Q.29How should neonatal hypoglycaemia be prevented and treated?

Bibliographic InformationStudy Type & Evidence LevelAim of StudyNumber of Patients & Patient CharacteristicsPopulation CharacteristicsOutcome measuresResults & CommentsStudy SummaryReviewer Comment
Wharton BA;Bower BD; 1965 Nov 13 370Study Type:
Intervention study non random.
Evidence Level: 2+
Immediate feed (within 3 hours) with undiluted breast milk (if <4lb 6oz) or half cream evaporated milk (if >4lb 6oz).239 premature babies:118 immediate feed, 121 later feed.Inclusion: All babies admitted to the unit weighing <5lb Exclusion: Death within two hours of birth, >than 8 hours old on admission. During second phase ill babies also excluded.Symptomatic hypoglycaemia (blood sugar level <20 mg per 100 ml (1.1 mmol/l) in a baby with one or more of the following features: Convulsions, cyanotic attacks, irritability, and collapse).
Aymptomatic hypoglycaemia (estimated blood sugar<20 mg per 100 ml (1.1 mmol/l)).
Symptomatic hypoglycaemia in 4/121 ‘later’ fed and 0/118 ‘immediate’ fed. Blood sugar estimated in 98 babies: The lowest level was <20 mg per 100 ml in 10/54 ‘later’ fed and 5/44 ‘immediate’ fed. Statistical significance was not reported.Immediate feeding reduces hypoglycaemia.The mortaility in the immediate group was 17% cf 6% in later group. Difference likely due to relatively large volumes of milk and inhalation of vomit.
Beard AG;Panos TC;Marasigan BV;Eminians J;Kennedy HF;Lamb J; 1966 Mar 369Study Type:
Intervention study non random.
Evidence Level: 2+
Feeding at 6 hours68 premature infants without complications: 41 fed at 72 hours 27 fed from 6 hours.Blood glucose measured at 1, 3, 24, 48 and 72 hours of age.In feeding withheld group 14 had blood glucose <25 mg per 100 ml (1.4 mmol/l) at 48 hours and 24 had values <25 mg per 100 ml (1.4 mmol/l) at 72 hours. Values below 25 mg per 100 ml (1.4 mmol/l) at both 48 and 72 hours were seen in 11 infants. Among early fed infants none had blood glucose measurements <25 mg per 100 ml (1.4 mmol/l).Early feeding of newborn premature infants decreases hypoglycaemia.
Lucas A;Boyes S;Bloom SR;ynsley-Green A; 1981 Mar 372Study Type: intervention study - non random.
Evidence Level: 2+
Breast fed45 breast fed, 34 formula fed.6 days old.Plasma concentrations of insulin, glucagon and gastric inhibitory polypeptide (GIP) blood levels of glucose, ketone bodies, pyruvate, lactate and glycerol measured pre- and post-prandially.Breast fed infants had higher basal and postprandiall blood ketones. P<0.001(difference in overall mean values of beta-hydroxybutyrate) and P < 0.05 (difference in overall mean values of acetacetate).

Formula fed infants had a greater insulin and GIP response to feeding and a significantly greater post feed rise in lactate and pyruvate concentrations.
It is possible that breast feeding enhances ketogenesis. Ketones may be important alternative substrates to glucose for brain metabolism in the neonatal period.
Bibliographic informationStudy level and evidence typeAim of studyNumber of patients and patient characteristicsPopulation characteristicsOutcome measuresResultsStudy summary
Ferris AM;Neubauer SH;Bendel RB;Green KW;Ingardia CJ;Reece EA; 1993 Jul 381Study Type:Case control. Evidence level: 2+33 women with type 1 diabetes
33 women without diabetes matched on gestational age of infant, method of delivery, sex of the infant, and prior lactation experience 11 healthy reference subjects who delivered vaginally
Follow-up period: 2, 3, 7, 14, 42 and 84 days postpartum. Outcome Measures: Percentage of time mother spent with infant from birth to day 2 (% of h possible)
Time mother spent with infant (h)
Mothers perception of time when milk came in after delivery (h)
Time from delivery that infant was first breastfed (h)
Number of times infant breastfed in first 12 h after birth

Duration of breastfeeding
Frequency of breastfeeding
Type of feeding
Perceived problems with feeding
Percentage of time mother spent with infant from birth to day 2 (% of h possible): Type1D 18.8±2.8, Control 31.9±2.7, Reference 47.6±4.6, P < 0.05.
Time mother spent with infant (h) Day 2: Type1D 8.0±0.6, Control 10.7±0.6, Reference 16.6±1.1, P < 0.05. Day3:
Type1D 11.1±0.6, Control 15.2±0.6, Reference 23.6±1.1, P < 0.05.
Mothers perception of time when milk came in after delivery (h): Type1D 78.2±4.5, Control 72.2±4.2, Reference 54.4±7.1, P < 0.05.
Time from delivery that infant was first breast fed (h): Type1D 26.1±2.8, Control 11.4±2.7, Reference 4.6±4.7, P < 0.05.
Number of times infant breastfed in first 12 h after birth: Type1D 0.5±0.2, Control 1.0±0.2, Reference 1.4±0.3, P < 0.05.

Significantly more women with type1 diabetes than control or reference mothers stopped breastfeeding before 42d postpartum (P < 0.01). Infants of mothers with type1D were supplemented with formula significantly more than were infants of control or reference mothers (P < 0.01). Women with type1 diabetes breastfed less frequently than either the control or reference women from days 2 to 42 postpartum (P < 0.0001). At 7 and 14 d postpartum more women with Type1D perceived that they had infants with feeding problems (44% and 33%) perceived that they had infants with feeding problems than did control (6% and 6%) and reference women (10% and 20%) P < 0.05).
Differences in feeding patterns attributed to:
Routine admission of IDM to neonatal units, increased rate of CS in diabtetic mothers, increased rate of macrosomic baby in diabetic mothers.
Diabetic mothers cited infant sleepiness as the most common infant-feeeding problem. A sleepy infant was not identified as a problem by any of the control mothers and by only one reference mother.
Bibliographic informationStudy type and evidence levelNumber of patients and patient characteristicsAim of studyOutcome measuresResultsStudy summaryReviewer comments
Hawdon JM;Ward Platt MP;ynsley-Green A; 1992 Apr 371Study Type: Cross sectional Evidence level: 2+156 term infants, 62 preterm infantsType of delivery
Method of feeding
Feeding frequency
Feed volume
Postnatal age
Follow-up period: 6 days. Outcome Measures: Whole blood concentrations of glucose Gluconogenic precursors (pyruvate, alanine, lactate, glycerol) Ketone bodies
Plasma concentrations of NEFA
Term infants(n = 156, 71 breast fed, 61 formular fed). Breastfed infants had significantly lower blood glucose concentration (mean 3.6 mmol/l, range 1.5–5.3 mmol/l) than formula fed (mean 4 mmol/l, range 2.5–6.2 mmol/l; P < 0.05). Breast fed infants had significantly higher blood ketone body concentrations (0.76 mmol/l) than formular fed (0.15 mmol/l, P < 0.05). Breast fed infants had significantly higher total glucogenic substrate concentrations (mean2.2 mmol/l) than formular fed infants (mean 1.9 mmol/l; P < 0.01).

Multiple regression analysis with method of feed, between feed interval, volume of feed, and postnatal age as independent variables demonstrated that only between feed interval was significantly correlated with blood glucose concentration(B= −0.003, SE=0.001, β= −0.32; P < 0.05).
The major determinant of blood glucose concentration was the interval between feeds, with lower blood concentrations when feed intervals were prolonged. Breast fed infants, who had the lowest blood glucose concentrations demonstrated effective counter regulation. This is reassuring in the light of current policies which encourage demand feeding of infants and exclusivity of breast feeding when this is the mother’s preference.
Lucas A;Morley R;Cole TJ; 1988 Nov 19 367Study Type: Cohort.
Evidence level: 2+
661 preterm babieshypoglycaemia defined as plasma blood glucose concentration<2.6 mmolFollow-up period: 18 months. Outcome Measures: Bayley motor and mental development scales
Hypoglycaemia (<2.6 mmol/l)
Number of days plasma blood glucose concentration <2.6 mmol/l
433/661 had plasma glucose<2.6 mmol/l. Regression analysis: Maximum slope and significance were seen for motor development (P<0.002) and mental development (P < 0.005) when a cut off of 2.5 mmol/l was used. Reduced developmental scores were associated independently with the number of days on which plasma glucose concentration was 0–1.5 mmol/l (P < 0.01) and the number of days on which it was 1.6 to 2.5 mmol/l (P < 0.01) whereas no relation was detected when it was in the range 2.6 to 4.0 mmol/l.Moderate hypoglycaemia (<2.6 mmol/l) is associated with adverse neurodevelopmental outcomes.
Bibliographic InformationStudy Type & Evidence LevelNumber of PatientsPatient CharacteristicsIntervention & ComparisonFollow-up & Outcome MeasuresEffect SizeStudy SummaryReviewer Comments
Plagemann A, Harder T, Franke K, Kohlhoff R.

2002

374
Study Type:
Cohort

Evidence level: 2+
112 children of women with diabetes (type 1 diabetes, n =83 and gestational diabetes, n = 29).Children born to women with diabetes who were delivered during 1980–1989 at the Clinic of Obstetrics and Gynecology, Berlin-Kaulsdorf.

They were part of the prospective cohort study on consequences of maternal diabetes during pregnancy for the children’s development.

Country: Germany
Intervention: Feeding on diabetic breast milk only.

Comparison:
  1. Feeding on some diabetic breast milk.
  2. Banked donor breast milk
Follow-up period: 2.5 years

Outcome Measures:
  1. Nutritional:
  2. Anthropometrical:
  3. Glucose levels
There was a positive correlation between the volume of diabetic breast milk ingested and risk of overweight at 2 years of age (OR 2.47, 95% CI 1.25 to 4.87).

In contrast, the volume of banked donor breast milk ingested was inversely correlated to body weight at follow-up (P = 0.001).

Risk of childhood impaired glucose tolerance decreased by increasing amounts of banked donor breast milk ingested neonatally (OR 0.19, 95% CI 0.05 to 0.70).

Stepwise regression analysis showed volume of diabetic breast milk to be the only significant predictor of relative body weight at 2 years of age (P = 0.001).
Early neonatal ingestion of breast milk from diabetic mothers may increase risk of becoming overweight and, consequently, developing impaired glucose tolerance during childhood.

Additional studies are needed to assess long-term consequences that might result from the type of neonatal nutrition in children of diabetic mothers.
This is a well designed and executed study taking into account potential confounding factors.

The sample size is reasonable and the likelihood of the role of chance is expected to be significantly small.
Rodekamp E;Harder T;Kohlhoff R;Franke K;Dudenhausen JW;Plagemann A;

2005

375
Study Type:
Cohort

Evidence level: 2+
317 children of women with type 1 diabetes.The participants of this study came from a population of 741 children of women with diabetes during pregnancy (type 1 diabetes and gestational diabetes) who delivered during 1980–1989 at the Clinic of Obstetrics and Gynecology, Berlin-Kaulsdorf.

They were part of the prospective cohort study on consequences of maternal diabetes during pregnancy for the children’s development.

A total of 112 infants (83 born to mothers with pre-existing diabetes and 29 with gestational diabetes) were followed-up with complete data on nutrition throughout the neonatal period, i.e., both the early neonatal period (1st neonatal week) and the late neonatal period (2nd–4th neonatal week), as well as data on duration of breast-feeding.

Gestational diabetes was diagnosed between the 26th and 28th gestational weeks.

Country: Germany
Intervention: Diabetic breast milk only.

Comparison:
  1. Some diabetic breast milk.
  2. No diabetic breast milk.
Follow-up period: 2.5 years.

Outcome Measures:
  1. Nutritional:
  2. Anthropometrical:
  3. Glucose levels
Regression analysis showed no significant influence of maternal third trimester glucose on the child’s body weight (OR 0.86, 95% CI 0.58 to 1.27) or impaired glucose tolerance (OR 0.97, 95% CI 0.56 to 1.67).

Relative body weight was lowest in children who had not ingested diabetic breast milk during the neonatal period and highest in those fed with diabetic breast milk only.

Exclusive breast-feeding was associated with increased childhood relative body weight (P = 0.011).

Breast-fed children of women with diabetes had increased risk of overweight (OR 1.98, 95% CI 1.12 to 3.50).

Breast-feeding duration was positively associated with childhood relative body weight (P = 0.004) and 120-min blood glucose during an oral glucose tolerance test (P = 0.022).

Adjustment for the breast milk volume ingested during the early neonatal period (1st week of life) eliminated all these relationships with late neonatal breast-feeding and its duration.

No relationship was observed between maternal blood glucose in the middle of the third trimester and the subsequent outcome.
Neither late neonatal diabetic breast milk intake nor the duration of breast-feeding has an independent influence on childhood risk of overweight or impaired glucose tolerance in children of women with diabetes. The 1st week of life appears to be the critical window for nutritional programming in children of women with diabetes by ingestion of maternal diabetic breast milk.The study was generally: well designed with detailed background information and statistical analysis and reporting of results.

The only issue not clear is “some diabetic breast milk”, the authors did not explain.
Gerstein HC;

1994 Jan

378
Study Type:
Systematic review - meta-analysis

Evidence level:
2++
3575 people who had diminished duration of breastfeeding or early exposure to cow's milk.People who were had diminished duration of breastfeeding or early exposure to cow's milk.

Country:
Data come from different countries.
Intervention:
Short duration of breastfeeding or early cow's milk exposure.

Comparison:
Long duration of breastfeeding.
Follow-up period:
Not reported.

Outcome Measures:
Development of type 1 diabetes.
Patients with type 1 diabetes were more likely to have been breastfed for < 3 months (overall OR 1.43, 95% CI 1.15 to 1.77) and to have been exposed to cow's milk before 4 months (overall OR 1.63, 95% CI 1.22 to 2.17).Early cow's milk exposure may be an important determinant of subsequent type 1 diabetes and may increase the risk approximately 1.5 times.
Norris,J.M.; Scott,F.W.

1996

379
Study Type:
Systematic review - meta-analysis

Evidence level:
2++
21039 participants
  1. Cases (n= 4656)
  2. Controls (n = 16383)
Children who were either breast fed or introduced to cow's milk constituents.

Country: Various countries
Intervention: Early breast feeding.

Comparison:
Early cow's milk exposure.
Follow-up period:

Outcome Measures:
1.

Ever breastfed

2.

Never breastfed.

2.

Breast feeding duration.

3.

Age at first exposure to breast milk substitutes.

The summary results showed a moderate effect of exposure to breast milk substitutes (OR 1.38, 95% CI 1.18 to 1.61])and cow's milk substitutes (OR = 1.61, 95% CI = 1.31 to 1.98) before 3 months of age.

The studies using existing records demonstrated little association compared to the studies relying on long-term recall.

Studies in which the controls had a participation rate more than 20% lower than the cases showed a stronger diabetogenic effect of never being breastfed (OR = 1.58) than studies whose cases and controls had similar participation rates (OR = 1.06).
The results showed that the effect of exposure to breast milk substitutes on type 1 diabetes is small.
Gagne,M.P.; Leff,E.W.; Jefferis,S.C.

1992

382
Study Type: Case-control

Evidence level: 2+
22 women with type 1 diabetes.Twenty-two mothers who were identified as having type 1 diabetes before pregnancy and who had given birth in the past 2 years.

Country: USA
Intervention:
Infant feeding practices of women with diabetes.

Comparison:
Infant feeding practices of women without diabetes.
Follow-up period:

Outcome Measures:
  1. Early breast-feeding
  2. Early exposure to bottle feeding
Diabetes was not a principal factor in the decision to breastfeed or bottle-feed for the majority of the women.

Participants who considered diabetes in their decision to breastfeed had on average 2 years’ more education than those who did not (14.82 years versus 12.94 years).

Although the women did not perceive diabetes as influencing their breastfeeding experiences, they found that maintaining good control of diabetes required greater effort and flexibility during breast feeding.
Diabetes was not a determinant of breast feeding experiences or early exposure to cow’s milk.
Meloni,T.; Marinaro,A.M.; Mannazzu,M.C.; Ogana,A.; La,Vecchia C.; Negri,E.; Colombo,C.

1997

380
Study Type: Case-control

Evidence level: 2+
200

100 children with diabetes and 100 without diabetes who were matched for age and sex.
The study subjects comprised children with type 1 diabetes and controls selected from children admitted at the Department of Pediatrics of the University of Sassari in Italy.

Country: Italy
Intervention:
Risk-factor assessment

Comparison:
Follow-up period:

Outcome Measures:
  1. Duration of complete or partial breastfeeding.
A larger proportion of the children with diabetes rather than the control children had been breastfed.

The risk of type 1 diabetes among children who had not been breastfed was < 1(OR 0.41; 95% CI 0.19 to 0.91).

No clear difference was observed between children with diabetes and those without diabetes in the duration of breastfeeding (medians: 3 and 2 months, respectively).

Although a larger proportion of control children rather than children with diabetes had been given cow's milk-derived formula and solid food before the age of 3 months, there was no time-risk relationship.
The data do not support the existence of a protective effect of breast-feeding on the risk of type 1 diabetes, nor do the data indicate that early exposure to cow's milk and dairy products has any influence on the development of type 1 diabetes in a high- risk population.
Plagemann A, Harder T, Kohlhoff R, Fahrenkrog S, Rodekamp E, Franke K, Dudenhausen JW.

2005

377
Study Type:
Cohort

Evidence level:
2++
242 children of mothers with diabetes.Subjects were participants of the Kaulsdorf Cohort Study, a prospective cohort study on short- and long-term consequences of maternal diabetes during pregnancy and lactation for the children’s development.

Country: Germany
Intervention: Glucose homeostasis monitoring.

Women maintaining mean 24-hour profiles < 5.5 mmol/l were treated with diet, but when a woman’s mean profile was > 5.5 mmol/l, insulin therapy was initiated.

Comparison:
Follow-up period:

Outcome Measures:
  1. Mean maternal blood glucose
  2. Gestational age
  3. Birthweight
  4. Neonatal hypoglycaemia
  5. Apgar score at 1, 5, and 10 min postpartum
Children of mothers with diabetes with early breast milk ingestion achieved early psychomotor developmental milestones (lifting head while prone, following with eyes, P = 0.002).

However, children who had ingested larger volumes of milk of mothers with diabetes had a delayed onset of speaking compared to those with lower milk intake (P = 0.002).
Ingesting larger volumes of milk of mothers with diabetes may normalise early psychomotor development in infants of these mothers, but may delay onset of speaking.
Ratzmann,K.P.; Steindel,E.; Hildebrandt,R.; Kohlhoff,R.

1988

373
Study Type:
Cohort

Evidence level: 2−
22 womenEleven women with type 1 diabetes and 11 age-matched controls without diabetes.

Country: Germany
Intervention: Women with diabetes were treated with intensified conventional insulin therapy according to the standard by Jovanovic and Peterson (1980) by intermediate-acting or multiple injections of short-acting insulin (lente and actrapid).

Comparison:
Control group without insulin therapy.
Follow-up period:

Outcome Measures:
  1. HbA1 values
  2. Birthweight
Although a near- normoglycaemic control of diabetic mothers was accomplished by intensified insulin treatment, the HbA1 value was significantly higher in comparison to non-diabetic mothers (8.1 ± 0.9% versus 6.2 ± 0.5%; P < 0.01).

The glucose concentration of breast milk did not differ between mothers with diabetes and mothers without diabetes (0.68 ± 0.50 versus 0.66 ± 0.55 mmol/l).

No correlation was found between glucose concentration of breast milk and relevant blood glucose concentration as well as HbA1c of the mother.
The data suggest that breastfeeding infants of mothers with diabetes is not associated with an increased glucose concentration in breastmilk and thus is not of importance as a possible mechanism to sustain a hyperinsulinaemic state in newborns.Sample size too small to exclude the role of chance.
Rodekamp,E.; Harder,T.; Kohlhoff,R.; Dudenhausen,J.W.; Plagemann,A.

2006

376
Study Type:
Cohort

Evidence level:
2++
242 children of mothers with diabetes.Subjects were participants of the Kaulsdorf Cohort Study (KCS), a prospective cohort study on short and long-term consequences of maternal diabetes during pregnancy and lactation on the child's development.

Country: Germany
Intervention: Late neonatal intake of breast milk of mothers with diabetes.
Comparison:
Follow-up period: Up to 12 months.

Outcome Measures:
  1. Developmental milestone as measured by Denver Developmental
  2. Onset of speaking
  3. Onset of walking
Ingestion of breast milk delayed onset of speaking: in children who did not take breast milk of mothers with diabetes, the median onset of speaking was 44 weeks (range 31–72 weeks); in children who took some breast milk of mothers with diabetes the median onset of speaking was 48 weeks (range 24–100 weeks);and in children who had only breast milk of mothers with diabetes, the median onset of speaking was 52 weeks (range 28–84 weeks); P = 0.037).

Ingestion of breast milk of mothers with diabetes halved the probability of the time of speaking at any time point (hazard ratio 0.53, 95% CI 0.31 to 0.91).

Adjustment for volume ofbreast milk of mothers withdiabetes ingested during theearly neonatal period weakened the hazard ratio towards non-significance.
Neonatal diabetic breast milk ingestion, particularly during the first week of life, may delay speech development, an important indicator of cognitive development.
van Beusekom,C.M.; Zeegers,T.A.; Martini,I.A.; Velvis,H.J.; Visser,G.H.; van Doormaal,J.J.; Muskiet,F.A.

1993

383
Study Type:
Cohort
Evidence level: 2−
6 women with type 1 diabetesSix women with tightly controlled type 1 diabetes mellitus (median glycosylated haemoglobin concentrations at parturition of 5.2% [range 4.9–5.3%], reference range 4.9– 6.6%) and five women without diabetes

Country: The Netherlands
Intervention:
Insulin treatment
Comparison: Women without diabetes and not receiving insulin.
Follow-up period:
Outcome Measures:
Macronutrients:
  1. Triglycerides
  2. Lactose
  3. Protein
  4. Cholesterol
  5. Glucose
  6. Myoinositol concentrations
  7. Fatty acid composition
  8. Duration of lactation
No abnormalities in concentrations of macronutrients (triglycerides, lactose, and protein), cholesterol, glucose, and myoinositol nor in fatty acid composition were found.

The duration of colostrum lactation was the same for women with diabetes and those without diabetes (3–5 days in both groups).

Two of three longitudinally studied women showed rather constant ratios between glucose concentrations in milk and capillary blood.
The data suggest that there are no differences in macronutrient concentration between tightly controlled glycaemic levels of women with diabetes and those without diabetes.Sample size small, and the role of chance cannot be ruled out

From: Evidence tables

Cover of Diabetes in Pregnancy
Diabetes in Pregnancy: Management of Diabetes and Its Complications from Preconception to the Postnatal Period.
NICE Clinical Guidelines, No. 63.
National Collaborating Centre for Women's and Children's Health (UK).
London: RCOG Press; 2008 Mar.
Copyright © 2008, National Collaborating Centre for Women’s and Children’s Health.

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