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Management of a woman with a previous preterm birth
CASE-BASED LEARNING
Management of a woman with a previous preterm birth
usually present once the process of parturition has already started. Secondly, preterm birth is associated with multiple aetiologies, so a single approach unlikely to be effective. Infection, uterine overdistension, haemorrhage, stress and uteroplacental ischaemia have all been implicated in preterm birth, but the precise mechanism controlling the initiation of labour has not been established. Nonetheless, research in this area has increased our understanding of the processes leading to preterm labour and revealed potential ways that may reduce preterm birth (Figure 1). Unfortunately, in many cases, interventions have not yet been shown to improve neonatal or longer-term outcomes, and caution must be used before instituting them without clear evidence of their benefit. As demonstrated by follow-up studies of clinical trials such as ORACLE (which showed an increase in cerebral palsy in children of women who were treated with antibiotics when they presented with symptoms of spontaneous preterm labour), therapies that we might expect to be beneficial can actually do harm. The aim of this article is to provide a case-based discussion of strategies to improve the outcome of pregnancies in women who have had a previous preterm delivery. Where there is lack of evidence of the best approach, management options are discussed and the need for further research highlighted. This article primarily relates to preventative strategies for preterm labour. The management of women who present with symptoms of preterm labour is dealt with elsewhere.
Sarah J Stock Charlotte Oyston Jane E Norman
Abstract Reducing the impact of preterm birth is one of the challenges in modern obstetric practice. This article provides a case-based discussion of management of women with a previous preterm birth. Estimating the risk of a subsequent preterm delivery can be improved by assessment of obstetric history. Primary preventative strategies include lifestyle advice and modification of pre-pregnancy risk factors. Antenatal care involves increased monitoring and supportive care. The usefulness of screening for preterm birth using cervical length ultrasound or biochemical tests of cervicovaginal secretions lie mainly in their negative predictive value, allowing recognition of women in whom subsequent preterm birth is unlikely. Potential prophylactic therapies in high-risk women include marine oils, progesterone pessaries and cervical cerclage, but none have been shown to improve neonatal outcome. The need for further research is highlighted.
Keywords cervical cerclage; cervical length measurement; fetal fibro-
Case history e part 1
nectin; preterm birth; progesterone
A woman presents pre-pregnancy. She has had one miscarriage, and one preterm delivery at 26 weeks. This baby died at 3 days of age. She wishes to become pregnant again but is concerned about the risk of preterm labour. What would you do? The initial aims of management should be to (a) assess the risk of preterm labour and (b) reduce the risk of preterm birth through modification of risk factors. Plans for antenatal care should then be made.
Introduction Preterm birth is a major healthcare problem, with clinical, social and economic consequences. Reducing its impact is one of the challenges in modern obstetric practice. Preterm birth is defined as delivery occurring at less than 37 weeks’ gestation and although the lower gestational cut-off varies with location, in the UK the threshold of viability is usually accepted as 24 weeks. In the UK 7e8% of births are preterm, whereas rates in USA are 12e13% and in the developing world estimates are as high as 25e30%. Preventative strategies have been hampered by two factors. Firstly, prediction of preterm birth is difficult, so women
Assessing the risk of PTB Overall, women who have had a previous preterm birth have approximately a 2.5-fold increased risk of delivering preterm again. However, this risk estimate can be modified by many factors and the importance of taking a comprehensive history cannot be underestimated. A full history of the events preceding and surrounding previous delivery is essential. If the woman delivered in another hospital, requesting the notes and results of pre and postnatal investigations can provide additional information to the woman’s own account.
Sarah J Stock MBChB PhD MRCOG is a Consultant at the University of Edinburgh, Department of Obstetrics and Gynaecology, Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK. Conflicts of interest: none declared.
Timing and number of previous deliveries: prior preterm birth is the strongest risk factor for future preterm birth. The risk of subsequent preterm birth is inversely related to the gestation of the previous delivery, being higher the earlier the previous delivery occurred. Relative risk rises from 2.5 with a previous delivery at less than 37 weeks, to approximately 5 with a delivery at less than 35 weeks, and is over 10 with a previous delivery at less than 28 weeks. The risk of preterm birth also increases with the number of previous preterm deliveries. Women with one previous delivery before 35 weeks have a 16% recurrence risk,
Charlotte Oyston MBChB BMedSc (Hons) is an Obstetric Research Fellow at the Liggins Institute, University of Auckland, New Zealand. Conflicts of interest: none declared. Jane E Norman MBChB MD FRCOG is a Consultant at the University of Edinburgh Department of Obstetrics and Gynaecology, Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK. Conflicts of interest: none declared.
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CASE-BASED LEARNING
Interventions which may decrease preterm birth
Interventions not shown to be of benefit
Smoking cessation Preconception folic acid Zinc supplementation Progesterone Marine oils Cervical cerclage
Antibiotics Rest Treatment of periodontitis Treatment of asymptomatic bacteruria
(if cervix <15mm on 2nd trimester USS)
Interventions shown to improve neonatal Outcome None to date Figure 1 Interventions aimed at decreasing the risk of preterm birth.
whereas the recurrence risk is 41% with two previous preterm deliveries and 67% with three previous deliveries. An additional factor to consider is the inter-pregnancy interval. An interpregnancy interval of less than 6 months is an independent risk factor for poor pregnancy outcome including preterm birth. It should be noted that women who have had a preterm birth are also more likely to have a short inter-pregnancy interval before their next pregnancy.
and placental histology can help confirm the presence of intrauterine infection as a causative factor. Histology can also detect inflammatory changes from other causes such as haemorrhage. Inflammatory lesions in the placenta are independently associated with recurrent preterm labour with an odds ration of 2.4. Cervical trauma: cervical trauma, occurring through cervical surgery or dilatation is thought to be a risk factor for spontaneous preterm delivery. There is good evidence from large studies that first trimester medical and surgical termination of pregnancy does not increase the risk of subsequent preterm delivery, but second trimester termination of pregnancy may slightly increase incidence of subsequent preterm delivery. In meta-analyses, cold knife conization has been shown to be associated with preterm delivery (less than 37 weeks) with a relative risk 2.59, and severe preterm birth (less than 32/34 weeks) with a relative risk of 2.78. The more commonly performed procedure large loop excision of the transformation zone (LLETZ) is also associated with preterm delivery less than 37 weeks (relative risk of 1.70), but is not associated with delivery at less than 32/34 weeks. A limitation of many of these studies is that treated women are compared to healthy controls rather than other women with cervical intraepithelial neoplasia (CIN). Some (but not all) studies have reported CIN is associated with preterm birth regardless of treatment. Using a control group of women without CIN may lead to an overestimate of the relative risk of preterm birth attributable to treatment. Although some authors have tried to identify whether multiple procedures or the depth of tissue removed in cervical surgery increase risk of subsequent preterm birth, evidence for this is conflicting.
Type of preterm delivery: preterm birth is influenced by factors such as age, ethnicity, socioeconomic status, nutrition, smoking and substance misuse, but these factors have low sensitivity in predicting subsequent preterm birth. The type of previous preterm birth is a better predictor of preterm delivery in the next pregnancy. Preterm birth can be divided into two broad obstetric categories e iatrogenic delivery and spontaneous preterm birth. Iatrogenic preterm delivery, necessitated by maternal or fetal condition, accounts for 30e35% of preterm births. The risk of recurrence in iatrogenic delivery is linked to the risk of the underlying condition. Pre-eclampsia, fetal growth restriction, suspected fetal compromise and placental abruption are the commonest indications for iatrogenic preterm delivery. Women with a previous iatrogenic delivery before 37 weeks are approximately three times more likely to have another medically indicated preterm delivery, and if the previous delivery was before 35 weeks the relative risk rises to greater than 10. Interestingly, medically indicated delivery before 35 weeks, also increases the risk of spontaneous preterm birth (relative risk 1.6), presumably as a result of aetiologies such as placental dysfunction which predispose to both fetal compromise and preterm labour. Spontaneous preterm birth accounts for 65e70% of preterm deliveries. It can be further divided into preterm premature rupture of membranes (PPROM) and spontaneous preterm labour. PPROM is defined as spontaneous rupture of membranes at less than 37 weeks, at least 1 hour before the onset of labour. It precedes approximately 25e30% of preterm births. Spontaneous preterm labour is the onset of regular uterine contractions and cervical change at less than 37 weeks gestation. It results in 40e45% of preterm births. Despite the different types of onset, risk factors for PPROM and spontaneous preterm labour are similar. Asymptomatic infection is frequently a precursor, and as the membranes prevent pathogens ascending into the uterus, secondary intrauterine infection commonly complicates PPROM. Microbiology
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Uterine anomalies: congenital uterine anomalies occur in about 4% of women overall, but are more common in women who have midtrimester loss or preterm delivery, with rates of up to 25% reported. Diagnosis is usually made by imaging, which may include hysterosalpingography, ultrasonography, sonohysterography or MRI. The risk of preterm labour depends on the type of anomaly, being lowest in arcuate uterus at around 7.5%, and highest in uterine didelphys at approximately 28%. Rates of miscarriage are also high in women with uterine anomalies, such that the term delivery rate is only 40e60%. However, small numbers and heterogeneity of anomalies confound accurate estimates of subsequent preterm delivery.
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Assisted conception techniques: it is well recognized that multiple pregnancies are more likely to deliver preterm, and approximately 60% of twins deliver before 37 weeks. The association between assisted conception techniques and multiple pregnancy is clear. However, singleton pregnancies achieved through in vitro fertilization are at also at increased risk of preterm birth, with a relative risk of 2.0.
be involved in the pathogenesis of recurrent preterm birth. For this reason, strategies of antibiotic treatments between pregnancies have been evaluated. However, these have not been shown to be beneficial in reducing subsequent preterm birth. Surgical procedures: it is thought that the mechanism through which uterine anomalies predispose to preterm birth is through overdistension of a reduced capacity uterus or uterine horn by the developing pregnancy. Correction of uterine abnormalities in an attempt to restore normal anatomy would seem a plausible way of improving pregnancy outcome. However, there is little published evidence of benefit. There have been no randomized controlled trials of surgical correction of uterine anomalies. Observational trials have suggested that hysteroscopic resection of uterine septae may improve pregnancy outcome. The pros and cons of other surgery must be carefully evaluated on a case-bycase basis, as research in this area is lacking. Pre-pregnancy laparotomy and abdominal placement of a cervical suture is sometimes undertaken in women with suspected cervical incompetence, particularly when previous vaginally placed sutures have failed. A systematic review of 13 case series and one non-randomized study reported a reduced risk of perinatal death or delivery prior to 24 weeks in women who had a transabdominal cerclage placed following failed transvaginal cerclage compared to women having repeat transvaginal cerclage. Transabdominal cerclage was associated with a significantly higher incidence of serious maternal morbidity. It is currently recommended that abdominal cerclage is only carried out in a research setting.
Risk reduction In addition to standard preconception advice, an attempt should be made to reduce the risk of preterm labour by modification of identified risk factors. Lifestyle factors: smoking cessation is advocated. Tobacco smoking in pregnancy is associated with a number of adverse pregnancy outcomes including preterm birth (relative risk 1.2). Initiation of smoking has been shown to increase the risk of recurrent preterm birth, whilst smoking cessation decreases the risk of preterm birth. A Cochrane review of 64 trials of smoking cessation interventions in pregnancy showed a reduction in the proportion of women who smoked and a reduction in preterm birth (relative risk 0.86). Pre-pregnancy weight optimization may be recommended, although there is little research to investigate whether weight management programs improve outcome. Women with a low body mass index (BMI <19 kg/m2) have higher incidences of spontaneous preterm birth (16.6%) than women with a BMI in the normal range (20e24.9 kg m2; 11.3%), and further weight loss between pregnancies increases the risk of recurrent preterm birth. Whilst increasing BMI reduces the risk of spontaneous preterm birth, obesity is a significant risk factor for iatrogenic preterm birth. Obese women have higher rates of delivery due to pre-eclampsia and gestational diabetes, and also have higher rates of congenital anomalies. There is conflicting evidence from observational studies as to whether type of work or level of physical activity affects preterm delivery. There is some evidence that shift work (particularly night shift) and heavy physical labour under stressful conditions may increase preterm delivery rates. There is however, no evidence that rest decreases rates of preterm labour.
Case history e part 2 The woman then presents at 13 weeks of pregnancy. How will you manage her pregnancy? The plan for antenatal management will usually involve supportive management and increased monitoring. There is some evidence that screening and treating infections may improve outcomes. Methods of predicting preterm birth and interventions to prevent or treat preterm labour are more contentious.
Nutritional supplements: low levels of micronutrients such as folate, zinc and iron have been associated with decreased duration of gestation. Evidence that folate supplementation in pregnancy can decrease preterm birth has been conflicting. However, a recent large study has shown that preconceptual folate supplementation for greater than one year is associated with a 70% reduction in preterm delivery before 28 weeks, and a 50% reduction before 32 weeks, with a trend for reduction with the duration of supplementation. Although the effect of preconceptual zinc supplementation on preterm birth has not been studied, a Cochrane review of zinc supplementation initiated prior to 27 weeks gestation has shown a small but significant reduction in preterm birth (relative risk 0.86). This risk reduction was predominantly seen in trials involving women of low income. Studies of other multinutrient supplements taken preconceptually or in early pregnancy, have not reduced preterm birth rates.
Screening and treatment of infection Intrauterine infection is an important and common cause of preterm labour, and is associated with over one third of cases of preterm birth. In most cases infections are thought to ascend from the lower genital tract, but can also arise from haematogenous spread of pathogens. Rare causes are after iatrogenic introduction during intrauterine procedures, or from retrograde spread down the Fallopian tubes. Lower genital tract infection: strategies of vaginal microbial decontamination have been proposed as a way of preventing ascending infections that can cause in preterm birth. Unfortunately, in most cases, clinical trials have been disappointing in improving pregnancy outcome, and some have suggested worsening outcome. There is no evidence that prophylactic antibiotics decrease preterm birth. A randomized controlled trial of metronidazole for the prevention of preterm birth in high-risk women (identified by
Antibiotics: it has been hypothesized that subclinical intrauterine infections originating around the time of conception may
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a positive fetal fibronectin test) was stopped early due to safety concerns over an increase in preterm births in women treated with metronidazole over placebo (relative risk 1.9). A metaanalysis of studies of antibiotic prophylaxis in asymptomatic women at risk of preterm birth (identified either through history of previous preterm birth, positive fetal fibronectin test results, or presence of abnormal bacterial flora) showed no benefit in terms of reduction of preterm labour. There is some evidence that selective treatment of infection may reduce preterm birth. One large randomized control trial has evaluated a program of screening and treatment of lower genital tract infections (bacterial vaginosis, trichomoniasis and candidiasis). This showed a reduction in preterm birth before 37 weeks with a relative risk of 0.55 when screening was preformed early in the second trimester in a low risk population. A Cochrane review found that in women who had a previous preterm birth, screening and treatment of bacterial vaginosis did not reduce subsequent delivery before 37 weeks, although it did reduce PPROM and low birthweight. The effect of screening and treating high-risk women before 20 weeks has not been fully assessed, but there is suggestion that this may improve outcome. This should be confirmed in adequately powered clinical trials. There is insufficient evidence to assess if treatment of vaginal Ureaplasmas decreases rates of preterm birth. There is no evidence that treatment of Chlamydia trachomatis, Neisseria gonorrhoeae or syphilis decreases rates of preterm birth, however, treatment of these infections is recommended due to the risks of congenital infection.
It should also be remembered, that testing itself can have detrimental effects. For example, predictive tests of preterm labour have been shown to be associated with high levels of maternal anxiety, even when results are negative; and stress itself could increase the likelihood of preterm birth. Cervical length ultrasound: the cervix is central to maintaining pregnancy, providing a barrier between the lower genital tract and the intrauterine contents. Cervical shortening and effacement precede delivery, and cervical length has been correlated with the likelihood of preterm delivery. The most effective way of measuring cervical length is by transvaginal ultrasound. Several groups have studied the efficacy of cervical length ultrasound in predicting preterm delivery in women who have had one or more previous preterm birth. The shorter the cervical length, the greater the risk of preterm delivery, and the sensitivity, specificity, positive and negative predictive value of the test varies with the cut-off used. Risk also increases the earlier in gestation that shortening is detected. A systematic review found that a cervical length of less than 25 mm at less than 20 weeks had a positive likelihood ratio of delivery before 34 weeks of 13.38 and a negative likelihood ratio of 0.8. At 20e24 weeks a cervical length of less than 25 mm had a positive likelihood ration of 4.68 and a negative likelihood ration of 0.68. Biochemical tests: there are two biochemical tests licensed for the prediction of preterm labour in the UK e Fetal Fibronectin (Hologic, Crawley, West Sussex) and Actim Partus (BHR Pharmaceuticals, Nuneaton, Warwickshire). Fetal fibronectin is a glycoprotein not normally found in cervicovaginal secretions in pregnancy, but its presence between 22 and 35 weeks gestation can indicate cervical ripening and impending delivery. It is measured in a sample of cervicovaginal secretions obtained at speculum examination, and measured by a near-bedside immunoassay to provide a qualitative result (positive or negative). A systematic review of the accuracy of testing cervicovaginal fetal fibronectin in asymptomatic women showed summary likelihood ratios for spontaneous preterm delivery before 34 weeks of 4.1 after a positive test and 0.78 after a negative test. In this review meta-regression analysis showed that the accuracy of the test did not depend on classification of risk. Actim Partus measures phosphorylated Insulin-like growth factor binding protein 1 (phIGFBP1) in cervical secretions. There is less evidence of its efficacy in asymptomatic women than there is for fetal fibronectin, although the small studies that have been performed suggest comparable efficacy.
Periodontal disease: epidemiological studies have linked periodontitis with poor pregnancy outcomes including preterm birth. Initial studies suggested that dental treatment (scaling and root planning) may be beneficial. However, the results of two recent large randomized control trials have shown no benefit in reduction of preterm birth. Asymptomatic bacteriuria: urinary tract infection has been associated with poor pregnancy outcome including preterm labour. Although a recent Cochrane review found antibiotic treatment of asymptomatic bacteriuria resulted in a reduction in pyelonephritis and low birthweight babies, there was no effect on rates of preterm births. Prediction of preterm delivery Screening tests are available that are purported to discriminate between women who are likely to deliver preterm, and women who are unlikely to deliver preterm. However, there has been little research performed investigating their clinical or costeffectiveness in routine practice. At present, the potential clinical significance of such tests is likely to be predominately associated with their negative predictive value. A test with a high negative predictive value could allow women and their clinicians to be reassured that subsequent preterm delivery is unlikely, and prevent unnecessary hospitalization and intervention. The lack of efficacious interventions to prevent preterm birth means that identification of women at high-risk of preterm labour is unlikely to improve clinical outcomes. Identification may, however, help target resource usage and be useful in the research studies of interventions of preterm labour.
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Interventions to prevent preterm labour Cervical cerclage: preterm labour of any cause involves premature dilatation of the cervix. It almost impossible to determine whether this has occurred due to an inherent weakness of cervix and thus a diminished capacity to retain the pregnancy, or whether dilatation has been stimulated by another process, for example infection. Nevertheless, recurrent late miscarriage or preterm labour is often attributed to cervical weakness or incompetence. Cervical cerclage has been proposed as a treatment to prevent pregnancy loss due to cervical incompetence. It involves suturing the cervix with the aim of keeping it
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CASE-BASED LEARNING
closed until the expected time of delivery. It can be performed as an elective procedure in the early second trimester, as an “emergent” treatment on evidence of cervical shortening on ultrasound, or as an emergency procedure if women present with cervical dilatation or visible fetal membranes (also called rescue cerclage). In one large randomized control trial of elective cervical cerclage versus no cervical cerclage in women thought to be at risk of midtrimester pregnancy loss by history, there was a reduction in preterm birth before 33 weeks (relative risk 0.75). However, in subgroup analysis, only women with three or more previous pregnancies ending before 37 weeks gestation benefited from cerclage. Overall, there was no evidence of improved neonatal outcome between the cerclage and control groups. Other studies have not shown any reduction in preterm delivery, and meta-analyses have failed to provide any conclusive evidence of benefit of elective cervical cerclage in cervical incompetence diagnosed on history and/or cervical resistance studies. Several trials have also evaluated whether “emergent” cervical cerclage reduces preterm birth in women with a short cervix on second trimester ultrasound. A meta-analysis of four trials of cervical cerclage using individual patient-level data suggested that in women with a history of previous preterm birth and a short cervix on second trimester ultrasound, cervical cerclage may reduce subsequent delivery before 35 weeks (relative risk 0.63). However, no improvements were seen in perinatal death. The study concluded that more clinical trials were required before this becomes the standard of care. A recent US multicentre randomized controlled trial of cerclage in women with a history of preterm birth and a short cervix on ultrasound (16e22 weeks) showed that in women with a cervical length less than 25 mm, cerclage reduced previable birth (14% vs 6.1%; p ¼ 0.03) and perinatal mortality (16% vs 8.8%; p ¼ 0.046) but did not prevent birth less than 35 weeks (32% vs 42%; p ¼ 0.09). However, in prespecified analysis there was a reduction in preterm birth <35 weeks in women who had a suture inserted with a cervical length less than 15 mm ( p ¼ 0.006) but not in women with cervical length 15e24 mm ( p ¼ 0.20). Observational trials have suggested that “rescue” cerclage may prolong pregnancy at least to viability. It remains unclear if this confers any benefit to neonatal outcome. Rates of membrane rupture and chorioamnionitis are high, even in carefully selected populations. Prolonging retention in a hostile intrauterine environment may be detrimental to fetal wellbeing, and there is a clear association between intrauterine infection and fetal inflammatory brain injury. The potential of worsening neonatal and longer-term outcomes must therefore be considered. There is also a potential for increasing maternal infectious morbidity. Cervical cerclage placement has been consistently associated with an increase in maternal pyrexia and infection. Although there is no evidence of long-term damage to mothers or babies, safety has not been assessed in adequately powered trials.
those with low fish intake. This led to the hypothesis that omega-3 polyunsaturated fatty acids (PUFAs) found in marine oils may be pro-gestational and prevent fetal growth restriction. Omega-3 PUFAs have been shown to be anti-inflammatory through several different mechanisms, and it is postulated that the effect on gestation may be mediated through modulation of the inflammatory response. Several randomized trials have been carried out examining the effect of marine oil supplementation on pregnancy outcome, and these have been reviewed in a Cochrane review. This showed that women who were allocated marine oil supplementation had a mean gestation that was 2.6 days longer than controls. No effect on birth before 37 weeks was seen, but there was a decrease in delivery before 34 weeks (relative risk 0.69) and the effects of supplementation appeared to be greater in high-risk women. There was not sufficient data to determine whether supplementation prolonged gestation or was safe, and more research is needed before introducing routine supplementation. Progesterone: several meta-analyses have provided evidence in support of the theory that progesterone prevents preterm delivery in high-risk women. Administration by either weekly intramuscular injection (not licensed in the UK) or daily vaginal pessary decreased delivery before 37 weeks (relative risk 0.42e0.80) in women with a past history of preterm delivery or ultrasonographic evidence of cervical shortening. Although progesterone therapy from the second trimester appears to be safe, data demonstrating an improvement in perinatal outcomes are limited. Research should continue into the safety of progesterones, optimal dosing and duration of therapy, and the presence of any long-term benefits for the infant. Cervical pessary e a recent randomized study evaluated the use of a cervical pessary in women with a cervical length of 25 mm or less, as identified by transvaginal ultrasound at 20e23 weeks gestation. Compared to the control group, spontaneous preterm delivery before 34 weeks was significantly less common in the women using the cervical pessary. The authors hypothesized this benefit occured due to an altered angle between the cervix and uterus, resulting in a reduction in pressure on the cervix and less contact between vaginal bacteria and fetal membranes. Further studies are required to confirm these findings.
Conclusion Although the majority of women who have had a previous preterm birth will deliver at term in a subsequent pregnancy, a history of previous preterm birth is a risk factor for another preterm birth. As the causes of preterm birth are diverse, it is unlikely that a single preventative measure will reduce rates of preterm delivery. Nevertheless, primary prevention through lifestyle advice and nutritional supplementation has potential to be an effective strategy. Predicting which women will spontaneously deliver preterm is problematic due to the lack of specificity of tests. Cervical length ultrasound and biochemical screening tests of preterm labour may be useful in identifying which women are unlikely to deliver preterm. Dietary supplementation with marine oils, treatment with progesterone and cervical cerclage in women with a short cervical length (<15 mm) appear to reduce preterm delivery. However, although it is clear that preterm birth has major adverse consequences, there is
Marine oils and omega-3 fatty acids: dietary supplementation with marine oils in the second trimester has been proposed as a strategy to prolong pregnancy and prevent preterm birth. Epidemiological studies have suggested that gestation is longer and birthweight higher in populations with high fish intake than
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Parry S, Simhan H, Elovitz M, Iams J. Universal maternal cervical length screening during the second trimester: pros and cons of a strategy to identify women at risk of spontaneous preterm delivery. Am J Obstet Gynecol 2012; 207: 101e6. Romero R, Nicolaides K, Conde-Aqudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012; 206: 124e1e19.
no evidence that there is benefit to prolonging pregnancy where spontaneous preterm birth would otherwise have occurred. Preterm labour could represent a survival mechanism for the fetus, escaping a hostile intrauterine environment and evidence that a reduction in the rate of preterm birth is accompanied by neonatal benefit is lacking. There is significant potential for worsening outcome and further research in this area is essential before policies of screening and treating preterm birth can be routinely introduced. A
FURTHER READING Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75e84. Goya M, Pratcorona L, Merced C, et al. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial research is recommended. Lancet 2012; 379: 1800. Honest H, Forbes CA, Duree KH, et al. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technol Assess 2009; 13: 1e627. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008; 372: 1319e27. Owen J, Hankins G, Iams JD, et al. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol 2009; 201: 375e1e8.
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Cervical length ultrasound and biochemical screening tests (e.g. Fetal Fibronectin) have a high negative predictive value, and may be useful in identifying women who are unlikely to deliver preterm Cervical cerclage, progesterone pessaries and marine oil supplementation may reduce preterm delivery in high-risk women but there is no evidence that they improve neonatal outcome, and these interventions have potential to do harm Further research is recommended before screening and treatment to prevent preterm birth should be routinely introduced into clinical practice
Ó 2013 Published by Elsevier Ltd.
Management of a woman with a previous preterm birth
usually present once the process of parturition has already started. Secondly, preterm birth is associated with multiple aetiologies, so a single approach unlikely to be effective. Infection, uterine overdistension, haemorrhage, stress and uteroplacental ischaemia have all been implicated in preterm birth, but the precise mechanism controlling the initiation of labour has not been established. Nonetheless, research in this area has increased our understanding of the processes leading to preterm labour and revealed potential ways that may reduce preterm birth (Figure 1). Unfortunately, in many cases, interventions have not yet been shown to improve neonatal or longer-term outcomes, and caution must be used before instituting them without clear evidence of their benefit. As demonstrated by follow-up studies of clinical trials such as ORACLE (which showed an increase in cerebral palsy in children of women who were treated with antibiotics when they presented with symptoms of spontaneous preterm labour), therapies that we might expect to be beneficial can actually do harm. The aim of this article is to provide a case-based discussion of strategies to improve the outcome of pregnancies in women who have had a previous preterm delivery. Where there is lack of evidence of the best approach, management options are discussed and the need for further research highlighted. This article primarily relates to preventative strategies for preterm labour. The management of women who present with symptoms of preterm labour is dealt with elsewhere.
Sarah J Stock Charlotte Oyston Jane E Norman
Abstract Reducing the impact of preterm birth is one of the challenges in modern obstetric practice. This article provides a case-based discussion of management of women with a previous preterm birth. Estimating the risk of a subsequent preterm delivery can be improved by assessment of obstetric history. Primary preventative strategies include lifestyle advice and modification of pre-pregnancy risk factors. Antenatal care involves increased monitoring and supportive care. The usefulness of screening for preterm birth using cervical length ultrasound or biochemical tests of cervicovaginal secretions lie mainly in their negative predictive value, allowing recognition of women in whom subsequent preterm birth is unlikely. Potential prophylactic therapies in high-risk women include marine oils, progesterone pessaries and cervical cerclage, but none have been shown to improve neonatal outcome. The need for further research is highlighted.
Keywords cervical cerclage; cervical length measurement; fetal fibro-
Case history e part 1
nectin; preterm birth; progesterone
A woman presents pre-pregnancy. She has had one miscarriage, and one preterm delivery at 26 weeks. This baby died at 3 days of age. She wishes to become pregnant again but is concerned about the risk of preterm labour. What would you do? The initial aims of management should be to (a) assess the risk of preterm labour and (b) reduce the risk of preterm birth through modification of risk factors. Plans for antenatal care should then be made.
Introduction Preterm birth is a major healthcare problem, with clinical, social and economic consequences. Reducing its impact is one of the challenges in modern obstetric practice. Preterm birth is defined as delivery occurring at less than 37 weeks’ gestation and although the lower gestational cut-off varies with location, in the UK the threshold of viability is usually accepted as 24 weeks. In the UK 7e8% of births are preterm, whereas rates in USA are 12e13% and in the developing world estimates are as high as 25e30%. Preventative strategies have been hampered by two factors. Firstly, prediction of preterm birth is difficult, so women
Assessing the risk of PTB Overall, women who have had a previous preterm birth have approximately a 2.5-fold increased risk of delivering preterm again. However, this risk estimate can be modified by many factors and the importance of taking a comprehensive history cannot be underestimated. A full history of the events preceding and surrounding previous delivery is essential. If the woman delivered in another hospital, requesting the notes and results of pre and postnatal investigations can provide additional information to the woman’s own account.
Sarah J Stock MBChB PhD MRCOG is a Consultant at the University of Edinburgh, Department of Obstetrics and Gynaecology, Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK. Conflicts of interest: none declared.
Timing and number of previous deliveries: prior preterm birth is the strongest risk factor for future preterm birth. The risk of subsequent preterm birth is inversely related to the gestation of the previous delivery, being higher the earlier the previous delivery occurred. Relative risk rises from 2.5 with a previous delivery at less than 37 weeks, to approximately 5 with a delivery at less than 35 weeks, and is over 10 with a previous delivery at less than 28 weeks. The risk of preterm birth also increases with the number of previous preterm deliveries. Women with one previous delivery before 35 weeks have a 16% recurrence risk,
Charlotte Oyston MBChB BMedSc (Hons) is an Obstetric Research Fellow at the Liggins Institute, University of Auckland, New Zealand. Conflicts of interest: none declared. Jane E Norman MBChB MD FRCOG is a Consultant at the University of Edinburgh Department of Obstetrics and Gynaecology, Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK. Conflicts of interest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 23:2
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Ó 2013 Published by Elsevier Ltd.
CASE-BASED LEARNING
Interventions which may decrease preterm birth
Interventions not shown to be of benefit
Smoking cessation Preconception folic acid Zinc supplementation Progesterone Marine oils Cervical cerclage
Antibiotics Rest Treatment of periodontitis Treatment of asymptomatic bacteruria
(if cervix <15mm on 2nd trimester USS)
Interventions shown to improve neonatal Outcome None to date Figure 1 Interventions aimed at decreasing the risk of preterm birth.
whereas the recurrence risk is 41% with two previous preterm deliveries and 67% with three previous deliveries. An additional factor to consider is the inter-pregnancy interval. An interpregnancy interval of less than 6 months is an independent risk factor for poor pregnancy outcome including preterm birth. It should be noted that women who have had a preterm birth are also more likely to have a short inter-pregnancy interval before their next pregnancy.
and placental histology can help confirm the presence of intrauterine infection as a causative factor. Histology can also detect inflammatory changes from other causes such as haemorrhage. Inflammatory lesions in the placenta are independently associated with recurrent preterm labour with an odds ration of 2.4. Cervical trauma: cervical trauma, occurring through cervical surgery or dilatation is thought to be a risk factor for spontaneous preterm delivery. There is good evidence from large studies that first trimester medical and surgical termination of pregnancy does not increase the risk of subsequent preterm delivery, but second trimester termination of pregnancy may slightly increase incidence of subsequent preterm delivery. In meta-analyses, cold knife conization has been shown to be associated with preterm delivery (less than 37 weeks) with a relative risk 2.59, and severe preterm birth (less than 32/34 weeks) with a relative risk of 2.78. The more commonly performed procedure large loop excision of the transformation zone (LLETZ) is also associated with preterm delivery less than 37 weeks (relative risk of 1.70), but is not associated with delivery at less than 32/34 weeks. A limitation of many of these studies is that treated women are compared to healthy controls rather than other women with cervical intraepithelial neoplasia (CIN). Some (but not all) studies have reported CIN is associated with preterm birth regardless of treatment. Using a control group of women without CIN may lead to an overestimate of the relative risk of preterm birth attributable to treatment. Although some authors have tried to identify whether multiple procedures or the depth of tissue removed in cervical surgery increase risk of subsequent preterm birth, evidence for this is conflicting.
Type of preterm delivery: preterm birth is influenced by factors such as age, ethnicity, socioeconomic status, nutrition, smoking and substance misuse, but these factors have low sensitivity in predicting subsequent preterm birth. The type of previous preterm birth is a better predictor of preterm delivery in the next pregnancy. Preterm birth can be divided into two broad obstetric categories e iatrogenic delivery and spontaneous preterm birth. Iatrogenic preterm delivery, necessitated by maternal or fetal condition, accounts for 30e35% of preterm births. The risk of recurrence in iatrogenic delivery is linked to the risk of the underlying condition. Pre-eclampsia, fetal growth restriction, suspected fetal compromise and placental abruption are the commonest indications for iatrogenic preterm delivery. Women with a previous iatrogenic delivery before 37 weeks are approximately three times more likely to have another medically indicated preterm delivery, and if the previous delivery was before 35 weeks the relative risk rises to greater than 10. Interestingly, medically indicated delivery before 35 weeks, also increases the risk of spontaneous preterm birth (relative risk 1.6), presumably as a result of aetiologies such as placental dysfunction which predispose to both fetal compromise and preterm labour. Spontaneous preterm birth accounts for 65e70% of preterm deliveries. It can be further divided into preterm premature rupture of membranes (PPROM) and spontaneous preterm labour. PPROM is defined as spontaneous rupture of membranes at less than 37 weeks, at least 1 hour before the onset of labour. It precedes approximately 25e30% of preterm births. Spontaneous preterm labour is the onset of regular uterine contractions and cervical change at less than 37 weeks gestation. It results in 40e45% of preterm births. Despite the different types of onset, risk factors for PPROM and spontaneous preterm labour are similar. Asymptomatic infection is frequently a precursor, and as the membranes prevent pathogens ascending into the uterus, secondary intrauterine infection commonly complicates PPROM. Microbiology
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Uterine anomalies: congenital uterine anomalies occur in about 4% of women overall, but are more common in women who have midtrimester loss or preterm delivery, with rates of up to 25% reported. Diagnosis is usually made by imaging, which may include hysterosalpingography, ultrasonography, sonohysterography or MRI. The risk of preterm labour depends on the type of anomaly, being lowest in arcuate uterus at around 7.5%, and highest in uterine didelphys at approximately 28%. Rates of miscarriage are also high in women with uterine anomalies, such that the term delivery rate is only 40e60%. However, small numbers and heterogeneity of anomalies confound accurate estimates of subsequent preterm delivery.
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Assisted conception techniques: it is well recognized that multiple pregnancies are more likely to deliver preterm, and approximately 60% of twins deliver before 37 weeks. The association between assisted conception techniques and multiple pregnancy is clear. However, singleton pregnancies achieved through in vitro fertilization are at also at increased risk of preterm birth, with a relative risk of 2.0.
be involved in the pathogenesis of recurrent preterm birth. For this reason, strategies of antibiotic treatments between pregnancies have been evaluated. However, these have not been shown to be beneficial in reducing subsequent preterm birth. Surgical procedures: it is thought that the mechanism through which uterine anomalies predispose to preterm birth is through overdistension of a reduced capacity uterus or uterine horn by the developing pregnancy. Correction of uterine abnormalities in an attempt to restore normal anatomy would seem a plausible way of improving pregnancy outcome. However, there is little published evidence of benefit. There have been no randomized controlled trials of surgical correction of uterine anomalies. Observational trials have suggested that hysteroscopic resection of uterine septae may improve pregnancy outcome. The pros and cons of other surgery must be carefully evaluated on a case-bycase basis, as research in this area is lacking. Pre-pregnancy laparotomy and abdominal placement of a cervical suture is sometimes undertaken in women with suspected cervical incompetence, particularly when previous vaginally placed sutures have failed. A systematic review of 13 case series and one non-randomized study reported a reduced risk of perinatal death or delivery prior to 24 weeks in women who had a transabdominal cerclage placed following failed transvaginal cerclage compared to women having repeat transvaginal cerclage. Transabdominal cerclage was associated with a significantly higher incidence of serious maternal morbidity. It is currently recommended that abdominal cerclage is only carried out in a research setting.
Risk reduction In addition to standard preconception advice, an attempt should be made to reduce the risk of preterm labour by modification of identified risk factors. Lifestyle factors: smoking cessation is advocated. Tobacco smoking in pregnancy is associated with a number of adverse pregnancy outcomes including preterm birth (relative risk 1.2). Initiation of smoking has been shown to increase the risk of recurrent preterm birth, whilst smoking cessation decreases the risk of preterm birth. A Cochrane review of 64 trials of smoking cessation interventions in pregnancy showed a reduction in the proportion of women who smoked and a reduction in preterm birth (relative risk 0.86). Pre-pregnancy weight optimization may be recommended, although there is little research to investigate whether weight management programs improve outcome. Women with a low body mass index (BMI <19 kg/m2) have higher incidences of spontaneous preterm birth (16.6%) than women with a BMI in the normal range (20e24.9 kg m2; 11.3%), and further weight loss between pregnancies increases the risk of recurrent preterm birth. Whilst increasing BMI reduces the risk of spontaneous preterm birth, obesity is a significant risk factor for iatrogenic preterm birth. Obese women have higher rates of delivery due to pre-eclampsia and gestational diabetes, and also have higher rates of congenital anomalies. There is conflicting evidence from observational studies as to whether type of work or level of physical activity affects preterm delivery. There is some evidence that shift work (particularly night shift) and heavy physical labour under stressful conditions may increase preterm delivery rates. There is however, no evidence that rest decreases rates of preterm labour.
Case history e part 2 The woman then presents at 13 weeks of pregnancy. How will you manage her pregnancy? The plan for antenatal management will usually involve supportive management and increased monitoring. There is some evidence that screening and treating infections may improve outcomes. Methods of predicting preterm birth and interventions to prevent or treat preterm labour are more contentious.
Nutritional supplements: low levels of micronutrients such as folate, zinc and iron have been associated with decreased duration of gestation. Evidence that folate supplementation in pregnancy can decrease preterm birth has been conflicting. However, a recent large study has shown that preconceptual folate supplementation for greater than one year is associated with a 70% reduction in preterm delivery before 28 weeks, and a 50% reduction before 32 weeks, with a trend for reduction with the duration of supplementation. Although the effect of preconceptual zinc supplementation on preterm birth has not been studied, a Cochrane review of zinc supplementation initiated prior to 27 weeks gestation has shown a small but significant reduction in preterm birth (relative risk 0.86). This risk reduction was predominantly seen in trials involving women of low income. Studies of other multinutrient supplements taken preconceptually or in early pregnancy, have not reduced preterm birth rates.
Screening and treatment of infection Intrauterine infection is an important and common cause of preterm labour, and is associated with over one third of cases of preterm birth. In most cases infections are thought to ascend from the lower genital tract, but can also arise from haematogenous spread of pathogens. Rare causes are after iatrogenic introduction during intrauterine procedures, or from retrograde spread down the Fallopian tubes. Lower genital tract infection: strategies of vaginal microbial decontamination have been proposed as a way of preventing ascending infections that can cause in preterm birth. Unfortunately, in most cases, clinical trials have been disappointing in improving pregnancy outcome, and some have suggested worsening outcome. There is no evidence that prophylactic antibiotics decrease preterm birth. A randomized controlled trial of metronidazole for the prevention of preterm birth in high-risk women (identified by
Antibiotics: it has been hypothesized that subclinical intrauterine infections originating around the time of conception may
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a positive fetal fibronectin test) was stopped early due to safety concerns over an increase in preterm births in women treated with metronidazole over placebo (relative risk 1.9). A metaanalysis of studies of antibiotic prophylaxis in asymptomatic women at risk of preterm birth (identified either through history of previous preterm birth, positive fetal fibronectin test results, or presence of abnormal bacterial flora) showed no benefit in terms of reduction of preterm labour. There is some evidence that selective treatment of infection may reduce preterm birth. One large randomized control trial has evaluated a program of screening and treatment of lower genital tract infections (bacterial vaginosis, trichomoniasis and candidiasis). This showed a reduction in preterm birth before 37 weeks with a relative risk of 0.55 when screening was preformed early in the second trimester in a low risk population. A Cochrane review found that in women who had a previous preterm birth, screening and treatment of bacterial vaginosis did not reduce subsequent delivery before 37 weeks, although it did reduce PPROM and low birthweight. The effect of screening and treating high-risk women before 20 weeks has not been fully assessed, but there is suggestion that this may improve outcome. This should be confirmed in adequately powered clinical trials. There is insufficient evidence to assess if treatment of vaginal Ureaplasmas decreases rates of preterm birth. There is no evidence that treatment of Chlamydia trachomatis, Neisseria gonorrhoeae or syphilis decreases rates of preterm birth, however, treatment of these infections is recommended due to the risks of congenital infection.
It should also be remembered, that testing itself can have detrimental effects. For example, predictive tests of preterm labour have been shown to be associated with high levels of maternal anxiety, even when results are negative; and stress itself could increase the likelihood of preterm birth. Cervical length ultrasound: the cervix is central to maintaining pregnancy, providing a barrier between the lower genital tract and the intrauterine contents. Cervical shortening and effacement precede delivery, and cervical length has been correlated with the likelihood of preterm delivery. The most effective way of measuring cervical length is by transvaginal ultrasound. Several groups have studied the efficacy of cervical length ultrasound in predicting preterm delivery in women who have had one or more previous preterm birth. The shorter the cervical length, the greater the risk of preterm delivery, and the sensitivity, specificity, positive and negative predictive value of the test varies with the cut-off used. Risk also increases the earlier in gestation that shortening is detected. A systematic review found that a cervical length of less than 25 mm at less than 20 weeks had a positive likelihood ratio of delivery before 34 weeks of 13.38 and a negative likelihood ratio of 0.8. At 20e24 weeks a cervical length of less than 25 mm had a positive likelihood ration of 4.68 and a negative likelihood ration of 0.68. Biochemical tests: there are two biochemical tests licensed for the prediction of preterm labour in the UK e Fetal Fibronectin (Hologic, Crawley, West Sussex) and Actim Partus (BHR Pharmaceuticals, Nuneaton, Warwickshire). Fetal fibronectin is a glycoprotein not normally found in cervicovaginal secretions in pregnancy, but its presence between 22 and 35 weeks gestation can indicate cervical ripening and impending delivery. It is measured in a sample of cervicovaginal secretions obtained at speculum examination, and measured by a near-bedside immunoassay to provide a qualitative result (positive or negative). A systematic review of the accuracy of testing cervicovaginal fetal fibronectin in asymptomatic women showed summary likelihood ratios for spontaneous preterm delivery before 34 weeks of 4.1 after a positive test and 0.78 after a negative test. In this review meta-regression analysis showed that the accuracy of the test did not depend on classification of risk. Actim Partus measures phosphorylated Insulin-like growth factor binding protein 1 (phIGFBP1) in cervical secretions. There is less evidence of its efficacy in asymptomatic women than there is for fetal fibronectin, although the small studies that have been performed suggest comparable efficacy.
Periodontal disease: epidemiological studies have linked periodontitis with poor pregnancy outcomes including preterm birth. Initial studies suggested that dental treatment (scaling and root planning) may be beneficial. However, the results of two recent large randomized control trials have shown no benefit in reduction of preterm birth. Asymptomatic bacteriuria: urinary tract infection has been associated with poor pregnancy outcome including preterm labour. Although a recent Cochrane review found antibiotic treatment of asymptomatic bacteriuria resulted in a reduction in pyelonephritis and low birthweight babies, there was no effect on rates of preterm births. Prediction of preterm delivery Screening tests are available that are purported to discriminate between women who are likely to deliver preterm, and women who are unlikely to deliver preterm. However, there has been little research performed investigating their clinical or costeffectiveness in routine practice. At present, the potential clinical significance of such tests is likely to be predominately associated with their negative predictive value. A test with a high negative predictive value could allow women and their clinicians to be reassured that subsequent preterm delivery is unlikely, and prevent unnecessary hospitalization and intervention. The lack of efficacious interventions to prevent preterm birth means that identification of women at high-risk of preterm labour is unlikely to improve clinical outcomes. Identification may, however, help target resource usage and be useful in the research studies of interventions of preterm labour.
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Interventions to prevent preterm labour Cervical cerclage: preterm labour of any cause involves premature dilatation of the cervix. It almost impossible to determine whether this has occurred due to an inherent weakness of cervix and thus a diminished capacity to retain the pregnancy, or whether dilatation has been stimulated by another process, for example infection. Nevertheless, recurrent late miscarriage or preterm labour is often attributed to cervical weakness or incompetence. Cervical cerclage has been proposed as a treatment to prevent pregnancy loss due to cervical incompetence. It involves suturing the cervix with the aim of keeping it
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closed until the expected time of delivery. It can be performed as an elective procedure in the early second trimester, as an “emergent” treatment on evidence of cervical shortening on ultrasound, or as an emergency procedure if women present with cervical dilatation or visible fetal membranes (also called rescue cerclage). In one large randomized control trial of elective cervical cerclage versus no cervical cerclage in women thought to be at risk of midtrimester pregnancy loss by history, there was a reduction in preterm birth before 33 weeks (relative risk 0.75). However, in subgroup analysis, only women with three or more previous pregnancies ending before 37 weeks gestation benefited from cerclage. Overall, there was no evidence of improved neonatal outcome between the cerclage and control groups. Other studies have not shown any reduction in preterm delivery, and meta-analyses have failed to provide any conclusive evidence of benefit of elective cervical cerclage in cervical incompetence diagnosed on history and/or cervical resistance studies. Several trials have also evaluated whether “emergent” cervical cerclage reduces preterm birth in women with a short cervix on second trimester ultrasound. A meta-analysis of four trials of cervical cerclage using individual patient-level data suggested that in women with a history of previous preterm birth and a short cervix on second trimester ultrasound, cervical cerclage may reduce subsequent delivery before 35 weeks (relative risk 0.63). However, no improvements were seen in perinatal death. The study concluded that more clinical trials were required before this becomes the standard of care. A recent US multicentre randomized controlled trial of cerclage in women with a history of preterm birth and a short cervix on ultrasound (16e22 weeks) showed that in women with a cervical length less than 25 mm, cerclage reduced previable birth (14% vs 6.1%; p ¼ 0.03) and perinatal mortality (16% vs 8.8%; p ¼ 0.046) but did not prevent birth less than 35 weeks (32% vs 42%; p ¼ 0.09). However, in prespecified analysis there was a reduction in preterm birth <35 weeks in women who had a suture inserted with a cervical length less than 15 mm ( p ¼ 0.006) but not in women with cervical length 15e24 mm ( p ¼ 0.20). Observational trials have suggested that “rescue” cerclage may prolong pregnancy at least to viability. It remains unclear if this confers any benefit to neonatal outcome. Rates of membrane rupture and chorioamnionitis are high, even in carefully selected populations. Prolonging retention in a hostile intrauterine environment may be detrimental to fetal wellbeing, and there is a clear association between intrauterine infection and fetal inflammatory brain injury. The potential of worsening neonatal and longer-term outcomes must therefore be considered. There is also a potential for increasing maternal infectious morbidity. Cervical cerclage placement has been consistently associated with an increase in maternal pyrexia and infection. Although there is no evidence of long-term damage to mothers or babies, safety has not been assessed in adequately powered trials.
those with low fish intake. This led to the hypothesis that omega-3 polyunsaturated fatty acids (PUFAs) found in marine oils may be pro-gestational and prevent fetal growth restriction. Omega-3 PUFAs have been shown to be anti-inflammatory through several different mechanisms, and it is postulated that the effect on gestation may be mediated through modulation of the inflammatory response. Several randomized trials have been carried out examining the effect of marine oil supplementation on pregnancy outcome, and these have been reviewed in a Cochrane review. This showed that women who were allocated marine oil supplementation had a mean gestation that was 2.6 days longer than controls. No effect on birth before 37 weeks was seen, but there was a decrease in delivery before 34 weeks (relative risk 0.69) and the effects of supplementation appeared to be greater in high-risk women. There was not sufficient data to determine whether supplementation prolonged gestation or was safe, and more research is needed before introducing routine supplementation. Progesterone: several meta-analyses have provided evidence in support of the theory that progesterone prevents preterm delivery in high-risk women. Administration by either weekly intramuscular injection (not licensed in the UK) or daily vaginal pessary decreased delivery before 37 weeks (relative risk 0.42e0.80) in women with a past history of preterm delivery or ultrasonographic evidence of cervical shortening. Although progesterone therapy from the second trimester appears to be safe, data demonstrating an improvement in perinatal outcomes are limited. Research should continue into the safety of progesterones, optimal dosing and duration of therapy, and the presence of any long-term benefits for the infant. Cervical pessary e a recent randomized study evaluated the use of a cervical pessary in women with a cervical length of 25 mm or less, as identified by transvaginal ultrasound at 20e23 weeks gestation. Compared to the control group, spontaneous preterm delivery before 34 weeks was significantly less common in the women using the cervical pessary. The authors hypothesized this benefit occured due to an altered angle between the cervix and uterus, resulting in a reduction in pressure on the cervix and less contact between vaginal bacteria and fetal membranes. Further studies are required to confirm these findings.
Conclusion Although the majority of women who have had a previous preterm birth will deliver at term in a subsequent pregnancy, a history of previous preterm birth is a risk factor for another preterm birth. As the causes of preterm birth are diverse, it is unlikely that a single preventative measure will reduce rates of preterm delivery. Nevertheless, primary prevention through lifestyle advice and nutritional supplementation has potential to be an effective strategy. Predicting which women will spontaneously deliver preterm is problematic due to the lack of specificity of tests. Cervical length ultrasound and biochemical screening tests of preterm labour may be useful in identifying which women are unlikely to deliver preterm. Dietary supplementation with marine oils, treatment with progesterone and cervical cerclage in women with a short cervical length (<15 mm) appear to reduce preterm delivery. However, although it is clear that preterm birth has major adverse consequences, there is
Marine oils and omega-3 fatty acids: dietary supplementation with marine oils in the second trimester has been proposed as a strategy to prolong pregnancy and prevent preterm birth. Epidemiological studies have suggested that gestation is longer and birthweight higher in populations with high fish intake than
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Parry S, Simhan H, Elovitz M, Iams J. Universal maternal cervical length screening during the second trimester: pros and cons of a strategy to identify women at risk of spontaneous preterm delivery. Am J Obstet Gynecol 2012; 207: 101e6. Romero R, Nicolaides K, Conde-Aqudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012; 206: 124e1e19.
no evidence that there is benefit to prolonging pregnancy where spontaneous preterm birth would otherwise have occurred. Preterm labour could represent a survival mechanism for the fetus, escaping a hostile intrauterine environment and evidence that a reduction in the rate of preterm birth is accompanied by neonatal benefit is lacking. There is significant potential for worsening outcome and further research in this area is essential before policies of screening and treating preterm birth can be routinely introduced. A
FURTHER READING Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75e84. Goya M, Pratcorona L, Merced C, et al. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial research is recommended. Lancet 2012; 379: 1800. Honest H, Forbes CA, Duree KH, et al. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technol Assess 2009; 13: 1e627. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008; 372: 1319e27. Owen J, Hankins G, Iams JD, et al. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol 2009; 201: 375e1e8.
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Cervical length ultrasound and biochemical screening tests (e.g. Fetal Fibronectin) have a high negative predictive value, and may be useful in identifying women who are unlikely to deliver preterm Cervical cerclage, progesterone pessaries and marine oil supplementation may reduce preterm delivery in high-risk women but there is no evidence that they improve neonatal outcome, and these interventions have potential to do harm Further research is recommended before screening and treatment to prevent preterm birth should be routinely introduced into clinical practice
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