = 3.4; 95 percent CI: 1.8 to 2.2) but remained statistically significant, as did the other six obesity measures. Although there was no R2 to assess the relative fit of the model, we conclude that the reported multivariate model was adjusted for covariates that are relevant both clinically and statistically to obesity and type 2 diabetes and were appropriately included in the model. Cheung et al.60 reported findings from Cox regression analyses. The authors chose to include factors that were clinically related to both type 2 diabetes and to underlying insulin resistance (as evidenced by fasting hyperglycemia in pregnancy): age, parity, BMI, number of episodes of prior gestational diabetes, family history of type 2 diabetes, and insulin use versus diet alone in pregnancy. We concluded that these authors appeared to have based the selection and adjustment of covariates on the a priori hypothesis of a relationship with hyperglycemia and the established association with type 2 diabetes in the development of the best predictive model. Both studies represented a systematic approach to the development of multivariate models for assessing the direction and magnitude of association of risk factors with type 2 diabetes.
Key Question 4
What are the performance characteristics (sensitivity, specificity, and reproducibility) of tests for diagnosing type 2 diabetes after pregnancy in patients with a history of gestational diabetes? Are there differences in the performance characteristics of the test results based on subgroup analysis?
Background and Conceptual Framework
The prevalence of type 2 diabetes is increasing in the United States and globally.1 Early detection and treatment of diabetes has been associated with improved outcomes related to microvascular complications and may prevent macrovascular complications as well.88 Women with gestational diabetes are at an increased risk of developing type 2 diabetes. An estimated 16 to 63 percent of women with gestational diabetes will develop type 2 diabetes in the 5 to 10 years immediately following pregnancy.29 While postpartum screening for type 2 diabetes among women with gestational diabetes has been supported by the ADA17 and ACOG,7 there is debate about which screening test to use and at what interval to screen. These are important questions for both clinical providers and public health officials. The fact that only limited evidence is available with regard to screening test performance in women with a history of gestational diabetes has prolonged the debate and perhaps delayed a consensus on appropriate screening. To further define our efforts in addressing this topic, we developed a conceptual framework (see Figure 9). Our model incorporates test performance, as measured by sensitivity, specificity, and reproducibility, as well as the time interval for screening.
Despite the known risk of type 2 diabetes among women with gestational diabetes, only 75 percent of ACOG fellows reported that they routinely perform postpartum screening with the 75-gm OGTT. Followup varies widely, and many women do not receive the recommended screening for type 2 diabetes.19 89 The barriers to use of the OGTT include the cost and inconvenience for a new mother. However, there is insufficient evidence supporting the use of an alternative screening test, such as the FBG. A recent cost-effectiveness analysis examined models for screening and found the OGTT to be cost-effective if used at 3-year intervals. Screening with the FBG was cost-effective if used at 1-year intervals.90 More precise knowledge of the performance characteristics of these tests may help improve our estimates of the effectiveness and total costs associated with screening.
In this report, we summarize and critically appraise the literature on the performance of currently available screening tests for postpartum glucose screening in order to support the development of clinical guidelines for postpartum glucose surveillance.
Table 6 summarizes the current tests available for postpartum glucose screening and their threshold values.
Results
Overview and population characteristics for screening tests for type 2 diabetes. Our literature search identified 8 studies and 10 evaluations of a reference test and comparison test. Each of the eight studies had a cohort design. Four studies collected data retrospectively.94–97 Each of these studies retrospectively applied the threshold glucose values of the comparison test to previously collected postpartum OGTT results. These studies used a clinic convenience sample, including all women who returned for postpartum testing within a specified time period. Four studies collected data prospectively.98–101 These four studies recruited patients with a history of gestational diabetes for screening for type 2 diabetes. Seven studies used the same OGTT results, but applied different diagnostic threshold criteria. One study100 independently performed the FBG and OGTT as two separate tests for comparison (see Appendix F, Evidence Table 27).
As shown in Evidence Table 27, the population in two studies98 100 was more than 50 percent Caucasian. One study,95 performed in the United Arab Emigrates, had mostly Arab (80 percent) subjects. One study101 was performed in the United Kingdom and included participants from three racial/ethnic groups: European, South Asian, and Afro-Caribbean. Three studies,94 97 99 including the study performed in the United States,97 did not report the racial composition of their study populations. The cohort included in the study by Reichelt et al.99 was part of a Brazilian Cohort Study, which previously reported high representation from non-white populations.102
The majority of the studies screened for type 2 diabetes within 1 year of delivery.94–97 100 Two studies98 101 reported wide ranges of postpartum testing intervals, from 1 to 86 months and from 6 to 72 months, respectively. Only one study99 conducted late screening of all subjects (between 4 and 8 years postpartum).
Overview of studies evaluating comparison and reference tests for type 2 diabetes. Our review yielded three general comparisons: (1) two different diagnostic threshold values applied to the 75-gm OGTT (the WHO 1985 criterion versus the WHO 1999 criterion); (2) FBG level greater than 7.0 mmol/L (126 mg/dL) (ADA 1997) and the 75-gm OGTT (WHO 1999); and (3) FBG greater than 7.0 mmol/L (126 mg/dL) (ADA 1997) and the 75-gm OGTT (WHO 1985).
For each eligible study, two of our investigators abstracted data serially to create a two-by-two table for each comparison test. The two-by-two tables contained data for the number of true positives (TP), false positives (FP), false negatives (FN), and true negatives (TN). We then calculated the sensitivity [# TP/(# TP + # FN)] and specificity [(# TN/ (# TN + # FP)] for each comparison test using the structured two-by-two tables. Since some cells included zero, standard errors and confidence intervals were calculated by means of the exact binomial formula using Stata command “cii” (Intercooled, version 8.2, StataCorp, College Station, TX).103 An example of our calculation of the sensitivity, specificity, and standard errors is shown in Table 7, using the study by Costa et al.100
Performance characteristics
Studies of different diagnostic threshold values applied to the 75-gm OGTT. Two studies97 101 compared different threshold values for the OGTT. They reported the same specificity of 98 percent for the OGTT using a threshold of FBG greater than 7.0 mmol/L (126 mg/dL) (WHO 1985) and using a threshold of FBG greater than 7.8 mmol/L (140 mg/dL) (see WHO 1999) (see Figure 10 and Appendix F, Evidence Table 28). For this comparison, the sensitivity was fixed at 100 percent because the threshold values used for the comparison test would by definition always meet the criteria of the reference test.
We concluded that relatively few “false positives” resulted from lowering the FBG threshold in the 75-gm OGTT to 7.0 mmol/L. Taking into consideration the quantity, quality, and consistency of the two studies of different diagnostic threshold values applied to the 75-gm OGTT, we graded the strength of the evidence as very low (see Appendix F, Evidence Table 29).
Studies of FBG level greater than 7.0 mmol/L (126 mg/dL) (comparison test; ADA 1997) as compared to the 75-gm OGTT (reference test; WHO 1999). Three studies94 95 99 reported data in which a single FBG greater than 7.0 mmol/L (126 mg/dL) (ADA 1997) was compared to an FBG greater than 7.0 mmol/L (126 mg/dL) or 2-hr plasma glucose after 75-gm OGTT greater than 11.1 mmol/L (200 mg/dL) (WHO 1999). The sensitivity for the FBG greater than 7.0 mmol/L (126 mg/dL) alone compared with a complete OGTT using the same FBG threshold (FBG > 7.0 mmol/L [126 mg/dL]) or 2-hr plasma glucose after 75-gm OGTT greater than 11.1 mmol/L (200 mg/dL) varied across the three studies, ranging from 46 to 89 percent (see Figure 11 and Appendix F, Evidence Table 28). For these comparisons, the specificity was fixed at 100 percent, since the threshold values for the comparison test would by definition meet the criteria for the reference test.
These three studies94 95 99 were heterogeneous because postpartum testing occurred less than 6 months after delivery in two studies94 95 but 4 to 8 years after delivery in the third study.99 In addition to this longer time period after delivery, the study population in the third study99 had a high prevalence of non-whites (previously reported by the Brazilian Gestational Diabetes Study Group)102, which may have affected the test performance.
We concluded that use of the FBG alone with a threshold of greater than 7.0 mmol/L (126 mg/dL) had unpredictable sensitivity. Taking into consideration the quantity, quality, and consistency of the studies that compared the FBG level greater than 7.0mmol/L (126mg/dL) to the 75-gm OGTT (WHO 1999), we graded the strength of the evidence as very low (see Appendix F, Evidence Table 29).
Studies of FBG greater than 7.0 mmol/L (126 mg/dL) (comparison test; ADA 1997) as compared to the 75-gm OGTT (reference test; WHO 1985). Five studies95 96 98 100 101 compared an FBG greater than 7.8 mmol/l (140 mg/dL) or a 2-hr plasma glucose level after 75-gm OGTT of greater than 11.1 mmol/l (200 mg/dL) (WHO 1985) as the reference test to an FBG greater than 7.0 mmol/L (126 mg/dL) (ADA 1997) as the comparison test.
These studies consistently reported high specificity (range: 94 to 99 percent). However, the sensitivities ranged from 14 to 100 percent (see Figure 12 and Appendix F, Evidence Table 28). Kousta et al.101 reported a sensitivity of 73 percent (95 percent CI: 50 to 89 percent), Agarwal et al.95 reported a sensitivity of 69 percent (95 percent CI: 53 to 82 percent), and Cypryk et al.98 reported a sensitivity of 14 percent (95 percent CI: 0.04 to 58 percent). Both Holt et al.96 and Costa et al.100 reported sensitivities of 100 percent (with 95 percent CIs of 29 to 100 percent and 16 to 100 percent, respectively) (see Appendix F, Evidence Table 28).
One study98 reported very low sensitivity for an FBG greater than 7.0 mmol/L (126 mg/dL) when compared to a reference OGTT with an FBG greater than 7.8 mmol/l (140 mg/dL) or 2-hr plasma glucose level after 75-gm OGTT greater than 11.1 mmol/l (200 mg/dL). This study population differed from the other studies' samples because 23 percent of the subjects were excluded from screening as a result of a new diagnosis of type 1 or 2 diabetes postpartum. Also, the study population was entirely Polish. These two study characteristics may have reduced the spectrum of risk for type 2 diabetes in the screened population as compared to other clinical populations, thereby lowering the test's sensitivity.
We concluded that use of the FBG with a threshold greater than 7.0 mmol/L had high specificity when compared to the 75-gm OGTT but had highly variable sensitivity. Taking into consideration the quantity, quality, and consistency of the studies that compared the FBG level greater than 7.0 mmol/L (126mg/dL) to the 75-gm OGTT (WHO 1985), we graded the strength of the evidence as very low (see Evidence Table 29).
Subgroup analysis. Only one study94 included analyses of high-risk subgroups: In this study, the FBG greater than 7.0 mmol/L (126 mg/dL) (ADA 1997) alone was compared to a complete OGTT (FBG > 7.0 mmol/L (126 mg/dL) or 2-hr plasma glucose after 75-gm OGTT greater than 11.1 mmol/L (200 mg/dL) (WHO 1999)). In 168 subjects with a family history of type 2 diabetes, the sensitivity was 47 percent (95 percent CI: 24 to 71 percent). In another 168 subjects who required insulin during pregnancy, the sensitivity was 55 percent (95 percent CI: 32 to 76 percent). We concluded that the FBG may perform better in subgroups with a family history of type 2 diabetes or that required insulin during pregnancy than in the general population, as reported in a single study.94
Test reproducibility. Test reproducibility affects diagnostic test accuracy. Five studies95–97 100 101 reported the type of laboratory equipment used to test samples as an indicator of quality control. Three articles reported the kappa statistic as the measure of agreement between the results of the comparison and reference test, but not as a standard measure of single-test reproducibility.95 98 100
For quantitative assays such as measures of blood glucose, the STARD Initiative recommends calculating imprecision as the coefficient of variation by repeating the test over several days.24 One study96 reported the coefficient of variation: Holt et al. reported the coefficient of variation for plasma glucose testing using the specified laboratory equipment and assay. The coefficient of variation for this assay was 1.2 percent at 3.3 mmol/L and 1.49 percent at 16.5 mmol/L.96
One study did not meet our inclusion criteria because it did not report the method of diagnosing gestational diabetes, but it is notable because it focused on the question of reproducibility of the OGTT using FBG greater than 7.0 mmol/L (126 mg/dL) or 2-hr plasma glucose after 75-gm OGTT greater than 11.1 mmol/L (200 mg/dL) (WHO 1999).104 The study population consisted of 696 Caucasian women with previous gestational diabetes at a median of 6.2 years postpartum. Women were administered an OGTT, which was repeated within 3 months when it met the criteria for diabetes. Type 2 diabetes was confirmed in only 60 percent of the women.
Quality assessment. No study fulfilled all the criteria related to methodological standards for evaluating studies of screening tests (see Appendix F, Evidence Table 30). All of the studies had notably high losses to followup (range: 20 to 82 percent). The rates were highest in those that did not recruit subjects specifically for the study but instead used a convenience sample,94 95 97 since the clinics experienced high rates of postpartum loss to followup. Only two studies96 97 described the subjects who were lost to followup. Two studies recruited patients specifically for their study, but did not describe the selection process or the response rates.100 101
Additional methodological comments. Two studies98 101 excluded women who were diagnosed with type 1 or 2 diabetes postpartum prior to the screening test, resulting in exclusion of 14 to 23 percent of the recruited participants (see Appendix F, Evidence Table 27). Based on our qualitative evaluation of the studies included in this review, a quantitative synthesis of the data was not feasible.
Limitations. There were several key limitations of these studies. First, six studies95–98 100 101 used the 2-hr 75-gm OGTT with the FBG greater than 7.8 mmol/L (>140 mg/dL) (WHO 1985) threshold as a reference. This test may no longer be clinically useful, given current recommendations to use a threshold of FBG greater than 7.0 mmol/L (>126 mg/dL) as part of the OGTT (WHO 1999).
Overall, the study quality was poor. The studies were limited by their sampling methods, specifically the use of convenience samples that had high losses to followup. It is not clear whether the higher-risk patients are more or less likely to attend their postpartum followup visits to receive type 2 diabetes screening, and any such pattern may vary according to the country studied. In any case, the high loss to followup clearly limited the generalizability of the results.
- Results - Therapeutic Management, Delivery, and Postpartum Risk Assessment and S...Results - Therapeutic Management, Delivery, and Postpartum Risk Assessment and Screening in Gestational Diabetes
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