Which intervention reduces the risk of preterm birth in women with risk factors?BMJ 2016; 355 doi: http://dx.doi.org/10.1136/bmj.i5206 (Published 05 October 2016) Cite this as: BMJ 2016;355:i5206
- Sarah J Stock, senior clinical lecturer in maternal and fetal medicine1,
- Khaled M K Ismail, professor of obstetrics and gynaecology2
- 1Tommy’s Centre for Maternal and Fetal Health, MRC Centre for Reproductive Health, University of Edinburgh Queen’s Medical Research Institute, Edinburgh, UK
- 2Birmingham Centre for Women’s and Children’s Health, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
- Correspondence to: K M K Ismail
What you need to know
The best intervention for prevention of spontaneous preterm birth in women with risk factors is still unclear
In women with a singleton pregnancy risk of preterm birth and with a short cervix, the evidence for use of cervical cerclage is clearer than that for progesterone or cervical pessary
Discuss with parents that prevention of preterm delivery might not necessarily translate into improved health in children
The aim of preventing preterm birth is to improve the health of babies by prolonging pregnancy. Preterm birth, or delivery before 37 weeks’ gestation, affects 7.3% of pregnancies in the UK.1 Around 75% of these births result from spontaneous preterm labour. The remaining 25% are delivered for medical reasons and are not considered further in this article.
Who is at risk?
Box 1 lists clinical risk factors and ultrasound scan findings that are associated with an increased risk of spontaneous preterm birth. However, these factors have poor predictive value. Women with multiple pregnancy are also at high risk of preterm birth, and their management is discussed in the supplementary online material.
History of mid-trimester loss
Preterm prelabour rupture of membranes in a previous pregnancy
Preterm birth in a previous pregnancy
History of cervical treatment for cervical intraepithelial neoplasia
Short cervix (<25 mm) on transvaginal ultrasound examination
*The presence of any of the clinical risk factors listed can be considered a trigger for screening of cervical length by transvaginal ultrasound scan
Appraising the evidence
Three treatment interventions are available to women at risk of spontaneous preterm birth (fig 1⇓). Considerable uncertainty exists over the effectiveness of these interventions, however, in part because clinical trials are hard to perform. Large numbers of trial participants are needed because most women at high risk of spontaneous preterm birth deliver at term, even without treatment. It is difficult and expensive to include neonatal and childhood outcomes in trials, therefore, trials mainly focus on rates of preterm birth, and not on longer term health outcomes of babies. Furthermore, inconsistencies in definitions, inclusion criteria, and outcomes in studies make it difficult to summarise trial data in meta-analyses and interpret relevance of the findings to individual women in the clinic setting.
What is the evidence of uncertainty?
Table 1⇓ provides a summary of evidence surrounding the effectiveness of interventions available to women at risk of spontaneous preterm birth.
A meta-analysis of individual patient data (five randomised controlled trials including 504 women) and a systematic review (12 randomised controlled trials including 3328 women) showed that cervical cerclage delayed the gestational age at delivery and reduced preterm birth in women at risk of early delivery.5 6 There was no statistically significant difference in perinatal mortality with cerclage.5 6 The meta-analysis of individual patient data, which only included women with a short cervix (<25 mm), showed a reduction in composite neonatal morbidity in the cerclage group.5 However, no reduction in morbidity was seen in the larger meta-analysis of summary data, where participants in the included studies had a more diverse range of risk factors for preterm birth.6 Higher rates of vaginal discharge, vaginal bleeding, pyrexia, and caesarean section were found in women who underwent cerclage.6
A meta-analysis of individual patient data (five randomised controlled trials including 775 women and 827 infants) and a systematic review (36 randomised controlled trials including 8523 women and 12 515 infants) support the use of vaginal progesterone to reduce preterm birth in women with singleton pregnancies at risk of preterm birth.7 8 The results of both systematic reviews are mainly driven by one randomised controlled trial in which all pregnant women were screened for cervical length, with transvaginal ultrasound and progesterone given if the cervix was 10-20 mm.12 It is difficult to interpret these data where universal screening of cervical length in pregnancy is lacking, such as in the UK.13
A large randomised controlled trial based in the UK (OPPTIMUM)9 was published after these systematic reviews and the release of National Institute for Health and Care Excellence (NICE) guideline for preterm labour and birth.4 OPPTIMUM is the largest randomised controlled trial of vaginal progesterone and the only one powered to include a childhood primary outcome. Researchers included women at risk of preterm birth (box 1) and found that vaginal progesterone did not reduce any of the primary outcomes: preterm birth, neonatal death or severe morbidity, or childhood neurodevelopment (standardised cognitive score (Bayley-III)) at 2 years of age.9 No harms were associated with progesterone use.9
In two randomised trials of several hundred women, researchers evaluated use of the Arabin pessary with a short cervix on transvaginal ultrasonography.10 11 The smaller trial reported a benefit in pessary use,10 whereas the larger trial found no statistically significant difference in preterm birth rate between women randomised to cervical pessary and those randomised to expectant management.11
Comparison of treatments to prevent preterm birth
As yet there are no reported trials comparing the effectiveness of cervical cerclage, progesterone supplementation, and cervical pessary against each other when used in isolation or in combined management strategies in women at risk of preterm birth.
Overall, there is less evidence regarding management of multiple pregnancy. See table 2⇓ (online) for summary of evidence.
A systematic review found no evidence that cervical cerclage reduces preterm birth in women with multiple pregnancy.14 However, only 128 women with multiple pregnancy were included, and firm conclusions about benefits and harms cannot be made.
Evidence from a meta-analysis of individual patient level data from 1735 women with multiple pregnancy shows no benefit from vaginal progesterone in this group as a whole.15 However, progesterone did reduce poor perinatal outcome in a small subgroup of 116 women who had both multiple pregnancy and a short cervix. Further evidence is required to confirm this observation.15
Two randomised controlled trials included twin pregnancies with no other risk factors for preterm birth and found no difference between cervical pessary and routine care.16 17 A third randomised controlled trial, confined to women with multiple pregnancy and a short cervix, has recently been published and did show a reduction in preterm birth with a cervical pessary.18
Is ongoing research likely to provide relevant evidence?
Clinical trials dealing with uncertainties in clinical management of women at risk of spontaneous preterm birth were identified through a search of clinical trials databases (box 2) and are summarised in table 3⇓. Only two of five identified studies (C-STITCH and STOPPIT-2) have primary outcomes focused on mortality or neonatal health, with other studies using the surrogate outcome of gestation at delivery.
Box 2: Search strategy
We searched clinical trials databases (www.controlled-trials.com/isrctn/; http://clinicaltrials.gov/) and the UK Clinical Research Network Portfolio database (http://public.ukcrn.org.uk/search/) with search terms relating to preterm birth, miscarriage, perinatal mortality, and neonatal morbidity. We also had personal communication with the Royal College of Obstetricians and Gynaecologists Preterm Birth Clinical Study Group.
An individual patient data meta-analysis of vaginal progesterone to prevent preterm birth is planned by the US Patient Centred Outcomes Research Initiative (www.pcori.org), which should help clarify whether progesterone is effective, and if so, which women should be offered it.
It is essential that future studies use standard definitions, protocols, and core outcomes so that data on important, but uncommon, outcomes—such as neonatal mortality—can be readily synthesised and guide decision making.
What should we do in the light of the uncertainty?
Parents should be aware that a reduction in incidence of early delivery might not necessarily translate into improved health in children.
It is reasonable to follow NICE (UK) guidance on the prevention of preterm birth and offer cervical cerclage when there has been a previous preterm birth, mid-trimester loss, preterm prelabour rupture of membranes, or cervical treatment, and the cervix is short.4 Alternatively, progesterone could be offered,4 although the OPPTIMUM trial (published after the NICE guideline), showed no benefit of vaginal progesterone in this group.9 We were unable to find any international guidance relating to prevention of preterm birth. We believe that further evidence is needed before offering the cervical pessary out of a research setting.10 11
In our opinion, women with multiple pregnancy should not be offered treatments to prevent preterm birth—except in the context of clinical trials—because no clear benefit has been shown.14 15 16 17 18 We suggest that doctors share the uncertainly about preterm birth and offer women the opportunity to participate in relevant clinical trials.
Box 3: Recommendations for future research
Future research should:
Use standard definitions, protocols, and core outcomes so that data can be meta-analysed
Be adequately powered for important outcomes, including neonatal morbidity and periatal mortality, rather than surrogate outcomes such as preterm birth
Include consent to allow follow-up studies so that long term outcomes can be determined
Data from trials should be made available for subsequent meta-analysis
How patients were involved in the creation of this article
“Which interventions are most effective to predict or prevent preterm birth?” was the number one uncertainty prioritised by the James Lind Alliance Preterm Birth Priority Setting Partnership, which brings together patients, carers, and clinicians to identify and prioritise research questions and uncertainties relating to a healthcare problem.18 No patients were directly involved in creating this article.
This is one of a series of occasional articles that highlight areas of practice where management lacks convincing supporting evidence. The series adviser is David Tovey, editor in chief, the Cochrane Library. This paper is based on a research priority identified and commissioned by the National Institute for Health Research’s Health Technology Assessment programme on an important clinical uncertainty. To suggest a topic for this series, please email us at [email protected]
We thank the members of the Royal College of Obstetricians and Gynaecologists Preterm Birth Clinical Study Group for advice on future research recommendations and information on ongoing trials.
Contributors: SJS and KMKI planned the organisation, content, and structure of the article. SJS performed the literature search and drafted the article, with crucial edits and additions from KMKI. Both authors participated in subsequent revisions. KMKI is guarantor.
Funding: The authors had no support from any organisation for the submitted work.
Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: SJS is an unpaid representative on Scottish governmental advisory groups, is a member of the Royal College of Obstetricians and Gynaecologists Preterm Birth Clinical Study Group, and has received travel expenses to attend meetings relating to these roles. SJS is chief investigator and a co-investigator in trials relating to preterm birth funded by National Institute for Health Research Health Technology Assessment, and the institution she works at has also received research funding from Sparks, Tommy’s, and the British Maternal and Fetal Medicine Society. SJS has been provided with ultrasound equipment and software for use in studies of preterm birth research from GE and Philips. SJS has received honorariums for contributing to book chapters, and travel and accommodation expenses as an invited speaker at conferences and academic institutions. KMKI is chief investigator for C-STICH, funded by National Institute for Health Research Health Technology Assessment. KMKI receives travel and accommodation expenses as an invited speaker at conferences and academic institutions; however, honorariums or royalty fees generated from academic activities fund academic activities related to women’s health.
Provenance and peer review: Commissioned; externally peer reviewed.