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National Collaborating Centre for Women's and Children's Health (UK). Multiple Pregnancy: The Management of Twin and Triplet Pregnancies in the Antenatal Period. London: RCOG Press; 2011 Sep. (NICE Clinical Guidelines, No. 129.)

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Multiple Pregnancy: The Management of Twin and Triplet Pregnancies in the Antenatal Period.

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8Preterm birth

8.1. Predicting the risk of preterm birth

Introduction

Spontaneous preterm birth (associated with preterm, prelabour rupture of the membranes or spontaneous preterm labour) and iatrogenic preterm birth (arising from a medical decision to deliver the baby or babies) occur more frequently in twin and triplet pregnancies than in singleton pregnancies. More than 50% of twins and almost all triplets are born before 37 weeks of gestation and about 15–20% of admissions to neonatal units are associated with preterm twins and triplets. Extreme prematurity (birth at less than 28 weeks of gestation) also occurs more frequently in twin and triplet pregnancies. Prematurity is the biggest cause of adverse neonatal and infant outcomes among twins and triplets compared to singletons, including higher levels of long-term neurodevelopmental problems. Predicting and preventing spontaneous preterm labour and birth are therefore important goals to optimise outcomes of twin and triplet pregnancies.

Review question

What is the optimal screening programme to predict the risks of spontaneous preterm delivery?

Existing NICE guidance

‘Antenatal care’ (NICE clinical guideline 62)14 recommends that healthy women with singleton pregnancies should not be offered routine screening to predict preterm birth.

Description of included studies

Fifteen studies were identified for inclusion.117–131 These investigated the diagnostic accuracy of a variety of measures as predictors of spontaneous preterm birth in twin and triplet pregnancies:

  • fibronectin test
  • additional antenatal care
  • obstetric history
  • composite measures based on the above approaches.

Eight studies reported on cervical length.117–124 One of these was a systematic review of cohort studies,119 four were prospective cohort studies120–123 and three were retrospective cohort studies.117;118;124 Three of the cohort studies were conducted in the UK,120–122 two in the USA,118;123 one in Brazil117 and one in Israel.124 The systematic review,119 included two studies from the UK, five from the USA, one from Denmark and Sweden, and one each from France, Sweden, the Netherlands, Austria, Canada, Egypt and Israel.

Four of the studies (including the systematic review) involved twin pregnancies117–119;122 and the other two involved triplet pregnancies.123;124

One study reported on using just the fetal fibronectin test.126 This study involved twin pregnancies and was conducted in Sweden. One study reported on using the fetal fibronectin test as well as measuring cervical length.125 The results for cervical length from this study were included in the published systematic review 119 and so only the results for fetal fibronectin are reported separately here. This study involved twin pregnancies and was conducted in the UK.

Two studies reported on a composite test of the fetal fibronectin test with cervical length measurement.127;128 One was a prospective cohort study128 while the other was a retrospective cohort study.127 Both involved twin pregnancies and were conducted in the USA.

Two studies examined home uterine activity monitoring in women with twin pregnancies.129;130 One was a meta-analysis of six randomised controlled trials (RCTs) that compared home monitoring with no monitoring as a predictor of preterm birth in twin pregnancies.129 The other was a three-arm RCT that compared home monitoring of uterine activity and daily contact with a nurse with daily contact alone and with weekly contact.130 The RCT was conducted in the USA but the meta-analysis did not report details of the countries where the individual trials were conducted.

One study examined obstetric history as a predictor of preterm birth.131 This study involved women with twin pregnancies whose previous pregnancy had been a preterm singleton pregnancy. The study was a retrospective cohort study and was conducted in the USA.

Published health economic evidence

No published health economic evidence was identified, although this question was prioritised for health economic analysis.

Evidence profiles

Evidence profiles for this question are presented in Tables 8.1 to 8.8. One study122 reported some results for the predictive value of cervical length measurements in the form of diagnostic test accuracy measures and other results in the form of relative risks (RRs). The evidence from this study is, therefore, presented in a separate evidence profile (Table 8.2). The RRs were considered by the GDG, but they did not influence its final recommendations and so Table 8.2 below does not include RRs (see the full evidence profile in Appendix J for these results).

Table 8.1. GRADE summary of findings for cervical length measurement in twin pregnancies (diagnostic accuracy studies reporting diagnostic accuracy measurements only).

Table 8.1

GRADE summary of findings for cervical length measurement in twin pregnancies (diagnostic accuracy studies reporting diagnostic accuracy measurements only).

Table 8.2. GRADE summary of findings for cervical length measurement in twin pregnancies (diagnostic accuracy studies reporting relative risks and diagnostic accuracy measurements).

Table 8.2

GRADE summary of findings for cervical length measurement in twin pregnancies (diagnostic accuracy studies reporting relative risks and diagnostic accuracy measurements).

Table 8.3. GRADE summary of findings for cervical length measurement in triplet pregnancies.

Table 8.3

GRADE summary of findings for cervical length measurement in triplet pregnancies.

Table 8.4. GRADE summary of findings for fetal fibronectin test in twin pregnancies.

Table 8.4

GRADE summary of findings for fetal fibronectin test in twin pregnancies.

Table 8.5. GRADE summary of findings for combined cervical length measurement and fetal fibronectin test in twin pregnancies.

Table 8.5

GRADE summary of findings for combined cervical length measurement and fetal fibronectin test in twin pregnancies.

Table 8.6. GRADE summary of findings for home uterine activity monitoring (with or without nursing contact) versus no monitoring in twin pregnancies.

Table 8.6

GRADE summary of findings for home uterine activity monitoring (with or without nursing contact) versus no monitoring in twin pregnancies.

Table 8.7. GRADE summary of findings for home uterine activity monitoring and daily contact with a nurse versus daily contact alone versus weekly contact in twin pregnancies.

Table 8.7

GRADE summary of findings for home uterine activity monitoring and daily contact with a nurse versus daily contact alone versus weekly contact in twin pregnancies.

Table 8.8. GRADE summary of findings for obstetric history (preterm singleton birth in the previous pregnancy) in twin pregnancies.

Table 8.8

GRADE summary of findings for obstetric history (preterm singleton birth in the previous pregnancy) in twin pregnancies.

Evidence statement

Evidence was identified for cervical length measurement, fibronectin testing, additional antenatal care and previous obstetric history in predicting preterm birth in twin and triplet pregnancies. The quality of the evidence ranged from very low to high.

There was evidence that a short cervical length, especially less than 25 mm, at 18–24 weeks of gestation in twin pregnancies is a good predictor of preterm birth at up to 35 weeks of gestation (high or moderate quality). A short cervix was, however, not predictive of birth before 37 weeks (high quality evidence).

There was evidence that a cervical length less than 25 mm measured at 14–20 weeks in triplet pregnancies was associated with spontaneous preterm birth before 32 weeks (low quality).

There was no association between a positive fetal fibronectin test result and the risk of spontaneous preterm birth in twin pregnancies (moderate to high quality). However, if used in conjunction with cervical length, the ability of the test to identify women who were at a significantly higher risk of preterm birth was improved (very low quality).

There was evidence that home uterine activity monitoring in twin pregnancies was not effective in predicting spontaneous preterm birth (very low to moderate quality).

There was evidence in twin pregnancies that the occurrence of a singleton preterm birth in the previous pregnancy significantly increased the risk of preterm birth in twin pregnancies (very low quality).

Health economics profile

No published health economic evidence was identified, although this question was prioritised for health economic analysis. This question is linked to the question considering effectiveness of interventions to prevent preterm birth once it has been predicted (see Section 8.2). There was evidence that a short cervical length, especially less than 25 mm, between 18 and 24 weeks of gestation in twin pregnancies is a good predictor of a preterm birth at up to 35 weeks; however, a short cervix was not predictive of delivery before 37 weeks. Also, the evidence identified in relation to interventions to prevent preterm birth showed that none of the interventions was clinically effective, and so the GDG did not proceed with the planned health economic analysis.

Evidence to recommendations

Relative value placed on the outcomes considered

Sensitivity is the proportion of pregnancies that resulted in preterm birth that were predicted to be preterm (true positive). One hundred minus sensitivity (100 − sensitivity) shows how many of these pregnancies were predicted to be term at scan (false negative).

Specificity is the proportion of pregnancies that resulted in a term birth that were predicted to be term (true negative). One hundred minus specificity (100 − specificity) shows how many of these pregnancies were predicted to be preterm at scan (false positive).

PPV is the proportion of pregnancies that were predicted to be preterm and that resulted in a preterm birth. One hundred minus PPV (100 − PPV) shows how many of these pregnancies resulted in a term birth.

NPV is the proportion of pregnancies that were predicted to be term that resulted in a term birth. One hundred minus NPV (100 − NPV) shows how many of these pregnancies resulted in a preterm birth.

The positive likelihood ratio (LR+) shows how much the odds of a birth being preterm increase when preterm birth is predicted. The negative likelihood ratio (LR) shows how much the odds of a pregnancy being preterm decrease when a scan predicts term birth.

The GDG prioritised likelihood ratios and sensitivity when considering the evidence for different methods of predicting preterm birth.

Trade-off between clinical benefits and harms

Correctly identifying women who are at risk of preterm birth (true positives) potentially allows more careful monitoring. It allows decisions to be made in consultation with women who are fully aware of the risks involved, including planning for an earlier birth date. If women are predicted to be at risk of preterm birth but then deliver at term (false positives), this may result in unnecessary extra monitoring, which could cause maternal anxiety and unnecessary interventions from healthcare professionals. Correctly identifying women who are not at risk of preterm birth (true negatives) saves resources and prevents anxiety by avoiding unnecessary extra monitoring. It allows the woman and her healthcare team to plan for an accurate birth date. Failing to identify women who go on to miscarry or deliver extremely prematurely (false negatives) could result in the delivery of preterm fetuses in a setting where neonatal facilities are suboptimal: these women would also miss the opportunity for antenatal administration of corticosteroids.

Trade-off between net health benefits and resource use

A more accurate test may be worth an extra cost if there is a way to reduce preterm birth in women who are true positives. The treatments that have been investigated with the intention of preventing preterm birth were not clinically effective (see Section 8.2) and so the GDG did not proceed with the planned health economic analysis. Ultrasound scans cost about £71 and, assuming two scans are conducted for each woman, could cost the NHS around £140 per pregnant woman (no additional scanning appointments would be needed but the duration of these appointments would be increased by approximately 15 minutes per scan, compared with routine antenatal care). The GDG concluded that it could not recommend routine ultrasound scanning to predict preterm birth.

Quality of evidence

All the evidence in triplet pregnancies was low quality. For predicting preterm birth in twin pregnancies the quality of evidence varied, as follows:

Other considerations

Some evidence was identified regarding preterm birth in triplet pregnancies. However, there was not enough evidence to compare the effectiveness of all methods of preventing preterm birth in twin and triplet pregnancies. The ‘Antenatal care’ (NICE clinical guideline 62)14 recommends against screening for preterm birth. The GDG believes that screening for preterm birth is an important consideration in twin and triplet pregnancies as there is a greater risk of preterm birth in such pregnancies. Cervical length measurement of less than 25 mm at 18–24 weeks of gestation in twin pregnancies and 14–20 weeks of gestation in triplet pregnancies predicts the risk of spontaneous preterm birth and the test may be improved further with the addition of fetal fibronectin. However, the GDG does not recommend that this test is undertaken routinely in twin or triplet pregnancies because no effective interventions to reduce this risk have been identified (see Section 8.2) and testing can create anxiety or offer false reassurance.

Recommendations

NumberRecommendation
47Be aware that women with twin pregnancies have a higher risk of spontaneous preterm birth if they have had a spontaneous preterm birth in a previous singleton pregnancy.
48Do not use fetal fibronectin testing alone to predict the risk of spontaneous preterm birth in twin or triplet pregnancies.
49Do not use home uterine activity monitoring to predict the risk of spontaneous preterm birth in twin or triplet pregnancies.
50Do not use cervical length (with or without fetal fibronectin) routinely to predict the risk of spontaneous preterm birth in twin or triplet pregnancies.
NumberResearch recommendation
RR 12Which clinical factors or laboratory tests are accurate predictors of spontaneous preterm birth in twin and triplet pregnancies?
Why this is important
Prematurity is the major contributor to increased adverse neonatal and infant outcomes in twin and triplet pregnancies (compared with singleton pregnancies), and being able to predict spontaneous preterm birth is an important goal to optimise outcomes of twin and triplet pregnancies for women and their babies. Several studies were identified in the guideline review in relation to accuracy of prediction of spontaneous preterm birth in twin and triplet pregnancies. The studies evaluated tests based on cervical length, fetal fibronectin, additional antenatal care, and obstetric history (preterm singleton birth in a previous pregnancy), and included composite measures based on the above tests. Most of the studies were observational in design (prospective or retrospective cohort studies), and few examined predictors of preterm birth in triplet pregnancies or the effects of chorionicity. Large, prospective studies are, therefore, needed to evaluate the accuracy of each of the tests as predictors of spontaneous preterm birth in twin and triplet pregnancies, with subgroup analysis by chorionicity.

8.2. Preventing preterm birth

Introduction

Spontaneous preterm birth and iatrogenic preterm birth that are secondary to other complications occur more frequently in twin and triplet pregnancies than in singleton pregnancies. Preterm birth (even near-term birth) is associated with considerable morbidity and use of healthcare resources, with many preterm babies being admitted to neonatal units. Extremely preterm birth (at less than 28 weeks of gestation) is associated with even greater morbidity and mortality and greater use of healthcare resources. It is, therefore, relevant to identify treatments which prevent spontaneous preterm birth without causing adverse effects in the woman or babies.

Review question

What interventions are effective in preventing spontaneous preterm delivery in multiple pregnancy, including bed rest, progesterone and cervical cerclage?

Existing NICE guidance

No existing NICE guidance was identified as being relevant to preventing spontaneous preterm birth, although ‘Diabetes in pregnancy’ (NICE clinical guideline 63)21 recommends using an alternative to betamimetics when tocolysis (administration of drugs to inhibit uterine contractions) is indicated in women with diabetes.

Overview of the evidence

Eighteen studies were identified for inclusion.132–149 The studies investigated the clinical effectiveness of the following interventions to prevent preterm birth in women with twin and triplet pregnancies:

Where evidence from systematic reviews of RCTs or individual RCTs was identified in relation to a particular intervention and associated outcomes prioritised for consideration by the GDG, evidence from study designs lower in the hierarchy of evidence (such as observational studies, including cohort studies and case–control studies) was excluded.

Women in two studies were advised to abstain from sexual intercourse. In one study that investigated hospital bed rest versus home bed rest, women in the intervention group only were advised to abstain from intercourse.134 In another study that investigated the effectiveness of vaginal progesterone in twin pregnancies, both the intervention and control groups were advised to abstain from intercourse.139

Bed rest

A Cochrane review reported meta-analysis of evidence relating to the effectiveness of routine hospital bed rest compared to no bed rest for preventing preterm birth in women with twin and triplet pregnancies.132 The review included six RCTs and one quasi-randomised controlled trial; five of the studies involved women with twin pregnancies and two involved women with triplet pregnancies. One of the RCTs was conducted in Finland, two in Australia and four in Zimbabwe.

One retrospective observational study, conducted in Denmark and involving women with twin pregnancies, compared hospital bed rest with bed rest at home or with no bed rest at all.133 Another retrospective study, conducted in the USA, involved women with triplet pregnancies and also compared hospital bed rest with home bed rest but, in addition, all women in the study were advised to discontinue vaginal intercourse at 20 weeks of gestation.134

One RCT examined the effectiveness of hospital bed rest and prophylactic oral salbutamol (as a combined intervention) compared to hospitalisation for bed rest alone.135 The study involved women with twin and triplet pregnancies and was conducted in Finland.

Progesterone

Seven RCTs evaluated the clinical effectiveness of progesterone compared to placebo in the prevention of preterm birth in women with twin or triplet pregnancies.136–142

Five of the studies reported data separately for spontaneous preterm birth.136;137;139;140;142 One study did not specify whether or not the reported preterm birth data included iatrogenic preterm births,138 and in another study, data for preterm birth and intrauterine death were reported together.141 This last study reported clinical effectiveness data from the Study of Progesterone for the Prevention of Preterm Birth in Twins (STOPPIT; a double blind, randomised, placebo-controlled study; see https://www.charttrials.abdn.ac.uk/stoppit/). A published economic evaluation relating to STOPPIT was identified separately (see later).150

Two of the six studies reported on daily vaginal progesterone gel and they were conducted in the UK.139;141 The other studies reported on weekly intramuscular progesterone:136–138;140;142 one of these studies was conducted in Finland136 and the other four in the USA.137;138;140;142

Two of the RCTs involved women with triplet pregnancies140;142 and the other five involved women with twin pregnancies.136–139;141

Cervical cerclage

One RCT,143 one prospective observational study144 and four retrospective observational studies145–148 evaluated the effectiveness of cervical cerclage in the prevention of preterm birth in women with twin or triplet pregnancies.

The RCT was conducted in Israel and involved women with twin pregnancies conceived after ovulation induction.143 Women in the intervention group underwent elective cervical suture (McDonald) at 13 weeks of gestation and they were compared with a control group who received no cervical suture.

The prospective observational study involved women with a short cervix, all of whom rested at home or in the hospital.144 The study was conducted in the USA. The other four studies used a retrospective cross-sectional review of medical records of women with triplet pregnancies who had undergone cervical cerclage compared to women who had not.145–148 Three of the studies were conducted in the USA145–147 and one in Israel.148

Tocolytic therapy

A Cochrane review involving women with twin pregnancies assessed the clinical effectiveness of prophylactic tocolytic therapy.149 The review included five RCTs, each examining a different betamimetic agent (salbutamol, feneterol, isoxurpine, ritodrine or terbutaline). The trials were conducted in the UK, Ireland, Sweden, South Africa and Zimbabwe.

No studies examining the role of other tocolytic agents were identified for inclusion.

Sexual abstinence

No studies examining the effectiveness of sexual abstinence alone were identified for inclusion.

Published health economic evidence

One published health economic evaluation was identified in relation to this question,150 which was prioritised for health economic analysis. The published economic evaluation related to STOPPIT, for which a separate publication reporting clinical effectiveness data only141 was included in the review of clinical evidence (see above). The main outcomes of the STOPPIT trial were birth or fetal death before 34 weeks of gestation. The use of progesterone in this population of women did not reduce the incidence of preterm birth. There was a tendency towards increased neonatal stay in special care units in the progesterone group. The mean hospital costs for the progesterone group were about £28,000 compared to £25,000 in the placebo group.

Cost effectiveness acceptability curves reported in the economic evaluation showed the probability of prophylactic vaginal progesterone being cost effective as a function of the decision makers’ willingness to pay to prevent a case of spontaneous preterm birth against the alternative of not providing prophylactic progesterone. In the health economic analysis, progesterone was 20% cost effective at a willingness to pay value of £30,000 per preterm birth prevented. The net benefit statistic confirmed the finding that progesterone was unlikely to be cost effective at £30,000 per preterm birth prevented, as the net benefit was negative (−£3,637, 95% CI−£3,853 to −£3,420), meaning that there would be a financial loss to the health service. The authors calculated the expected value of perfect information, which showed that using placebo consistently produced higher net health benefits.

The authors of the economic evaluation concluded that the probability of prophylactic vaginal progesterone being cost effective was low in women with twin pregnancies, and sensitivity analysis showed the findings to be robust. This was a well conducted and presented health economic analysis. The study did not consider quality adjusted life years (QALYs) as an outcome, although the QALY is NICE’s preferred measure of outcome. However, the GDG believes the QALY approach would be unlikely to change the conclusions of the analysis, since preterm birth and fetal death are good proxies for the quality and quantity of life that would be needed to calculate QALYs.

Evidence profiles

Evidence profiles for this question are presented in Tables 8.9 to 8.18.

Table 8.9. GRADE summary of findings for routine hospitalisation for bed rest versus no bed rest for the prevention of spontaneous preterm birth in twin pregnancies.

Table 8.9

GRADE summary of findings for routine hospitalisation for bed rest versus no bed rest for the prevention of spontaneous preterm birth in twin pregnancies.

Table 8.10. GRADE summary of findings for routine hospitalisation for bed rest versus no bed rest for the prevention of spontaneous preterm birth in triplet pregnancies.

Table 8.10

GRADE summary of findings for routine hospitalisation for bed rest versus no bed rest for the prevention of spontaneous preterm birth in triplet pregnancies.

Table 8.11. GRADE summary of findings for hospital bed rest versus home bed rest for the prevention of spontaneous preterm birth in twin pregnancies.

Table 8.11

GRADE summary of findings for hospital bed rest versus home bed rest for the prevention of spontaneous preterm birth in twin pregnancies.

Table 8.12. GRADE summary of findings for hospital bed rest versus home bed rest (with advice for women in both groups to discontinue vaginal intercourse at 20 weeks of gestation for the prevention of spontaneous preterm birth in triplet pregnancies.

Table 8.12

GRADE summary of findings for hospital bed rest versus home bed rest (with advice for women in both groups to discontinue vaginal intercourse at 20 weeks of gestation for the prevention of spontaneous preterm birth in triplet pregnancies.

Table 8.13. GRADE summary of findings for hospital bed rest and oral salbutamol versus hospital bed rest only for the prevention of spontaneous preterm birth in twin and triplet pregnancies.

Table 8.13

GRADE summary of findings for hospital bed rest and oral salbutamol versus hospital bed rest only for the prevention of spontaneous preterm birth in twin and triplet pregnancies.

Table 8.14. GRADE summary of findings for intramuscular or vaginal progesterone versus placebo for the prevention of spontaneous preterm birth in twin pregnancies.

Table 8.14

GRADE summary of findings for intramuscular or vaginal progesterone versus placebo for the prevention of spontaneous preterm birth in twin pregnancies.

Table 8.15. GRADE summary of findings for intramuscular progesterone versus placebo for the prevention of spontaneous preterm birth in triplet pregnancies.

Table 8.15

GRADE summary of findings for intramuscular progesterone versus placebo for the prevention of spontaneous preterm birth in triplet pregnancies.

Table 8.16. GRADE summary of findings for cervical cerclage versus no cerclage for the prevention of spontaneous preterm birth in twin pregnancies.

Table 8.16

GRADE summary of findings for cervical cerclage versus no cerclage for the prevention of spontaneous preterm birth in twin pregnancies.

Table 8.17. GRADE summary of findings for cervical cerclage versus no cerclage for the prevention of spontaneous preterm birth in triplet pregnancies.

Table 8.17

GRADE summary of findings for cervical cerclage versus no cerclage for the prevention of spontaneous preterm birth in triplet pregnancies.

Table 8.18. GRADE summary of findings for oral betamimetics versus placebo for the prevention of spontaneous preterm birth in twin pregnancies.

Table 8.18

GRADE summary of findings for oral betamimetics versus placebo for the prevention of spontaneous preterm birth in twin pregnancies.

Evidence statement

Evidence was identified for all outcomes prioritised in relation to the interventions used to prevent preterm birth in twin and triplet pregnancies, although the studies varied in the number of outcomes reported. The quality of the evidence was mostly low or very low, with some being of moderate or high quality.

Bed rest

In twin pregnancies, routine hospitalisation for bed rest had no significant effect on the following compared with no bed rest:

  • spontaneous preterm birth before 37 weeks of gestation (very low quality evidence)
  • gestational age at birth (moderate quality evidence)
  • perinatal mortality (very low quality evidence)
  • caesarean section rates (moderate quality evidence)
  • admission to neonatal care unit (moderate quality evidence)
  • low birthweight (moderate quality evidence)
  • very low birthweight (low quality evidence)
  • neonatal stay of 7 days or more (moderate quality evidence).

The hospital bed rest group showed significantly fewer spontaneous births before 34 weeks of gestation in one study (very low quality evidence), but not in another (very low quality evidence). Compared to bed rest at home, hospital bed rest also had no significant effect on spontaneous preterm birth or perinatal mortality (very low quality evidence).

In triplet pregnancies, routine hospitalisation for bed rest had no significant effect on the following compared with no bed rest:

  • spontaneous preterm birth (low quality evidence)
  • gestational age at birth (moderate quality evidence
  • perinatal mortality (moderate quality evidence)
  • caesarean section rates (moderate quality evidence)
  • admission to neonatal care unit (moderate quality evidence)
  • low birthweight (moderate quality evidence)
  • very low birthweight (moderate quality evidence)
  • neonatal stay of 7 days or more (moderate quality evidence).

Compared with bed rest at home, hospital bed rest had no significant effect on:

  • gestational age at birth (very low quality evidence)
  • perinatal mortality (very low quality evidence)
  • maternal length of stay (very low quality evidence)
  • caesarean section rates (very low quality evidence)
  • neonatal respiratory distress syndrome rates (very low quality evidence)
  • necrotising enterocolitis (very low quality evidence)
  • neonatal length of stay (very low quality of evidence).

The hospital bed rest group had a lower incidence of neonatal intraventricular haemorrhage than the home bed rest group when intraventricular haemorrhage grades 1 to 4 were pooled (very low quality evidence). There was, however, no effect on the incidence of the more severe grades (grades 3 and 4) when these were considered alone (very low quality evidence). Both bed rest groups also had advice to discontinue vaginal intercourse at 20 weeks of gestation.

For twin and triplet pregnancies, routine hospitalisation for bed rest combined with maternal oral salbutamol had no significant effect on spontaneous preterm birth (low quality evidence), perinatal mortality (moderate quality evidence), low or very low birthweight (moderate quality evidence) or neonatal respiratory distress syndrome (low quality evidence) compared to hospital bed rest alone.

Progesterone

In twin pregnancies, when compared with placebo, progesterone (intramuscular or vaginal) had no significant effect on:

  • spontaneous preterm birth (very low or moderate quality evidence)
  • gestational age at birth (moderate quality evidence)
  • perinatal mortality (very low quality evidence)
  • caesarean section rates (moderate quality evidence)
  • maternal side effects (high quality evidence)
  • maternal satisfaction (moderate quality evidence)
  • maternal quality of life (moderate quality evidence)
  • admission to neonatal care unit (low quality evidence)
  • low birthweight (high quality evidence)
  • very low birthweight (moderate quality evidence)
  • neonatal respiratory distress syndrome (low quality evidence)
  • neonatal intraventricular haemorrhage (low quality evidence)
  • neonatal necrotising enterocolitis (low quality evidence)
  • neonatal stay (low quality evidence).

In triplet pregnancies, when compared with placebo, intramuscular progesterone had no significant effect on:

  • spontaneous preterm birth (low quality evidence)
  • gestational age at birth (low quality evidence)
  • perinatal mortality (low and very low quality evidence)
  • caesarean section rates (very low quality evidence)
  • low birthweight (moderate quality evidence)
  • very low birthweight (low quality evidence)
  • neonatal respiratory distress syndrome (very low quality evidence)
  • neonatal intraventricular haemorrhage (low quality evidence)
  • neonatal necrotising enterocolitis (low quality evidence)
  • neonatal length of stay in hospital (low quality evidence).
Cervical cerclage

In twin pregnancies, cervical cerclage had no significant effect on caesarean section rate (low quality evidence) or spontaneous preterm birth, gestational age at birth, perinatal mortality or very low birthweight (all very low quality evidence) compared with no cerclage.

In triplet pregnancies, cervical cerclage had no significant effect on the following when compared to no cerclage:

  • spontaneous preterm birth (very low quality evidence)
  • gestational age at birth (low quality evidence)
  • perinatal mortality (very low quality evidence)
  • admission to neonatal intensive care unit (low quality evidence)
  • very low birthweight (very low quality evidence)
  • extremely low birthweight (very low quality evidence)
  • neonatal respiratory distress syndrome (very low quality evidence)
  • neonatal intraventricular haemorrhage (very low quality evidence)
  • or neonatal length of stay (low quality evidence).
Tocolytic therapy

In twin pregnancies, oral betamimetics had no significant effect on spontaneous preterm birth (low and very low quality evidence), perinatal mortality (very low quality evidence) or low birthweight (low quality evidence) compared to placebo. However, there was a significantly lower incidence of neonatal respiratory distress syndrome in the group receiving tocolytic therapy compared to the placebo group (low quality evidence).

No studies were identified that examined the role of other tocolytic agents in twin pregnancies.

No studies were identified that examined the role of tocolytic agents in preventing preterm birth in triplet pregnancies.

Sexual abstinence

No studies were identified that examined sexual abstinence alone.

Health economics profile

One well-conducted health economic analysis was identified for inclusion and this concluded that the probability of prophylactic vaginal progesterone being cost effective in women with twin pregnancies is low. The findings were shown to be robust in sensitivity analysis.

This question was prioritised for further health economic evaluation. The question is linked to the question considering tests to predict preterm birth (see Section 8.1), in that this question addresses the cost effectiveness of interventions to prevent preterm birth once it has been predicted. None of the interventions considered for preventing preterm birth, including bed rest, cervical cerclage, progesterone and tocolytic drugs, was found to be clinically effective and so a formal health economic analysis was not required. Data from NHS reference costs show that a cervical cerclage procedure will cost the NHS about £320, while the British National Formulary (BNF) 59 shows that tocolytic drugs will cost £56 on average and progesterone £90 per pregnant woman. Given that the interventions are not clinically effective, these resources could be used for other more clinically effective and, therefore, cost-effective interventions.

Evidence to recommendations

Relative value placed on the outcomes considered

Primary outcomes:

  • neonatal:
  • maternal:
    • length of stay
    • maternal side effects (infection, haemorrhage, drug effects, tachycardia, caesarean section).

Secondary outcomes:

The GDG considered all outcomes to be important but believed perinatal mortality to be the most critical.

Trade-off between clinical benefits and harms

Preventing preterm birth can lead to better short- and long-term outcomes for the baby. This will also result in less use of healthcare resources. The clinical harms associated with preventing preterm birth include keeping a woman in an environment she does not wish to be in (for example, hospitalisation for bed rest), which may not be beneficial in the long term. Interventions may have unexpected adverse side effects for women and babies, and may result in higher preterm labour rates.

Trade-off between net health benefits and resource use

This review question was prioritised for health economic analysis but there was no evidence of clinical effectiveness for any of the interventions considered by the GDG (bed rest at home or in hospital, intramuscular or vaginal progesterone, cervical cerclage, oral tocolytics or sexual abstinence) and so no formal health economic analysis was conducted because the GDG was not going to recommend use of any of the interventions. NHS reference costs show that cervical cerclage will cost the NHS about £320 while BNF 59 shows that tocolytic drugs will cost on average £56 and progesterone £90 per pregnant woman. These cost data illustrate that these are expensive interventions that should not be used. Given that the interventions are not clinically effective, these resources could be freed for more clinically effective, and hence cost-effective, interventions.

Quality of evidence

Evidence for bed rest ranged from very low to moderate quality (mainly low); for progesterone from very low to high quality (mainly low); for cervical cerclage it was very low or low quality; and for tocolytics (oral betamimetics) it was low or very low quality.

Other considerations

Although the GDG recommended that bed rest (at home or in hospital), intramuscular or vaginal progesterone, cervical cerclage and oral tocolytics should not be used routinely to prevent spontaneous preterm birth in twin or triplet pregnancies, this does not preclude their use when clinically indicated (that is, targeted use appropriate to individual circumstances).

It was not possible to determine whether chorionicity affected the effectiveness of the methods used to prevent preterm birth.

Since the GDG had identified some evidence to suggest that the risk of spontaneous preterm birth could be predicted accurately (see Section 8.1), the group included a recommendation for further research to evaluate interventions for preventing spontaneous preterm birth in women with twin and triplet pregnancies, including those at high risk.

Recommendations

NumberRecommendation
51Do not use the following interventions (alone or in combination) routinely to prevent spontaneous preterm birth in twin or triplet pregnancies:
NumberResearch recommendation
RR 13What interventions are effective in preventing spontaneous preterm birth in women with twin and triplet pregnancies, especially in those at high risk of preterm birth?
Why this is important
The guideline review considered several interventions aimed at preventing spontaneous preterm birth in women with twin and triplet pregnancies, including cervical cerclage, tocolytic drugs and sexual abstinence. The existing evidence for the effectiveness of cervical cerclage is of low quality (mostly originating from observational studies). The existing evidence in relation to tocolytics is also limited: there is evidence for the effectiveness of betamimetics, but no randomised controlled trials were identified for the effectiveness of ritodrine, magnesium sulphate or nifedipine. No evidence was identified for the effectiveness of sexual abstinence alone in preventing preterm birth.
Further research in the form of randomised controlled trials is, therefore, needed to evaluate the effectiveness of cervical cerclage, tocolytics other than betamimetics, and sexual abstinence. Future research should place particular emphasis on women at high risk of preterm birth in twin and triplet pregnancies. Some evidence suggested that a cervical length of less than 25 mm at 18–24 weeks of gestation in twin pregnancies or 14–20 weeks of gestation in triplet pregnancies, or a history of preterm labour in singleton pregnancies, increases the risk of spontaneous preterm birth in twin and triplet pregnancies. The evidence was limited in quality and additional research into the predictive accuracy of these factors would inform future NICE guidance. All research into the prevention of preterm birth should report spontaneous preterm birth separately from other preterm births. Data should also be reported separately for twin and triplet pregnancies, for different chorionicities, and for different gestational ages at birth (that is, less than 28 weeks, between 28 and less than 32 weeks, and 32–37 weeks).

8.3. Untargeted corticosteroids

Introduction

It is well established that antenatal administration of corticosteroids reduces neonatal complications in preterm babies resulting from singleton pregnancies. Since the risk of preterm birth is increased in twin and triplet pregnancies, consideration should be given to whether routine antenatal administration of corticosteroids (when preterm birth is not expected imminently) is effective in reducing neonatal complications in twin and triplet pregnancies. Since the interval between antenatal administration of corticosteroids and birth reduces their effectiveness, and recognising the difficulty in predicting time of birth in twin and triplet pregnancies, consideration should also be given to the effectiveness of multiple courses of corticosteroids in high-risk twin and triplet pregnancies, including those at higher risk of preterm birth.

However, a Cochrane review of studies involving singleton pregnancies showed a reduction in birthweight and head circumference in babies of women who received multiple courses of corticosteroids compared to those who received single courses.151 Furthermore, there is a lack of evidence about the long-term benefits and risks152 and there is evidence from retrospective studies that corticosteroids are less effective in multiple pregnancies than in singleton pregnancies.

This review question aims to establish whether routine (untargeted) courses of corticosteroids are effective in reducing perinatal morbidity in twin and triplet pregnancies.

Review question

Is routine/elective antenatal corticosteroid prophylaxis effective in reducing perinatal morbidity, including neonatal respiratory distress syndrome, necrotising colitis and intravenous haemorrhage, in multiple pregnancy?

Existing NICE guidance

No existing NICE guidance was identified as being relevant to this review question.

Overview of the evidence

Four studies were identified for inclusion for this question.153–156 The studies comprised one RCT155 and three observational studies.153;154;156

The RCT was a multicentre trial conducted at 80 centres in 20 countries (Argentina, Bolivia, Brazil, Canada, Chile, China, Colombia, Denmark, Germany, Hungary, Israel, Jordan, Peru, Poland, Russia, Spain, Switzerland, Netherlands, UK and the USA).155 The study of 1858 pregnant women included 320 women with twin pregnancies and 70 women with triplet pregnancies. All of the pregnancies were at 25–32 weeks of gestation and the women had already completed a course of antenatal corticosteroids. If birth did not take place 14–21 days after the initial course, the women were randomly assigned to repeated courses of intramuscular betamethasone or to a placebo every 2 weeks until 33 weeks of gestation or birth. The ethnicity of the women and the chorionicity of the pregnancies were not reported.

Two of the observational studies were conducted in the UK.153;156 One was a retrospective cohort study of 1038 twin pregnancies (including 137 monochorionic twin pregnancies), comparing women who received repeated courses of dexamethasone prophylaxis (route of administration not reported) every 2 weeks from 24 to 32 weeks of gestation with those who received corticosteroids as rescue therapy when there was an immediate risk of preterm birth.156 The ethnicity of the women involved in the study was not reported. The other study was a retrospective case note review of 173 triplets, comparing three groups:153

The fourth study was a prospective cohort study conducted in Kuwait.154 The study involved twin, triplet and quadruplet pregnancies. For some outcomes, data were not reported separately for triplet and quadruplet pregnancies and so triplet data could not be extracted for the guideline for every outcome reported in the study. Half of the 44 twin pregnancies received routine dexamethasone (route of administration not reported) and half received no drug. The gestational age at which corticosteroid treatment started was not reported. The ethnicity of the women and the chorionicity of the pregnancies were not reported.

Published health economic evidence

No published health economic evidence was identified and this question was not prioritised for health economic analysis.

Evidence profiles

Evidence profiles for this question are presented in Tables 8.19 to 8.22.

Table 8.19. GRADE summary of findings for routine single course of corticosteroids versus no routine corticosteroids.

Table 8.19

GRADE summary of findings for routine single course of corticosteroids versus no routine corticosteroids.

Table 8.20. GRADE summary of findings for routine multiple courses of corticosteroids versus no routine corticosteroids.

Table 8.20

GRADE summary of findings for routine multiple courses of corticosteroids versus no routine corticosteroids.

Table 8.21. GRADE summary of findings for routine multiple courses of corticosteroids versus routine single course of corticosteroids.

Table 8.21

GRADE summary of findings for routine multiple courses of corticosteroids versus routine single course of corticosteroids.

Table 8.22. GRADE summary of findings for routine multiple courses of corticosteroids versus targeted (rescue) corticosteroids.

Table 8.22

GRADE summary of findings for routine multiple courses of corticosteroids versus targeted (rescue) corticosteroids.

Evidence statement

Limited evidence was identified for the effectiveness of routine (elective) corticosteroids for reducing perinatal morbidity in twin and triplet pregnancies. The evidence compared different aspects of treatment and was mostly very low in quality.

The evidence that was reported addressed neonatal mortality, neurodevelopmental outcomes at 1 year, respiratory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis, neonatal length of stay, birthweight and composites of these outcomes.

No studies were identified that examined development of gestational diabetes, development of gestational hypertension, maternal satisfaction or neurodevelopmental outcomes after 1 year in twin or triplet pregnancies treated with corticosteroids.

The corticosteroids for which data were reported were betamethasone and dexamethasone. No data were reported that allowed a direct comparison between the two corticosteroids, between different routes of administration for the same corticosteroid or between different doses of the same corticosteroid. There were limited data comparing the number of courses of dexamethasone or betamethasone, with a single course showing a lower mortality rate than multiple courses (very low quality evidence). However, the significance of the difference was not reported.

Routine single course of corticosteroids compared to no corticosteroids (or suboptimal course)

There were significantly fewer perinatal and neonatal deaths and significantly fewer babies with respiratory distress syndrome among twins in the corticosteroid group (very low quality evidence). There was inconsistent evidence that corticosteroids may be associated with differences in birthweight at different gestational ages, but this did not impact on the improved outcome as a result of the use of corticosteroids.

In twins, there was no significant difference between the groups in length of stay in the neonatal intensive care unit (very low quality evidence).

Routine multiple courses of corticosteroids compared to no corticosteroids (or suboptimal course)

There were significantly fewer perinatal and neonatal deaths in triplet pregnancies in the group that received multiple courses of corticosteroids, but gestational age at birth was the only independent predictor of survival (very low quality evidence).

No evidence was identified for effectiveness of multiple courses of corticosteroids by themselves in twin pregnancies.

Routine multiple courses of corticosteroids compared to routine single course

There was no significant difference in a composite score of neonatal mortality and morbidity in twin and triplet pregnancies (low quality evidence).

Routine multiple courses of corticosteroids compared to targeted (rescue) corticosteroids

There were no significant differences in perinatal and neonatal mortality or neonatal length of stay between twins in the group that received multiple courses of routine corticosteroids and those that received targeted (rescue) corticosteroids (low and very low quality evidence). There was no significant difference in the incidence of respiratory distress syndrome, intraventicular haemorrhage or necrotising enterocolitis (very low quality evidence).

The birthweights of twins whose mothers received multiple courses of corticosteroids were significantly higher than those of babies whose mothers received a targeted course (low quality evidence), but this may have been due to the later gestational age at delivery in the group that received multiple courses.

Routine single course of corticosteroids compared to targeted (rescue) corticosteroids

No evidence was identified for the effectiveness of a single course of corticosteroids compared to targeted corticosteroids in twin or triplet pregnancies.

Health economics profile

No published health economic evidence was identified and this question was not prioritised for health economic analysis.

Evidence to recommendations

Relative value placed on the outcomes considered

All outcomes specified in the review protocol, including neonatal mortality and morbidity (respiratory distress syndrome, necrotising enterocolitis, intraventricular haemorrhage) and long-term neurodevelopmental outcomes, were considered by the GDG to be critical to the formulation of recommendations for clinical practice. Birthweight was considered a particularly important outcome given the potential harm of multiple courses of corticosteroids.

Trade-off between clinical benefits and harms

No clear evidence of benefit in giving routine single or multiple courses of antenatal corticosteroids in twin or triplet pregnancies was identified and there is limited evidence of harm from multiple courses compared to no treatment or targeted (rescue) treatment. However, the effect of corticosteroids on long-term neurodevelopmental outcomes is unknown.

Trade-off between net health benefits and resource use

The cost impact and opportunity costs of using corticosteroids prophylactically can be significant. Intramuscular corticosteroids cost up to £4.70 per dose and oral corticosteroids cost up to £1.40 per dose. If multiple doses were to be used (in one of the included studies up to eight doses were used) a course of treatment could cost almost £40 per pregnant woman. A recommendation not to use routine antenatal corticosteroid prophylaxis in twin and triplet pregnancies will save the NHS money because routine antenatal corticosteroid prophylaxis is sometimes used in current practice.

Quality of evidence

Few studies were identified for inclusion, with only one being an RCT. The resulting body of evidence considered by the GDG was generally of very low quality. The evidence for perinatal and neonatal mortality was very low in quality, as was the evidence for long-term neurodevelopmental outcomes, respiratory distress syndrome, intraventricular haemorrhage and necrotising enterocolitis. The evidence for a composite of mortality and morbidity was low in quality. Evidence for birthweight and neonatal length of stay was low quality.

Other considerations

The majority of the studies identified did not report chorionicity and no studies reported ethnicity. Some evidence specific to triplet pregnancies was identified, although most studies focused on twin pregnancies. It is not possible to extrapolate twin data to triplets because triplets have a higher preterm birth rate. There was very little evidence in relation to choice of corticosteroids (for example betamethasone or dexamethasone), dosages or route of administration, or gestational age at administration or delivery. The studies identified were of poor quality and significant differences in birthweight between corticosteroid and no corticosteroid groups may be due to corticosteroid exposure.

It is unclear whether antenatal corticosteroids should be given routinely or targeted. There is no strong evidence of the benefit or harm of a single course of corticosteroids compared to multiple courses in twin and triplet pregnancies. A recommendation not to use antenatal corticosteroids routinely (as prophylaxis) in twin and triplet pregnancies does not preclude targeted (or rescue) administration when indicated (for example when preterm labour or birth is imminent).

The GDG considered reporting of gestational age at birth to be very important as differences in gestational age may account for some observed differences in outcomes: in one study, logistic regression showed that gestational age was the best predictor of survival.153 The incidence of respiratory distress syndrome was very high in the control and experimental groups in another study,154 and no explanation was provided by the study authors.

Recommendations

NumberRecommendation
52Inform women with twin and triplet pregnancies of their increased risk of preterm birth and about the benefits of targeted corticosteroids.
53Do not use single or multiple untargeted (routine) courses of corticosteroids in twin or triplet pregnancies. Inform women that there is no benefit in using untargeted administration of corticosteroids.
NumberResearch recommendation
RR 14What is the clinical and cost effectiveness, and safety, of routine antenatal administration of a single course of corticosteroids for women with twin and triplet pregnancies who are not in labour and in whom labour and birth are not imminent?
Why this is important
The evidence reviewed for the guideline is limited and of poor quality. The only evidence from randomised controlled trials relates to twin pregnancies investigated through subgroup analysis in a trial comparing a routine (prophylactic) single course of corticosteroids to routine multiple courses. No evidence was identified in relation to chorionicity, ethnicity, or acceptability of corticosteroid administration in women with twin or triplet pregnancies, or incidence of gestational hypertension or gestational diabetes following administration of corticosteroids. Further research in the form of large, prospective randomised controlled trials is, therefore, needed to evaluate the effectiveness of routine antenatal administration of a single course of corticosteroids compared to no (routine) corticosteroids for women with twin and triplet pregnancies. The research should address each of the following factors: acceptability of corticosteroid administration to women with twin or triplet pregnancies; effectiveness in terms of reducing perinatal mortality and morbidity and long-term physical and neurodevelopmental outcomes; subgroup analyses for twin and triplet pregnancies and for different chorionicities; whether a short cervix is an indication for receiving routine (prophylactic) corticosteroids; timing of corticosteroid administration (in terms of gestational age) if it is to be offered.
Copyright © 2011, National Collaborating Centre for Women’s and Children’s Health.

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