Exploration and confirmation of factors associated with uncomplicated pregnancy in nulliparous women: prospective cohort study
- “Exploration and confirmation of factors associated with uncomplicated pregnancy in nulliparous women: prospective cohort study” by Lucy C Chappell and colleagues (BMJ 2013;347:f6398, doi:10.1136/bmj.f6398).
Objective To identify factors at 15 and 20 weeks’ gestation associated with a subsequent uncomplicated pregnancy.
Design Prospective international multicentre observational cohort study.
Setting Auckland, New Zealand and Adelaide, Australia (exploration and local replication dataset) and Manchester, Leeds, and London, United Kingdom, and Cork, Republic of Ireland (external confirmation dataset).
Participants 5628 healthy nulliparous women with a singleton pregnancy.
Main outcome measure Uncomplicated pregnancy, defined as a normotensive pregnancy delivered at >37 weeks’ gestation, resulting in a liveborn baby not small for gestational age, and the absence of any other significant pregnancy complications. In a stepwise logistic regression the comparison group was women with a complicated pregnancy.
Results Of the 5628 women, 3452 (61.3%) had an uncomplicated pregnancy. Factors that reduced the likelihood of an uncomplicated pregnancy included increased body mass index (relative risk 0.74, 95% confidence intervals 0.65 to 0.84), misuse of drugs in the first trimester (0.90, 0.84 to 0.97), mean diastolic blood pressure (for each 5 mm Hg increase 0.92, 0.91 to 0.94), and mean systolic blood pressure (for each 5 mm Hg increase 0.95, 0.94 to 0.96). Beneficial factors were prepregnancy fruit intake at least three times daily (1.09, 1.01 to 1.18) and being in paid employment (per eight hours’ increase 1.02, 1.01 to 1.04). Detrimental factors not amenable to alteration were a history of hypertension while using oral contraception, socioeconomic index, family history of any hypertensive complications in pregnancy, vaginal bleeding during pregnancy, and increasing uterine artery resistance index. Smoking in pregnancy was noted to be a detrimental factor in the initial two datasets but did not remain in the final model.
Conclusions This study identified factors associated with normal pregnancy through adoption of a novel hypothesis generating approach, which has shifted the emphasis away from adverse outcomes towards uncomplicated pregnancies. Although confirmation in other cohorts is necessary, this study implies that individually targeted lifestyle interventions (normalising maternal weight, increasing prepregnancy fruit intake, reducing blood pressure, stopping misuse of drugs) may increase the likelihood of normal pregnancy outcomes.
Trial registration Australian New Zealand Clinical Trials Registry ACTRN12607000551493.
Why do the study?
With 255 births every minute around the world, pregnancy is common. Research on pregnancy tends to focus on adverse outcomes, in an attempt to understand why things go wrong and how they can be prevented. This study takes a different approach and asks what factors are associated with healthy pregnancies, thus identifying factors that can be modified before pregnancy to help women make decisions about actions and interventions that can increase the likelihood of a normal pregnancy.
What did the authors do?
The authors carried out a prospective cohort study of women who were in their first pregnancy. Cohort studies are a type of observational study and involve assembling a group of people and following them over time to see what happens to them. Researchers collect data about the people participating in the study (the study cohort) and can then look for patterns between a particular variable and an outcome.
The authors invited nulliparous women with singleton pregnancies before 15 weeks’ gestation to participate in the study. They recruited 5628 women between August 2004 and November 2008 through hospital antenatal clinics, general practitioners, obstetricians, and community midwives in New Zealand, Australia, the United Kingdom, and the Republic of Ireland.
The participants were interviewed and examined by a research midwife at 14-16 weeks’ gestation and again at 19-21 weeks’ gestation. A lot of different information was collected during these visits, including personal information, such as socioeconomic status; obstetric, gynaecological, and medical history; family history; dietary information before conception and during pregnancy; drug history; social history, including social supports, domestic violence, and use of cigarettes and alcohol; lifestyle questionnaires on work, exercise, and sedentary activities; psychological questionnaires; physical examination; and, at the later visit, an ultrasound examination. This gave the authors a large dataset of variables to examine and analyse in relation to pregnancy outcomes.
The women were then followed prospectively throughout their pregnancy to delivery. The research midwives collected information on the outcome of the pregnancy and the health of the baby. The main outcome of interest was uncomplicated pregnancy. This was defined as a pregnancy with delivery of a liveborn baby after 37 weeks’ gestation who was not small for gestational age, where the mother’s blood pressure was normal throughout, and with no other important pregnancy complications.
In cohort studies, researchers calculate the probability of developing the outcome of interest for a given variable. For example, in this study the authors looked at the probability of having an uncomplicated pregnancy in women who were obese (body mass index >30). A measure of probability that is commonly used in cohort studies is relative risk. Relative risk presents the probability for each variable as a comparison of those who develop the outcome of interest and those who do not. For the example given above, the relative risk for a body mass index over 30 in this study would represent the probability of obese women having an uncomplicated pregnancy, compared with those who have a complicated pregnancy. The authors were interested in and included in their analysis several other prespecified variables.
As part of the analysis of the results, the authors split the participants into three groups: an exploratory group made up of 2129 women in New Zealand and Australia, a local replication set made up of 1063 women in New Zealand and Australia, and an external confirmation group comprising 2432 women in the United Kingdom and the Republic of Ireland. The authors first looked for evidence on an association between variables and uncomplicated pregnancy in the exploratory group. They then sought to confirm whether those associations still existed in a group of women who were similar to the initial exploratory group and recruited from the same area. This was the local replication set. Finally, having identified a set of associations in the exploratory group then confirmed whether those associations remained in a local replication set, the authors tested whether these associations were present in an external confirmation group. This was made up of the women in the United Kingdom and Republic of Ireland. By testing their findings in a group of women based far away from where the original associations were identified, the authors were trying to account for any local factors in New Zealand that may have given rise to the results. This increases the extent to which the results can be applied to another setting, also known as the external validity.
What did the authors find?
Of the 5628 women, 3452 (61.3%) had an uncomplicated pregnancy. The authors found that some variables were associated with an increased relative risk of uncomplicated pregnancy—that is, were beneficial, whereas others were associated with a decreased relative risk of uncomplicated pregnancy.
The results suggested that eating three pieces of fruit a day before pregnancy was associated with uncomplicated pregnancy, as was being in paid employment at 15 weeks’ gestation. Detrimental factors, indicated by a decreased relative risk of uncomplicated pregnancy, were being overweight or obese, having a raised blood pressure, and drug use in the first trimester. Non-modifiable detrimental factors included reduced socioeconomic status, vaginal bleeding (more than spotting) in the first 15 weeks of pregnancy, and a family history of hypertensive disorder in any pregnancy.
The table shows the factors that were identified in the external confirmation group and remained important in the local replication set and exploratory set. A relative risk greater than 1 suggests a beneficial effect, as it represents an increased probability of uncomplicated pregnancy. A relative risk of less than 1 suggests a detrimental effect. For results to be considered statistically significant, the 95% confidence intervals should not include 1.
|Variables||Risk ratio (95% CI)|
|Decreased risk of uncomplicated pregnancy/detrimental|
|Body mass index at 15 weeks’ gestation:|
|≥30 (v <25)||0.74 (0.65 to 0.84)|
|25-29.9 (v <25)||0.87 (0.80 to 0.94)|
|Mean blood pressure (per 5 mm Hg increase) at 15 weeks’ gestation:|
|Diastolic||0.92 (0.91 to 0.94)|
|Systolic||0.95 (0.94 to 0.96)|
|Misuse of drugs in first trimester*||0.90 (0.84 to 0.97)|
|Increased risk of uncomplicated pregnancy/beneficial|
|Prepregnancy fruit intake at least 3 times/day||1.09 (1.01 to 1.18)|
|Hours worked in paid employment (per 8 hours increase) at 15 weeks’ gestation||1.02 (1.01 to 1.04)|
What are the strengths and limitations of this study?
This study has several strengths. As previous literature has tended to focus on adverse outcomes, by focusing on factors associated with an uncomplicated pregnancy, this study is original. It also covers a topic that is relevant and interesting to patients and healthcare professionals. Confirming the findings in a local and external set of participants gives readers confidence that the results can be generalised to a population outside of New Zealand and Australia. It is unclear, however, if the results can be generalised to other women, such as multiparous women or women with twin or triplet pregnancies, as these women were not part of the original study.
There are two general limitations for all cohort studies that are important to remember. Firstly, cohort studies can only show correlation, not causality. Although a cohort study might suggest a relation between a variable and an outcome, it cannot be inferred that the variable has caused the outcome. Using this study as an example, although eating three pieces of fruit a day before pregnancy was associated with uncomplicated pregnancies, it is unknown whether this causes a healthy pregnancy because there are many other variables that may also have a role to play. To try and establish causality a different type of study would need to be done that would control for these other variables, such as a randomised controlled trial.
The second thing to consider with cohort studies is the presence of confounding factors. A confounder is a hidden, sometimes unmeasured, variable that might affect the relation between the variable being measured and the outcome of interest. This is a well recognised phenomenon, and most authors will try and identify confounding factors so that they can take them into account when doing their analysis. An example of a confounding factor that might apply to this study would be the relation between alcohol use and uncomplicated pregnancy; another variable that might affect this relation is socioeconomic status. The authors of the study did try and adjust for several different confounding factors using the wealth of information they collected during the initial interviews.
What does this study mean?
The study identified several factors that may be associated with uncomplicated pregnancies in nulliparous women. It offers a starting point for further research to strengthen this evidence base. The study findings give women the opportunity to modify these factors before and during pregnancy, and the focus on healthy behaviours reduces the “medicalisation” of pregnancy. It can also prompt public health teams and policy makers to consider interventions that promote uncomplicated pregnancies.Navjoyt Ladher, clinical editor, BMJ
1British Medical Association, London
Correspondence to: firstname.lastname@example.org
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed.
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Cite this as: Student BMJ 2014;22:g399