Analysis of data from this large prospective cohort of low-risk nulliparous pregnant women have demonstrated that clinical risk factors, including cervical length and uterine artery Doppler ultrasound measurements at 20 weeks, have only a modest predictive capacity for the two major phenotypes of SPTB. In this particular analysis we selected a case-control approach instead of a case – non case approach because of potential overlap in pathophysiology not only between the 2 major phenotypes but also between iatrogenic preterm birth and SPTB. Most likely, a strict case-non case approach would have further dropped the performance of the models. While it is clear that these risk markers by themselves cannot be translated into a useful clinical tool for daily practice, the data provide further insight into these conditions.
The minimal overlap between risk factors for SPTB-PPROM and SPTB-IM reinforces the increasingly accepted view that SPTB is a heterogeneous entity with different pathological pathways leading to SPTB with or without intact membranes 
and also differences between patients with SPTB at different gestational ages 
. This heterogeneity is illustrated by the observation that antepartum haemorrhage (APH) is significantly more common in the SPTB-IM group (24%) than the SPTB-PPROM group (8.6%) or term births (5.5%). APH was not entered in the multivariate analysis since it occurs by definition after 20 weeks’ gestation.
Regarding variables related to placentation, we found a lengthier sexual relationship (as a continuum) known to exert a protective effect for preeclampsia and intra-uterine growth restriction 
, to be associated with a small but significant increased risk for SPTB-PPROM. It should be noted that in univariate analysis (), conceiving within 3 months () was also less common in both SPTB phenotypes compared with term birth (SPTB-IM p
0.038; SPTB-PPROM p
0.06). In contrast, donor insemination was significantly (p
0.005) more common in the SPTB-PPROM group (8 out of 60; 13.3%) versus term birth (4.8%). While, the presence of abnormal uterine Doppler flow patterns at the time of the morphology scan nearly doubled the risk for SPTB-IM this was not an independent risk factor for SPTB-PPROM. Also recurrent vaginal bleeding in early pregnancy, a previously described risk factor 
, while doubling the risk for SPTB-IM was not a risk factor for SPTB-PROM.
Decreased cervical length (per mm decrease) was the only variable with a comparable effect in both SPTB phenotypes; 4 and 5% increased risk for SPTB-IM and SPTB-PPROM, respectively. This would mean that for example the risk for SPTB for two comparable nulliparous pregnant women with cervical length of 41 mm versus 28 mm at 20 weeks gestation would be at least 60% higher in the woman with the shorter cervix. Using a cost-effectiveness analysis, Werner et al 
predicted if there were universal cervical length screening, there would be a net health improvement of 735 quality adjusted life years and net savings to the healthcare system (USA data) of $19 million for every 100 000 women screened. This cost-effectiveness analysis was primarily based on the Fonseca et al 
study, but the results were analysed and confirmed by including the recent result of the Hassan et al multicentre study 
. Unfortunately, these 2 large multicentre vaginal progesterone studies do not specifically address the SPTB phenotype.
Most of the independent risk factors for SPTB-IM could, at least in theory, fit in one of the seven major molecular pathways previously described by Romero et al 
. ‘Not feeling as well’ could be a marker of stress or lack of support, and as such fits in one of the pathways to preterm birth 
. In contrast to several epidemiological studies on stress and employment 
, the other variables capturing data on employment, income, anxiety and depression were not independent risk factors.
We have shown that marijuana is a strong ‘environmental risk factor or SPTB-IM in this population. We are unable to determine whether this association is due to a toxic effect of marijuana or is a marker of a suite of lifestyle factors that contribute to the risk. Pre-pregnancy marijuana use may be a more reliable marker since one can anticipate that women would be more likely to disclose it than persistent marijuana use during pregnancy. In contrast to the results of this large prospective cohort study, large American population studies 
, did not find an association between maternal marijuana use and preterm birth.
In this cohort of 3234 low risk nulliparous women, with 156 cases of SPTB, we do find the highest rate of smokers amongst the SPTB-IM group (22.9% versus 10.6% in term births; p 0.00), with an intermediate rate in the SPTB-PPROM group (15%; p 0.291). However, smoking was not an independent risk factor for either phenotype. Because of our very rich data it is possible that the effect of smoking is now explained by other variables in the models such as abnormal uterine artery Doppler 
. Maternal tobacco smoking has typically been described as a risk factor for SPTB in many studies; however the mechanism for this effect remains unclear 
. In a retrospective cohort study covering all preterm births in the major tertiary referral centre in Western Australia during the period 2004–2008, Henderson et al 
found a significant association of smoking in only one SPTB subtype: SPTB-PPROM between 27 and 33 weeks’ gestation, and suggested that these data indicate that tobacco smoking may have a specific effect on the fetal membranes while not influencing spontaneous labour. Furthermore, an analysis based on a large Swedish population cohort 
demonstrated that smoking (≥10 cigarettes per day; odds ratio 1.7) was primarily associated with increased risks of very preterm birth and there were small numbers of very preterm births in this cohort.
Ethnic differences in the prevalence of various adverse pregnancy outcomes, including SPTB, have been previously described 
. Although specific high risk genetic polymorphisms may partially explain those ethnic differences, most studies appear to point to socio-economic deprivation, smoking, obesity, poverty-induced stress and the associated poor nutrition as the key mediators. It should be noted that the non-Caucasian pregnant women in this SCOPE cohort consisted primarily of women of Asian descent and to a lesser degree also Maori and Pacific Island women. The low total number of non-Caucasian ethnicities did not permit further sub-analysis. Surprisingly (on univariate comparison) Caucasian ethnicity was significantly more common in the SPTB-IM group. Being of Caucasian ethnicity, as an independent variable in the regression model, more than doubled the risk for SPTB-IM, although the 95% CI just crossed 1. Although this was not captured by our socio-economic variables, these findings might be explained by the fact that women in the Australian part of the SCOPE study come from one of the most underprivileged urban areas in Australia with a primarily Caucasian population 
. Our data demonstrate that taking a full family history can provide potentially important indicators for risk for SPTB, as a strong family history of low birth weight babies was the strongest risk factor with odds exceeding 5 (albeit present in just over 1% of the whole cohort) for SPTB-IM, while a positive family history in the mother for preeclampsia and any type of diabetes more than doubled the risk.
In addition to decreased cervical length, BMI was the only variable present in both models. Conventional wisdom indicates that women with low BMI are at increased risk for SPTB, while the association between maternal overweight or obesity and SPTB remains controversial. Heterogeneity in the definitions of pregnancy outcomes (spontaneous vs. medically indicated PTB) and the inclusion of different gestational ages in delivery categories in various studies are probably only a partial explanation for these controversies 
. In this prospective cohort low BMI, doubled the risk for SPTB-PPROM with the odds ratio just crossing 1 (odds ratio 2.1; 95% CI 0.93–4.54). It is not surprising that the contemporary literature regarding BMI and the risk for preterm birth, and indeed any adverse pregnancy outcome, is often conflicting. In the past low BMI was associated with undernutrition. However, more recently obesity has become a marker of socio-economic deprivation with overconsumption of calorie-dense but nutrient-poor food 
In contrast to the independent risk factors associated with SPTB-IM, those associated with SPTB-PPROM are largely difficult to explain, and considering the number of variables in the final analysis for SPTB-PROM (49 variables) could well represent false discoveries for some of these findings.
To our knowledge, these data are the first to suggest that greater maternal height only provides protection from SPTB-PPROM but not SPTB-IM. Chan et al 
previously reported that Asian women of shorter stature were at a higher risk of preterm birth. Transgenerational reproductive adaptation, i.e. earlier birth to allow safe passage through a smaller pelvis has been suggested 
, while other explanations like women of shorter stature having a shorter cervix have been rejected 
While being born preterm has received recent recognition as a risk factor for developing hypertension as an adult 
, this is to our knowledge the first time that having mild hypertension (patients with severe hypertension requiring medication were excluded) has been identified as an independent risk factor for SPTB-PPROM with an odds ratio of 9.65 (95% CI 2.5–37.1). Interestingly a family history of recurrent gestational diabetes was associated with SPTB-PPROM, albeit with wide confidence intervals. It is tempting to speculate that the presence of the insulin resistance syndrome would explain these associations 
. This may also explain the risk associated with hormonal fertility treatment, but again one would typically expect a clear association with the use of clomiphene; an association not demonstrable in this dataset.
It is difficult to explain why waking up during the night would be protective against SPTB-PPROM. Future studies on the full international SCOPE cohort of 5600 women may finally reveal whether this ‘protective’ factor represents a true finding. Similarly, inexplicable at this moment in time, appears to be the risk reduction associated with having a mother who had a miscarriage. Just as surprising was the finding of a doubling of risk associated with the index mother not being the first-born. Thinking of possible suboptimal placentation in the first pregnancy, one would anticipate the opposite.
Variables relating to dental health were only available in just over 30% of recruited women. In these women dental health, as assessed by several specific questions on easily bleeding gums, swollen gums, and sore teeth was no different between women with term birth and women with SPTB-IM or SPTB-PPROM. It should be noted that a recent systematic review 
on periodontal disease came to an estimated odds ratio of 1.78 (CI 95%: 1.58, 2.01) for SPTB. Our negative findings regarding periodontal health and preterm labour could also be explained by the fact that self-assessed dental health by pregnant women is poorly associated with more objective markers as identified by a professional oral and dental examination 
A major strength of this study was its large multicentre prospective design with excellent follow-up. It should be noted that although the current study reports on a large very well defined prospective cohort of more than 3000 healthy nulliparous women, identification of risk factors in the current study risk factor was based on only 156 women with their pregnancies complicated by SPTB. To identify risk factors for very-early preterm birth, much larger prospective cohorts will be required.
The dissimilarity of clinical risk factors for SPTB-IM compared with SPTB-PPROM indicates different pathophysiological pathways underlie these distinct sub-phenotypes of spontaneous preterm birth. The ability to predict SPTB in healthy nulliparous women using clinical characteristics is modest. Given no reliable biomarkers have emerged as risk predictors of SPTB 
, the development of a clinically useful test will probably require SPTB phenotype-specific combinations of clinical risk factors and the discovery and evaluation of novel biomarkers.