preterm birth review

Best Practice & Research Clinical Obstetrics and GynaecologyVol. xx, No. xx, pp. 1–17, 2007doi:10.1016/j.bpobgyn.2007.03.001

available online at http://www.sciencedirect.com

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3

Epidemiology and environmental

factors in preterm labour

Deirdre J. Murphy* MD, MRCOG

Professor of Obstetrics and Gynaecology, Trinity College, University of Dublin

Department of Obstetrics and Gynaecology, Trinity Centre for Health Sciences, St James’s Hospital, Dublin 8, Ireland

An epidemiological and environmental approach is the appropriate starting point to understandingpreterm labour. Although there are multiple aetiologies it seems likely that anthropometricand environmental risk factors in combination with inherent genetic susceptibilities contributeto an increased risk of preterm labour for certain women. Poct 2pulation-based studies identi-fying risk factors and quantifying outcomes facilitate informed counselling and provide a frame-work for developing prediction tools. Carefully conducted case-control and cohort studiesidentify associations that may contribute to an understanding of causation. A combined approachencompassing epidemiology, pathophysiology and clinical research is required to understand theaetiologies, prevention and optimal management of preterm labour. This review focuses on theepidemiology of preterm labour and the role of environmental factors.

Key words: preterm labour; epidemiology; environmental factors; risk factor; risk assessment.

The precise aetiologies of preterm labour remain elusive, limiting the development ofpreventative and therapeutic strategies. An understanding of the pathogenesis andmechanisms of preterm labour should start with an exploration of epidemiologicaland environmental factors. There may be clues within patient demographics, fetaldemographics, the intrauterine and extrauterine environment, genetic profiling (mater-nal, paternal and fetal) and interactions between these factors. Epidemiologicalresearch aims to identify causative risk factors and, although our current knowledgemay not prevent preterm labour, it may allow prediction and early intervention withoptimisation of the clinical circumstances around birth. Risk-based screening andassessment can influence the type of care received, place of birth and judicious useof steroids, all determinants of perinatal outcome. Epidemiological research has animportant role in patient counselling for any pregnancy complicated by preterm labour

* Tel.: þ353 (0)1 4531888; Fax: þ353 (0)1 4531614.

E-mail address: [email protected]

1521-6934/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Deirdre J Murphy, Epidemiology and environmental factors in preterm

labour, Best Practice & Research Clinical Obstetrics and Gynaecology (2007), doi:10.1016/

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but particularly for future potential pregnancies where there may be significant risksfor the mother and baby.

EPIDEMIOLOGY

Defining the problem

Preterm birth may result from preterm labour, spontaneous or induced, or it may beplanned by caesarean section due to maternal or fetal complications. The term ‘indi-cated’ delivery is used to describe circumstances where preterm birth is the preferredmanagement approach and preterm labour usually refers to unplanned spontaneouslabour. It is now recognised that there is a degree of overlap between ‘indicated’ pretermbirth and spontaneous preterm labour, and that these two clinical subtypes may sharecommon aetiologies.1,2 For example, a woman may present at 36 weeks’ gestationand be diagnosed clinically with a placental abruption. The decision may be to proceedto delivery (induced labour or caesarean section) because of unacceptable maternaland fetal risks. Equally, it is likely that she would labour spontaneously with an evolvingretroplacental bleed. The former would be described as an ‘indicated’ delivery in manystudies although clearly antepartum haemorrhage is a recognised aetiology of pretermlabour. For the purposes of this review the emphasis will be on spontaneous pretermlabour with recognition that there is an overlap with ‘indicated’ delivery.

Preterm labour refers to labour with an onset before 37 weeks’ gestation. This isessentially an arbitrary lower cut-off for a ‘term’ pregnancy and there is clearly a bigdifference between labour at 27 weeks’ gestation and labour at 36 weeks and 6 days.From an epidemiological perspective it is possible to evaluate exposures (potential riskfactors) and outcomes (morbidity or mortality) on a gestational week by week basisand this approach offers certain statistical advantages. However, most studies catego-rise births to allow comparisons of gestational age groups that share similarities andare of a reasonable sample size. Epidemiological studies of preterm labour vary interms of categorisation but in general terms labour at <24 weeks is consideredpre-viable, <28 weeks is extremely preterm, 28–31 weeks very preterm and 32–36weeks mildly (or moderately) preterm.3 The risk factors for worsening degrees ofprematurity may be similar but there is evidence that the strength of associationsincreases.4 The emphasis in this review will be on preterm labour at <32 weeks’gestation where there is greatest risk and the strongest evidence base.

Many studies categorise neonatal events and outcomes by birth weight but clearlythis has the added complication of including small for gestational age babies who maynot be preterm. In addition the presence within a cohort of small for gestational agebabies, some of whom may be growth restricted, may confound associations.5 There-fore, studies that are defined by gestational age are preferred when exploring theaetiologies and outcomes of preterm labour.

The critics of epidemiology will argue that population-based studies may describeany number of associations but they do not define the cause of disease. The argumentbetween association and causation is an old one and in fact the epidemiological ap-proach has remarkable similarities to laboratory-based approaches. Careful systematicresearch of clearly defined questions with biologically plausible mechanisms repeatedin different settings and different populations, and with a dose–response relationshipleads to a tentative suggestion of causation. These criteria were laid down by BradfordHill in 19656 and are outlined in Table 1. This approach can be demonstrated in some



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carefully designed epidemiological studies of preterm labour and has been exploited bygeneticists and laboratory-based scientists within the relatively new fields of ‘geneticepidemiology’ and ‘bioinformatics’. Recent studies have recognised the importanceof looking at the interaction between epidemiological, environmental and geneticfactors when seeking to understand the origins of preterm labour.

Changing epidemiology

Preterm births comprise 6–10% of all births in Western countries and account formore than two-thirds of all perinatal deaths. Even small changes in rates of pretermbirth could have a major impact on perinatal mortality, disability and healthcare needswithin communities. There are challenges in comparing rates of preterm labour overtime and between different settings due to inconsistent approaches to registration,ascertainment and classification of preterm birth.7 Nonetheless, factors that mightbe contributing to epidemiological changes in preterm birth include social inequality,maternal age, marital status, immigration, maternal anthropometry and exposure tocigarettes, drugs and alcohol.7

A Swedish population-based register study reported that the preterm birth ratehad decreased from 6.3% in 1984 to 5.6% in 2001 ( p< 0.0001) but with an increasein the proportion of multiple births born preterm from 0.34% to 0.71%.8 Thecomposition of different subtypes in the Scandinavian low-risk population appearedto be similar to populations with higher incidence of preterm birth and perinatal infec-tions. In contrast, the overall proportion of preterm deliveries in Denmark increasedby 22% from 1995 to 2004.9 Spontaneous preterm deliveries in primiparous women atlow risk rose 51% from 3.8% to 5.7%. There was also a significant increase in multiplebirths. There was a similar increase in singleton preterm rates in New Zealand overa 20 year period (1980–1999) and of note, the greatest increase (72%) was amongthose living in the most affluent areas.10 There was evidence of a change in risk factorsfor preterm births in France between 1981 and 1995, suggesting that the classificationof high-risk groups should be brought up to date regularly.11

Recently evaluated risk factors for preterm labour are summarised in Table 2. Thesearch for epidemiological risk factors for preterm labour needs to be a dynamicprocess as the profile of populations and the environment in which we live is subjectto change over time.

Table 1. Epidemiological studies – association or causation.

Bradford Hill criteria for causation6

Strength e strong magnitude of association

Consistency e consistent findings between different studies/settings

Specificity e exposure associated with very specific disease

Temporality e plausible temporal relationship

Biological gradient e doseeresponse relationship; increased risk with greater exposure

Plausibility e credible scientific mechanism

Coherence e consistent with natural history of disease

Experimental evidence e exposure shows results consistent with association

Analogy e similar result we can draw a relationship to



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Maternal factors

Race and ethnicity

African–American women are over-represented in rates of preterm birth which isthought to reflect multiple aetiologies. The race/ethnic-specific relations betweenpre-pregnancy body mass index (BMI) and vaginal inflammation have been exploredin a multicentre cohort of over 11,000 American women.12 Ethnicity substantiallymodified the magnitude of the BMI effect with underweight having a greater impacton preterm birth among blacks and Hispanics than among whites. Low BMI also

Table 2. Epidemiological and environmental risk factors for preterm labour.

Maternal Demographic

AfricaneAmerican/Aboriginal/Hispanic races

Low BMI/poor weight gain/excess weight gain

Young maternal age

Obstetric

Previous early pregnancy loss e induced/miscarriage

Previous preterm birth e indicated or spontaneous labour

Short inter-pregnancy interval (<12 months)

Medical

Procedures e LLETZ/amniocentesis

Fetal Male gender

Multi-fetal pregnancy

Assisted conception

Paternal Older paternal age

Environmental Infection

Bacterial vaginosis/sexually transmitted infection

Periodontal infection

Socioeconomic/psychosocial

Social inequality/poverty/neighbourhood disadvantage

Physical violence

Marital status e single/cohabitation in context of high marriage rates

Stressful/traumatic life events/anxiety/depression

Substance use/toxins

Excess alcohol e �3 drinks per day/�7 drinks per week

Smoking e any but particularly moderate or heavy

Cocaine e usually influenced by smoking

Pollutants e sulphur dioxide, particulate matter

Nutrition

Elevated homocysteine/suboptimal vitamin B-12 and B-6

Unbalanced polyunsaturated fatty acids (PUFA)

Multivitamin (non-use)

Genetic TNF-a pro-inflammatory cytokine e polymorphisms

Factor VII/XIII e polymorphisms



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increased the risk of a high level of neutrophils and high vaginal pH measurement.Cardiovascular reactivity was examined in another US study of black and white militarywomen. The two-fold increase in risk of preterm delivery among black women mayreflect their higher cardiac reactivity on computerised stress testing (autonomicdysfunction) compared to white women.13

In Minnesota, USA, native-born black women were at almost 1.5 times the riskof foreign-born blacks for delivery preterm, suggesting an association with residentialracial segregation.14 The social context has been explored further in a study in Ohio,USA, including measures of neighbourhood disadvantage.15 Neighbourhood povertyrates and housing vacancy rates increased the rate of very preterm birth for blacksbut with direct effects of cumulative exposure to inequality only for Hispanics.

There are higher rates of spontaneous preterm birth among aboriginal women inCanada compared to non-aboriginal women with modifiable risk factors, includinglow weight gain during pregnancy, inadequate prenatal care and high levels of perceivedstress.16 Similarly, rates of preterm birth are much higher for women living in Francewho were born in the overseas French territories in the Caribbean, Indian Ocean andsub-Saharan Africa. Excess risk was reported for spontaneous and medically indicatedpreterm delivery.17

Anthropometric and demographic factors

There has been a growing awareness of the adverse pregnancy consequences of ma-ternal obesity; however, preterm labour may be associated with extremes of maternalweight. Three anthropometric measurements were evaluated as predictors for spon-taneous preterm birth in a systematic review.18 The predictive value of BMI, weightgain in pregnancy and maternal height were reported in eight primary studies of122,647 women. All three maternal factors were poor predictors of preterm labourwith heterogeneity between studies. The main criticism of the studies related tothe use of a 37 weeks’ gestation cut-off with a recommendation for future studiesto use a more clinically appropriate reference standard of birth before 32–34 weeks’gestation. A more recent study has evaluated the combined effects of pre-pregnancyBMI and weight gain during pregnancy with categorisation of prematurity as very(20–31 weeks) and moderately (32–36 weeks) preterm.18 There was a strongassociation between very low weight gain and very preterm delivery that was of great-est magnitude among underweight women (adjusted OR 9.8, 95% CI 7.0–13.8).Women with very high weight gain had approximately twice the odds of very pretermdelivery, regardless of pre-pregnancy BMI.

Physical activity correlates with weight and weight gain but there is a need todifferentiate between leisure time exercise and the activities of daily living. In a studyof low income women in Maryland, USA, leisure-time exercise (�60 days in first andsecond trimester) had a protective effect on preterm delivery (<37 weeks) (OR 0.51,95% CI 0.27–0.95) but the risk was increased for women who had to climb stairsmore than ten times per day (OR 1.60, 95% CI 1.05–2.46).19 There was a U-shapedrelationship with television watching. These findings warrant further investigationwith attention to potential confounding or interaction with maternal weight. Similarly,women with poor physical function reflecting the mother’s pre-pregnancy healthstatus were nearly twice as likely to deliver preterm (OR 1.97; 95% CI 1.18–3.30)even after adjusting for sociodemographic and pregnancy risk factors.20

The association between young maternal age and preterm labour remains contro-versial. In a Brazilian study where the prevalence of teenage pregnancy was high (29%)



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the risks of preterm birth were compared for women aged under 18 years, 18–19years and a reference group aged 25–29 years.21 In the analysis adjusted for relevantconfounding factors, the risk of preterm birth was higher for women aged under18 years (OR 1.70, 95% CI 1.02–3.08) but the risk was no higher for woman aged18–19 years or among non-primiparous teenagers. This suggests that the associationbetween young maternal age and preterm birth may have a biological basis or may bedue to residual confounding. The adolescents in a US study were significantly morelikely to be African–American, single and to have been diagnosed with a sexually trans-mitted infection in pregnancy which may confound the reported association with pre-term delivery (RR 1.12, 95% CI 1.04–1.21).22

Previous obstetric history

There is an increased tendency for preterm birth to recur in subsequent pregnancies.In a US study of over 150,000 consecutive singleton births, if the first pregnancyresulted in a spontaneous preterm birth, then affected women were more likely todeliver preterm spontaneously in the subsequent pregnancy (adjusted OR 3.6, 95%CI 3.2–4.0).2 This applied even if the first pregnancy was a medically indicated pretermbirth (OR 1.6, 95% CI 1.3–2.1). The greatest risk of recurrence tended to occuraround the same gestational age as the preterm birth in the first pregnancy.

The inter-pregnancy interval appears to contribute to the recurrence of pretermbirth. Women in Taiwan with inter-pregnancy intervals of <12 months were atincreased risk for a preterm birth in the subsequent pregnancy (OR 4.2, 95% CI3.0–6.0).23 The risk decreased as the inter-pregnancy interval increased with a rela-tively low risk at 18–48 months. Similarly, in a case-control study in Israel an intervalof <12 months was associated with an increased risk of preterm labour before34 weeks.24

In a Swedish study of over 600,000 women, previous spontaneous and missed mis-carriages were associated with an increased risk of preterm premature rupture ofmembranes and preterm labour with the strongest association for delivery before32 weeks.25 Similarly, threatened miscarriage in the first trimester has been associatedwith preterm delivery (OR 3.0) in a large US prospective study.26 Induced abortion hasbeen associated with very preterm delivery (<33 weeks) in the French regionalEPIPAGE study (OR 1.5, 95% CI 1.1–2.0)27 and this was confirmed by the InternationalEUROPOP study across ten European countries.28 The strength of associationincreased with decreasing gestational age and was consistent across countries withvarying rates of induced abortion. The increased risk included idiopathic preterm la-bour, preterm premature rupture of membranes and antepartum haemorrhage, butnot maternal hypertension indicated delivery. In a high-risk population of Americanwomen a previous second trimester delivery or termination before 20 weeks was as-sociated with pre-viable premature rupture of membranes or labour (14–24 weeks).29

Medical procedures

A systematic review of obstetric outcomes after conservative treatment for intraepi-thelial or early invasive cervical lesions explored the relationship between large loopexcision of the transformation zone (LLETZ) and the risk of preterm delivery.30 Therisk of preterm delivery was increased (RR 1.70, 95% CI 1.24–2.35) as was the risk ofpremature rupture of the membranes (RR 2.69, 95% CI 1.62–4.46).



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For the index pregnancy, genetic amniocentesis performed in the second trimesteris associated with an increased risk of both spontaneous and induced preterm delivery(adjusted OR 1.59, 95% CI 1.31–1.92).31

Fetal factors

The existence of a male excess among preterm births may shed some light on the ae-tiology of preterm labour. A study measuring the association between fetal sex andpreterm birth in four original datasets reported more males among preterm andvery preterm births in most populations, including in vitro fertilisation (IVF) births(OR 1.09–1.24).32 There was no male excess for two cohorts of black births or forspontaneous onset births after IVF. The male excess appeared to be strongest forspontaneous preterm births but not for induced births in the general population,and remains unexplained.

Multi-fetal pregnancy is a well known contributor to spontaneous preterm labourand accounts for 10% of all preterm births.3 The impact of increasing numbers of twinsand triplets on rates of preterm births has been investigated in an Internationalstudy.33 In each country (Canada, England and Wales, France, United States) theincrease in preterm delivery among multiple births contributed to the rise or stabili-sation of the overall rates of preterm delivery. The increase in multi-fetal pregnancy asa result of subfertility treatment has an important role to play as twins resulting fromsubfertility treatment have an increased risk of preterm birth compared with naturallyconceived twins, albeit confined to mildly preterm birth (34–36 weeks) (OR 1.6, 95%CI 1.3–1.8).34

Paternal factors

Advanced paternal age has been reported to impair pregnancy outcome. In an Italianstudy of women aged 20–29 years the odds of preterm birth increased with paternalage, with the strongest association for very preterm birth (<32 weeks).35 The ORamong men aged 45–49 years reached 1.91 (95% CI 1.08–3.38). Similarly, in a Danishstudy of first born babies to mothers aged 20–29 years the risk of preterm birth in-creased with paternal age almost entirely resulting from an association with very pre-term birth (<32 weeks).36 Compared with fathers aged 20–24 years the odds ratiosincreased linearly to 2.1 for fathers aged 50þ. The relationship between paternal andmaternal age differences and adverse perinatal outcomes was investigated in a USstudy of almost 9 million births.37 An increase in preterm delivery was reportedamong white women who were older than their partners but there was little evidenceof an increase for black women with varying parental age differences. This studydemonstrated that race and maternal age contribute to the effects of parental agedifference on the risk of preterm birth.

ENVIRONMENTAL FACTORS

Infection

Many studies have confirmed associations between genital tract infection and pretermlabour. A large number of clinical trials have evaluated antibiotic regimens as potentialtherapeutic strategies. Bacterial vaginosis and Trichomonas vaginalis are two of the most



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studied organisms in this context, with two recent large scale trials.38,39 Concomitantinfection with Chlamydia trachomatis among women with bacterial vaginosis or Tricho-monas vaginalis was not associated with a statistically increased risk of preterm birth.40

Similarly, the gestational age at which bacterial vaginosis was screened and diagnoseddid not influence the increased risk of preterm birth.41 However, in a prospective lon-gitudinal study of 3614 women, increased psychosocial stress was associated withgreater bacterial vaginosis prevalence and incidence independent of other riskfactors.42 There is also evidence to suggest that a change in vaginal flora following an-tibiotic therapy, with an increase in Escherichia coli or Klebsiella pneumoniae, results inan increased risk of preterm birth (OR 1.5, 95% CI 1.05–2.1).43

The role of oral pathogens in the aetiology of preterm labour is a relatively recentarea of research. The hypothesis is that chronic periodontal infection serves as a res-ervoir for bacterial products and/or inflammatory mediators that play a role in the de-velopment of preterm labour and preterm low birth weight.44 The Oral Conditionsand Pregnancy (OCAP) study investigated 1020 women with antepartum and postpar-tum periodontal examination.45 Antepartum moderate–severe periodontal diseasewas associated with an increased incidence of spontaneous preterm births (adjustedRR 2.0, 95% CI 1.2–3.2). There was also a higher rate of very preterm delivery amongwomen with periodontal disease progression (RR 2.4, 95% CI 1.1–5.2). A case-controlstudy of 161 mothers in Hungary reported an association between maternal periodon-tal disease and preterm delivery with more than six implicated pathogens (e.g. Prevo-tella and Pophyromomas species).46 However, earlier results conflict with studiesreporting no association.47 There appears to be an association between vaginal bleed-ing, fetal exposure to oral pathogens and preterm birth at <35 weeks.48 It remains tobe determined whether the bleeding is the cause or result of fetal exposure to oralpathogens but it is certainly a plausible hypothesis.

Socioeconomic factors

Preterm labour is strongly associated with social disadvantage and recurs in successivepregnancies, increasing the burden of healthcare needs and disability on vulnerablefamilies. The role of social class inequality was examined in a Scottish cohort study be-tween 1980 and 2000.49 The distribution of social class changed over time with greaterinequalities by the end of the 1990s than at the start of the 1980s. Over that timeperiod the relative index of inequality (RII) for preterm birth increased from 1.52(95% CI 1.44–1.61) to 1.75 (95% CI 1.65–1.86). Despite a previous decrease in the1980s, social inequality and its effects on preterm birth increased in the 1990s. Socialfactors are also reported to be important determinants of preterm birth in transitionalRussia with increased risk among women with lower levels of education and in students.50

Physical violence during pregnancy has been evaluated in a number of studies.Severe physical violence was significantly associated with spontaneous preterm labourin a study of 550 participants in North Carolina, USA.51 The body site injured, timingof violence and number of violent incidents were significant factors. A further study inBirmingham, Alabama, USA confirmed this finding with preterm birth in 10.2% ofwomen subjected to physical violence (OR 1.6, 95% CI 1.3–2.5).52 In a South Africanstudy of 229 interviewees, violence alone did not seem to cause preterm labour butwas part of a low socioeconomic lifestyle, including high maternal alcohol use.53

There is a significant elevated risk of preterm birth associated with both cohabita-tion (OR 1.29, 95% CI 1.08–1.55) and single motherhood (OR 1.61, 95% CI 1.26–2.07)



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for women living in European countries where fewer than 20% of births occur outsidemarriage.54 In contrast, there is no excess risk associated with marital status whenout-of-marriage births are more common.

Stress and psychosocial factors

It has been postulated that maternal stress may modulate the pregnant woman’ssusceptibility to preterm labour. A biobehavioural model has been proposed whereinmaternal stress may act via a neuroendocrine pathway that activates the maternal–placental–fetal endocrine systems that promote parturition, and/or via an immune/inflammatory pathway where maternal stress may increase susceptibility to intrauterineand fetal infectious–inflammatory processes.55 A review of published studies reportsconflicting results but the combined evidence from the three largest Scandinavian studiessuggests an association between perceived maternal life event stress and pretermdelivery.56 The concept of ‘premature ageing’ has been suggested as a result ofcumulative stress or a major traumatic event.57 Maternal stress has been suggested asan explanation for racial disparity in preterm labour; however, the results of the fewstudies to date are mixed.58

In a study of French women, anxiety and depression combined with specific bio-medical factors (underweight) was associated with spontaneous preterm labour.59

Similarly, thin women with a poor psychosocial profile who were depressed duringpregnancy were at increased risk of preterm birth in a prospective study of low in-come, predominantly African–American, women in Alabama, USA.60 In another studyof maternal psychosocial factors, an unplanned pregnancy was not associated with anincreased risk of preterm birth.61

Substance use

The difficulty with studies evaluating alcohol exposure in pregnancy relates to under-reporting of intake and discrepancies in the description of a ‘drink’ or unit of alcohol.Moderate intake defined as three or more drinks a day increased the risk of pretermbirth in an Italian study (OR 2.0, 1.8 and 1.9, respectively, for each trimester of preg-nancy).62 There appeared to be a dose–response effect in a large Danish study withthe highest risk for very preterm delivery among women consuming seven or moredrinks per week (RR 3.26, 95% CI 0.80–13.24).63

The relationship between smoking and adverse pregnancy outcomes, includingpreterm birth, has been described. Smokers were more likely to give birth to very pre-term babies in a French study (adjusted OR 1.7, 95% CI 1.3–2.2).64,65 The relationshipbetween heavy smoking and very preterm birth was complex with a reduced risk ofvery preterm birth due to gestational hypertension but an increased risk due to othercauses for both low to moderate and heavy smoking. Similarly, in a Swedish study,moderate and heavy smokers were at increased risk of preterm labour from all causes(OR 1.9; 95% CI 1.0–3.6,and OR 2.6, 95% CI 1.1–1.6, respectively).66

Prenatal cocaine exposure increased the risk of prematurity (OR 2.24) in a study ofwomen in Kentucky, USA.67 Tobacco but not marijuana significantly influenced theoutcome with a greater aetiological fraction attributable to tobacco. In another studyof psychiatric and substance use disorders, each had an independent association withpreterm delivery (OR 2.4, 95% CI 2.3–2.6 for substance use).68



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Few therapeutic drugs are tested in pregnancy but inadvertent or clinically indicatedexposure can occur. A pharmaco-epidemiological study of Danish women reportedthat sumatriptan (for headache) was associated with an increased risk of pretermdelivery and low birth weight.69 The authors acknowledged that this may reflect theimpact of disease severity or residual confounding rather than the treatment itself.

Nutrition

A few studies have explored nutritional factors as potential aetiological factors forpreterm labour. A small case-control study of Chinese women reported elevatedhomocysteine and suboptimal vitamin B-12 and B-6 status in association with pretermbirth (<37 weeks).70 Folate status was not associated with preterm birth. Theseresults would need to be confirmed in larger studies. Women who take pre-conceptional multivitamins appear to have a lower risk of both early (<35 weeks)and late (35–36 weeks) preterm birth (OR 0.59, 95% CI 0.12–2.76, and OR 0.40,95% CI 0.12–1.40, respectively).71

Dietary supplementation of omega-3 has been suggested as secondary prophylaxisof preterm delivery in response to data suggesting that omega-3 fatty acids are capableof prolonging the duration of gestation in the range of 4–7 days and that dietary intakeis marginal in Western populations.72 Carefully conducted randomised controlled tri-als would be required to establish the efficacy and effectiveness of such an approach.The research on polyunsaturated fatty acids (PUFA) is not entirely consistent and maydepend on the environmental setting. The relation between intake of seafood in preg-nancy and preterm delivery was evaluated in a Danish prospective cohort of 8729women73, Adjusted odds for preterm delivery were increased by a factor of 3.6(95% CI 1.2–11.2) in the zero consumption group compared with the highest con-sumption group. There was a dose–response relation reflecting an intake of up to0.15 g n-3 fatty acids. It was postulated that small amounts of fish or fish oil may conferprotection against preterm delivery. However, in a US study of seafood intake andlength of gestation, elongated n-3 PUFA intake and seafood intake were not associatedwith length of gestation or risk of preterm birth.74

Coffee drinking in pregnancy was evaluated in a case-control study of over 2000women in Italy. Compared with no consumption, a low consumption of coffee duringpregnancy did not have any significant effects on preterm birth, with results close tounity for overall intake of caffeine.75

Pollution

Low level air pollution was evaluated in a cohort of 3988 newborn singletons in thecity of Kaunas, Lithuania.76 The risk of preterm birth increased by 25% (adjustedOR 1.25; 95% CI 1.07–1.46) per 10 mg/m3 increase in nitrogen dioxide concentrationbut there was no association with formaldehyde exposure. A time series analysis ofpreterm births in Pennsylvania, USA provided evidence of an increase in preterm birthwith exposure to particulate matter �10 mm (PM10) and increasing levels of sulphurdioxide.77 Traffic air pollution in Los Angeles, USA disproportionately affected lowsocioeconomic status neighbourhoods in a study of traffic-related air pollution,economic hardship and preterm birth.78 The authors concluded that efforts need tofocus not only on individual risk factors but also on the reduction of localised airpollution in any strategy to reduce preterm births.



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There was little effect of occupational exposures to pesticides on pregnancy out-comes among gardeners and farmers in Denmark, although the authors emphasisedthat these findings may not apply to other countries.79 Similarly the risk of pretermbirth was not increased with use of the pesticides DDT and DDE in a study of20,754 pregnancies in San Francisco, USA, but more robust studies were recommen-ded prior to concluding safety, especially given the continuing role of these agents inmalaria control.80 A number of studies from Taiwan have addressed industrial air pol-lution from the petrochemical, petroleum, cement and thermal power industries.81–84

Each study reported a significant association between air pollution and the risk ofpreterm delivery with varying odds ratios (1.14–1.30).

GENETIC EPIDEMIOLOGY

Recent attention has focussed on the potential for genetic epidemiology to contributeto our understanding of preterm labour. The emphasis is not only on identifyingpotential maternal and fetal genetic susceptibilities but on exploring how these factorsinteract with demographic, socioeconomic and psychosocial factors in activatingneuroendocrine and inflammatory pathophysiological processes.

In a review of 18 studies that examined associations between polymorphisms in thematernal or fetal genome and preterm birth, polymorphisms in tumour necrosis factoralpha (TNF-a), a proinflammatory cytokine, showed the most consistent increase inthe risk of preterm birth.85 A case-control study from Philadelphia, USA reportedan increased risk of spontaneous preterm birth with maternal carriage of the TNF-2 allele and the association was modified by the presence of bacterial vaginosis (OR6.1, 95% CI 1.9–21.0).86 This study provides preliminary evidence that an interactionbetween TNF genetic susceptibility and environmental factors (i.e. bacterial vaginosis)is associated with an increased risk of spontaneous preterm birth. In a further study,selected TNF haplotypes were associated with spontaneous preterm birth in bothAfrican–American and white subjects.87

The impact of genetic polymorphisms with prothrombotic and antithrombotic ef-fects on the occurrence of preterm birth has been investigated in a large cohort ofvery low birth weight infants and their mothers.88 Factor V Leiden, Factor VII, FactorXIII and the prothrombin G20210A mutation were examined. The maternal carrierstatus of the Factor VII-121del/ins polymorphism (OR 1.7, 95% CI 1.1–2.5) andthe lower frequency of infant’s factor XIII-Val34Leu polymorphism (OR 0.5, 95% CI0.3–0.96) were found to be independently associated with preterm delivery.

Dihydrofolate reductase (DHFR) is required to convert the folic acid used in sup-plements and food fortification to the reduced folate forms used for cell division. TheDHFR 19-base pair deletion allele was associated with a greater risk of preterm deliv-ery in a US study of 324 women (adjusted OR 3.0, 95% CI 1.0–8.8).89 In the presenceof low dietary folate, the allele may be a risk factor for preterm birth, reflectinga gene–environment interaction.

Intergenerational effects would support the role for genetic susceptibility in theaetiology of preterm labour, although clearly environmental factors may persist throughgenerations of families. The Scandinavian countries have high quality longitudinal birthregistries that allow an evaluation of intergenerational effects on perinatal outcomes.In a study of over 38,000 Swedish mother–first born offspring pairs, there was noconsistent evidence of an intergenerational effect for preterm birth, although such anassociation was present for reduced intrauterine growth.90 Changes in putative genetic



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and environmental risk factors were investigated in a Danish study of over 10,000women with successive births.91 There was a strong tendency to repeat pretermdelivery with a moderate increase in recurrence with social decline and moving froma rural to an urban municipality, but no change in recurrence risk with change ofmale partner.

PREDICTION OF PRETERM LABOUR

The epidemiological and environmental risk factors for preterm labour can be ex-ploited to allow identification of high-risk women. The challenge lies in identifyingthe high-risk first time mother given the wide range of risk factors that could applyto the entire pregnant population in settings of deprivation. The woman who has la-boured preterm in a previous pregnancy is readily identifiable and this is one of thestrongest predictors of recurrent preterm labour.

The accuracy of risk scores in predicting preterm birth has been explored in a sys-tematic review of 19 primary accuracy articles evaluating 12 different risk-scoringsystems.92 The point estimates for the likelihood ratios varied widely among thedifferent risk-scoring systems. In otherwise asymptomatic women risk scoring in earlypregnancy had a wide range of accuracy in predicting spontaneous preterm birth andpoor specificity.

The combination of individual patient factors with cervical length scanning and/or rapid fetal fibronectin testing has been proposed to allow prediction of pretermdelivery in patients with preterm labour. One such risk score (CLEOPATRA) hasbeen evaluated in 170 patients with preterm labour at 24–34 weeks.93 Themodel with fetal fibronectin (CLEOPATRA II) performed better, with a discrimina-tory power 0.81 (95% CI 0.69–0.93). In contrast, for twins the prediction of spon-taneous preterm delivery was not improved by combining maternal characteristicsand measurement of cervical length at 22–24 weeks.94 It has been proposed thatnew screening tests (epidemiological and clinical) should not be applied systemati-cally to all pregnant women until their advantages and drawbacks are fullyevaluated.95

SUMMARY

There are many clues to the aetiologies of preterm labour within carefully con-ducted epidemiological and environmental studies. It is clear that no single approachwill be effective for prevention or treatment as there appear to be complex inter-actions between maternal anthropometry, environmental exposures and genetic sus-ceptibility of the mother and fetus. In some ways this should be a source ofoptimism as there may be several targets for intervention once the complete path-way to preterm labour is understood. Risk-scoring tools have been disappointing forlow-risk populations but the woman who has laboured and delivered preterm ina previous pregnancy should be advised to delay pregnancy for at least a year andcan be monitored closely for recurrence. Women should be counselled on modifi-able risk factors which will also encourage a healthier lifestyle. A coordinated re-search approach that brings together the disciplines of epidemiology, laboratory-based science and clinical trials offers the best hope of significant advances in thisimportant aspect of perinatal care.



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� a careful antenatal booking history can screen for risk factors for pretermlabour, although the predictive value and specificity of scoring systems are poor� advise women about modifiable risks factors for preterm labour, including low

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