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00004872-201109000-0000600004872_2011_29_1703_macdonald_preeclampsia_9article< 103_0_10_5 >Journal of Hypertension© 2011 Lippincott Williams & Wilkins, Inc.Volume 29(9)September 2011p 1703–1711Established preeclampsia risk factors are related to patterns of blood pressure change in normal term pregnancy: findings from the Avon Longitudinal Study of Parents and Children[Original papers: Epidemiology]Macdonald-Wallis, Corriea; Tilling, Kateb; Fraser, Abigaila; Nelson, Scott M.c; Lawlor, Debbie A.aaMRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of BristolbSchool of Social and Community Medicine, University of Bristol, Bristol, UKcCentre for Population and Health Sciences, University of Glasgow, Glasgow, Scotland, UKCorrespondence to Corrie Macdonald-Wallis, MRC CAiTE Centre, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK Tel: +44 117 3310086; fax: +44 117 3310123; e-mail: C.Macdonald-Wallis@bristol.ac.ukAbbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; BP, blood pressure; HDP, hypertensive disorder of pregnancy; sFlt1, soluble fms-like tyrosine kinase 1This study was presented by C. Macdonald-Wallis, K. Tilling, A. Fraser, S.M. Nelson, D.A. Lawlor, Patterns of blood pressure change in pregnancy and their determinants, at the 5th Conference of Epidemiological Longitudinal Studies in Europe, 13–15 October 2010, Paphos, Cyprus.Received 21 March, 2011Revised 2 June, 2011Accepted 15 June, 2011Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website ().AbstractObjective: Hypertension during pregnancy is one of the diagnostic criteria for preeclampsia. We investigated the pattern of blood pressure (BP) change across pregnancy and associations of risk factors for preeclampsia with BP changes in normal pregnancy.Methods: We examined repeat antenatal BP measurements (median 14 per woman) of 11 789 women from the Avon Longitudinal Study of Parents and Children cohort with a live-term birth and no evidence of preeclampsia or previous hypertension. Linear spline random effects models with knots at 18, 30 and 36 weeks gestation described changes in BP with gestational age.Results: On average, SBP and DBP decreased slowly until 18 weeks and rose from 18 weeks onwards, with increasing rate at 30 weeks and then again at 36 weeks. In obese women, BP was higher at 8 weeks and rose more slowly between 18 and 30 weeks and more rapidly between 30 and 36 weeks than in normal-weight women. Nulliparous women had higher BP at 8 weeks and faster increases in DBP from 30 weeks and SBP from 36 weeks onwards than multiparas. Women who smoked throughout pregnancy had lower BP at 8 weeks and throughout pregnancy; women who only smoked in the first trimester soon attained the same pattern of change as never smokers. In twin pregnancies, BP rose more rapidly from 30 weeks onwards than in singleton pregnancies.Conclusion: Established preeclampsia risk factors are associated with higher BP in early pregnancy and faster BP increases later in gestation in normal pregnancy, suggesting a continuum of risk.IntroductionPreeclampsia is associated with increased risk of maternal and perinatal mortality [1–3], iatrogenic preterm birth and intrauterine growth restriction [4,5], higher childhood blood pressure (BP) in offspring [6,7] and future cardiovascular disease in mothers [8,9]. The cause of preeclampsia is unknown; however, it is positively associated with a range of maternal risk factors including maternal age, nulliparity, BMI and multiple pregnancy [10] and negatively associated with smoking [11,12] and possibly socioeconomic position [13–16]. Hypertension in late pregnancy is part of the diagnostic criteria, in conjunction with proteinuria, for preeclampsia. Several studies conducted in the 1960–1980s demonstrated that on average BP decreases towards mid-pregnancy and increases in late pregnancy [17–19]. More recently, a Swedish study of 600 women without hypertensive disorders of pregnancy (HDPs), with a minimum of 10 BP measurements per woman, and a larger study in the USA (N = 1733, mean 7.4 measurements per woman), including women with HDPs, found similar patterns for DBP, but only increases across pregnancy in SBP [20,21]. Statistical methods have progressed since the 1980s, enabling longitudinal changes in BP in individuals to be modeled, but studies that have done so have been relatively small [21] or used few repeat BP measurements [22].The relationships of age [23], parity [20,23], prepregnancy BMI [21,24] and smoking [18,22] with BP during pregnancy have been explored in early and contemporary studies, often with conflicting findings [18,20,22,23]. As many of these have included women with preeclampsia, it is currently unclear whether the preeclampsia risk factors are associated with BP changes in healthy term pregnancies. This is important, as this would suggest that preeclampsia may represent the upper end of a continuum of pregnancy-related changes. Furthermore, the relationships of smoking and socioeconomic position with preeclampsia risk differ from those with BP outside of pregnancy (positive association of smoking [25] and consistent inverse association of socioeconomic position [26–29] with BP). Examining associations of these characteristics with BP change in healthy pregnancy should provide insight into whether these changes are related to an underlying risk for hypertension or to distinct pregnancy effects.We therefore sought to describe the patterns of change in BP during normal pregnancy, using repeated antenatal BP measurements in a large cohort of women, and to investigate the associations of a number of established risk factors for preeclampsia (maternal age, parity, BMI, smoking, socioeconomic position and multiple pregnancy) with patterns of change.MethodsThe Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective birth cohort study investigating the health and development of children. The study has been described in full elsewhere [30] and on the Web site www.bristol.ac.uk/alspac . Women with expected delivery dates between 1 April 1991 and 31 December 1992 living in Avon during pregnancy were eligible for recruitment. Ethical approval for the study was obtained from the ALSPAC Law and Ethics Committee and from the National Health Service (NHS) local ethics committee. In total, 14 541 women were enrolled, 13 863 had singleton or twin pregnancies resulting in all live births and 13 644 of these women had data abstracted from obstetric records. We excluded women with preeclampsia [defined according to International Society for the Study of Hypertension in Pregnancy criteria: SBP ≥140 mmHg or DBP ≥90 mmHg, measured on two occasions after 20 weeks gestation, with proteinuria of at least 1+ on dipstick testing (Albustix; Ames Company, Elkhart, Indiana, USA) [31]] and those who reported a previous diagnosis of hypertension (N = 739). We restricted analyses to term pregnancies (≥37 weeks gestation) and excluded mothers with triplets (N = 3) and quads (N = 1) due to the small numbers and potential that their identity would be known. After these exclusions, 11 789 women remained.All BP measurements taken routinely as part of antenatal care by midwives or obstetricians were abstracted from obstetric medical records by six trained research midwives. There was no between-midwife variation in mean values of the data abstracted and error rates were consistently less than 1% in repeated data entry checks. These were single BP measurements taken in the seated position using the appropriate cuff size and DBP was measured using Korotkoff phase V. This resulted in a median of 14 and interquartile range of 11–16 measurements of BP per woman across pregnancy. The gestational age at each visit was derived from the date of measurement and the expected delivery date.Maternal age at delivery, number of fetuses and offspring sex were abstracted from obstetric records. Maternal parity, highest educational qualification, prepregnancy weight and height and smoking status were obtained from questionnaires administered during early pregnancy. BMI was calculated as weight (kg)/height (m)2 and classed according to World Health Organization definitions of underweight (<18.5 kg/m2), normal (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2) and obese (≥30.0 kg/m2). Smoking status was categorized as ‘never’ for women who did not smoke regularly immediately prior to or during pregnancy; ‘prepregnancy/first trimester’ for women who smoked immediately prior to pregnancy or in the first 3 months and then stopped; and ‘throughout’ for women who continued to smoke after the first 3 months.Statistical analysisThe BP data are clustered within women, and thus all analyses used multilevel models with two levels (antenatal visit within woman) to take into account the correlation between BP measures on the same woman.Using data for the entire cohort of 11 789 women, fractional polynomial curves were fitted to obtain the average shape trajectories of SBP and DBP by gestational age. These were used to determine the approximate positions of knots (indicating changes in slope) in linear spline random effects models with SBP and DBP as outcomes and gestational age in weeks as the exposure. Although earlier measurements were included in the models (as part of the first spline), baseline was set at 8 weeks gestation because there were few observations prior to this. The best-fitting linear spline models had three knots at 18, 30 and 36 weeks gestation, providing five parameters: mean BP at 8 weeks gestation and mean BP change per week between 8 and 18 weeks, 18 and 30 weeks, 30 and 36 weeks and from 36 weeks until delivery. Further information on the development of these models is included in supplemental material on the journal Web site.A subset of 9023 women with complete data on all maternal characteristics (prepregnancy BMI, age, parity, smoking status, education and number and sex of fetuses) was then used to create a multivariable model, including a main effect and an interaction term between each maternal characteristic and each spline. The resultant coefficients provide the association of each characteristic with BP at baseline (8 weeks gestation) and with the average rate of change in BP between each pair of knot points.As the first knot point represented a nadir in BP and because definitions of preeclampsia use elevated BP after a point assumed to be the natural nadir, we calculated an approximate 95% confidence interval for the position of the first knot using the profile likelihood method [32] assuming that knot locations could occur only at whole weeks.ResultsTable 1 shows the characteristics of all the women with antenatal BP measurements abstracted from obstetric notes (N = 11 789) and of women who had no missing data for any of these characteristics (N = 9023, subset for multivariable models). The distributions of each of the maternal characteristics were similar in both subsets.Table 1 Characteristics of all women in the full dataset and in the subset with no missing data used in the multivariable modelThe average patterns of SBP and DBP change are shown in Fig. 1 and described in Web Table 1, http://links.lww.com/HJH/A106 . Both SBP and DBP decreased on average until 18 weeks gestation, increased between 18 and 30 weeks, then increased more rapidly between 30 and 36 weeks and more rapidly again from 36 weeks onwards. However, the 95% reference ranges demonstrate that in each period, some individual women experience changes in the opposite direction to the overall average. The 95% confidence interval for the location of the first knot in the SBP model was from weeks 17 to 18 of gestation and for DBP from weeks 18 to 19.Fig. 1. no caption available.Figures 2a–f shows how the predicted SBP trajectories varied with each of the risk factors in the multivariable models. Obese women had higher SBP throughout pregnancy, which began to rise later than in normal-weight women and showed a smaller absolute increase (Fig. 2a). Women over 35 years of age had the highest SBP on average throughout most of pregnancy and a steeper gain in SBP in late pregnancy (Fig. 2b). Nulliparous women had higher SBP throughout pregnancy and a steeper rise in late pregnancy than multiparous women (Fig. 2c). Women who smoked throughout pregnancy had lower SBP throughout pregnancy then never smokers, whereas women who smoked only prepregnancy/first trimester had lower SBP in early pregnancy but similar SBP later in pregnancy to women who never smoked (Fig. 2d). SBP trajectories varied little by maternal education level, although women qualified to O level had the highest SBP throughout pregnancy (Fig. 2e). Women pregnant with twins had relatively small changes in SBP during early pregnancy but a steep rise in late pregnancy (Fig. 2f). The equivalent trajectories for DBP are shown in Web Figs 1a–f, http://links.lww.com/HJH/A106 and showed similar relationships to the SBP trajectories, except that there was a clearer trend of higher DBP in early pregnancy with increasing maternal age (Web Fig. 1b, http://links.lww.com/HJH/A106 ).Fig. 2. no caption available.Tables 2 and 3 give the associations of each of the risk factors with SBP and DBP at 8 weeks gestation, respectively, and with average change in each period of pregnancy from the multivariable spline model. In the reference category (normal BMI, aged 25–29 years, nulliparous, never smoked, O level qualification and male singleton pregnancy) at 8 weeks gestation, the mean SBP was 113 mmHg and mean DBP was 66 mmHg; both SBP and DBP decreased to 18 weeks and increased from 18 weeks onwards, with increasing rate from 30 weeks and then again from 36 weeks. SBP and DBP at 8 weeks were higher in overweight or obese compared with normal-weight women, those aged over 35 years compared with those aged 25–29 years, for nulliparas than for multiparas and for women who never smoked compared with women who smoked either prepregnancy/first trimester only or throughout pregnancy. Women qualified to O level had higher SBP at 8 weeks than those with any other education level and women pregnant with male singletons had higher SBP than those with female singletons. DBP at 8 weeks was not associated with maternal education and there was no difference in BP at 8 weeks between singleton and twin pregnancies.Table 2 Mean differences (95% confidence interval) in SBP at 8 weeks gestation and average changes in SBP at different stages of pregnancy associated with maternal characteristics in multivariable mutually-adjusted spline model (N = 9023)aTable 3 Mean differences (95% confidence interval) in DBP at 8 weeks gestation and average changes in DBP at different stages of pregnancy associated with maternal characteristics in multivariable mutually-adjusted spline model (N = 9023)aIn obese women, SBP changed more slowly and in the opposite direction to that of normal-weight women prior to 30 weeks, but increased more rapidly between 30 and 36 weeks and more slowly than for normal-weight women from 36 weeks onwards. The DBP of both underweight and obese women rose more slowly between 18 and 30 weeks and more rapidly between 30 and 36 weeks than in normal-weight women and obese women had a slower DBP increase from 36 weeks onwards. Women aged over 35 years had a faster increase in SBP from 36 weeks onwards than 25–29-year-old women and women aged less than 20 or 20–24 years had a smaller increase in DBP between 30 and 36 weeks compared with 25–29 year-old women. Multiparous women had a slower rise in DBP from 30 weeks onwards and SBP from 36 weeks onwards compared with nulliparous women. Women who smoked prepregnancy/first trimester only had a faster rise in SBP and DBP between 18 and 30 weeks and a slower rise in SBP between 30 and 36 weeks compared with women who never smoked. Smoking throughout pregnancy was not associated with changes in BP. SBP rose more slowly between 18 and 30 weeks for women with a certificate of secondary education (CSE)/vocational qualification than for those qualified to O level, but maternal education was not associated with changes in DBP. Twin pregnancies had average SBP changes in the opposite direction to those of singleton pregnancies prior to 30 weeks and were associated with greater SBP and DBP increases from 30 weeks onwards.DiscussionIn this large study of women without preeclampsia, we found that SBP and DBP decreased slowly until 18 weeks gestation and rose from 18 weeks onwards, with increasing rate at 30 weeks and then again at 36 weeks. With the exception of twin pregnancy, established risk factors for preeclampsia (maternal obesity, age and parity) were associated with higher mean BP at 8 weeks gestation and greater rates of increase in later gestation. Twin pregnancy was associated with a greater rise in BP in later pregnancy but not with earlier levels.A similar but smaller analysis of repeated gestational BP measurements also demonstrated a positive association of prepregnancy BMI category with BP in early pregnancy and with a later and smaller overall rise [21]. Another study found that BP was higher in all trimesters of pregnancy for overweight or obese compared with normal-weight women [24]. Strevens et al.[20], although reporting a greater increase in DBP in late pregnancy in nulliparous compared with multiparas, did not observe any difference in SBP with parity, despite parity consistently being associated with a lower risk of preeclampsia. This may reflect the number of patients studied and lack of power to detect differences in SBP. Christianson [23] found that nulliparous women had higher SBP and DBP throughout pregnancy than multiparous women.We found that smoking throughout pregnancy was associated with consistently lower BP, but not with changes in BP. Remarkably, women who smoked immediately prepregnancy or in the first trimester only had reduced BP in early pregnancy, but then attained similar patterns of change to women who never smoked. In contrast, a study with fewer BP measurements per woman (maximum of three) found steeper rises in SBP and DBP across pregnancy in women who smoked compared with nonsmokers [22]. However, they did not investigate specific associations of smoking with BP changes in different periods of pregnancy. Consistent with our findings in women without preeclampsia, studies have shown that women who only smoke in early pregnancy have a slightly reduced risk of preeclampsia, although not to the extent of women who smoke throughout pregnancy, whereas women who quit smoking prior to pregnancy have little or no difference in risk compared with nonsmokers [12]. Studies have demonstrated an increased risk of preeclampsia in users of Swedish snuff (a smokeless tobacco) compared with non-tobacco users, suggesting that it is not nicotine but some product of combustion that is associated with the protective effect [33,34].Lower socioeconomic position is generally associated with hypertension outside of pregnancy [26–29], but there is conflicting evidence about its association with preeclampsia risk [13–16]. We found no clear relationship of lower maternal education with BP early in pregnancy or patterns of change in BP in our study. The similarity of associations of socioeconomic position and smoking with BP in normal term pregnancy to associations of these risk factors with preeclampsia (which differ from associations with BP outside of pregnancy) suggests that there are distinct BP changes in pregnancy that differ from underlying risk for higher BP. Understanding more about the mechanisms underlying these pregnancy-related changes may facilitate the development of effective treatments for and means of preventing preeclampsia.The notable finding of our study is that in term pregnancies in which the woman has no evidence of established hypertension or preeclampsia, the majority of risk factors for preeclampsia are associated with higher blood pressure at 8 weeks gestation and greater increases during pregnancy. Preeclampsia is characterized by two stages, the first involving poor placentation and the second, in which the clinical symptoms of hypertension and proteinuria are manifested, resulting from the maternal response to factors such as soluble fms-like tyrosine kinase 1 (sFlt1) released into the circulation by the hypoxic placenta; although in some cases, abnormal placentation does not occur [35]. The patterns of association we observed might reflect the general association of these risk factors (even in healthy pregnancy) on these two stages. Thus, factors associated with BP at 8 weeks and change in early pregnancy may act via mechanisms that affect placentation; associations with later change in BP may be related to the mother's ability to respond to the hypoxic placenta. There is evidence that circulating sFlt1 levels are higher in twin compared with singleton pregnancies without preeclampsia [36]; however, this may be due to the greater placental mass rather than placental hypoxia [36].The nadir in BP occurred at around 18 weeks gestation and our approximate 95% confidence intervals for this change in BP direction did not include the 20 weeks marker used for diagnosis of HDPs. This feature is likely to depend on the population studied, as BP did not begin to rise until later in obese women and twin pregnancies. However, if the 18-week nadir was confirmed in other cohorts, it may be appropriate to use this earlier cutoff in the definition of HDPs.Limitations to our study include the use of routinely collected clinic BP measurements, meaning that we are unable to ascertain the type of BP monitor used or the extent to which assessments were standardized within clinics. Information on clinic of delivery was available for 60% of women and findings were comparable between the two main clinics suggesting that variation in practice between clinics was not an important source of bias; however, use of routinely collected measurements may have increased random measurement error. BP is also subject to high variability throughout the day, but this is unlikely to introduce bias, as preference in appointment times is unlikely to change over pregnancy or between different subgroups of women. Despite these limitations, use of routine clinical measurements is also a relative strength of the generalizability of our findings, as such measurements continue to form the basis upon which diagnoses of HDPs are made in clinical practice.We specifically did not include women with preeclampsia in this analysis, as they would have been more likely to have a preterm delivery. In future studies, it will be possible to compare BP change up to a given gestational age (e.g. 33 weeks) to incorporate the high proportion of women with preeclampsia being delivered preterm, but in this article, we have importantly described patterns of BP change up to term in healthy women. There were relatively few twin pregnancies in the study, with only three having BP measurements after 40 weeks gestation, so BP predictions after 40 weeks may be unreliable in twin pregnancies. However, as few twin pregnancies last to term, the patterns found for this subgroup are likely to be generalizable to twin pregnancies. The pregnancies we studied occurred approximately 20 years ago and due to changes in lifestyle and nutritional habits since then, these findings should be replicated in more recent cohorts to ensure that similar patterns of association are present. We would not expect the associations to change over time if they represent true biological effects, and have adjusted for several characteristics related to lifestyle, but cannot rule out the possibility of a small degree of residual confounding by unmeasured lifestyle factors. Also, the recent rise in maternal obesity in the UK population [37] may mean that in a more recent UK cohort, the nadir in BP would occur slightly later on average, as in our study, we found the rise in BP started at a later gestational age in obese compared with normal-weight women. The study's strengths are that it is large, provides many repeated measurements per woman and has the ability to examine associations of multiple risk factors for HDPs with BP change at different stages of pregnancy.In conclusion, in normal healthy pregnancy, we found the BP nadir to be 18 weeks. The 20 weeks threshold used to define HDPs is based on an assumed nadir of 20 weeks and changing the definition to 18 weeks gestation should be considered if our findings are replicated in other studies. We also found that established risk factors for preeclampsia are associated with greater BP at 8 weeks gestation and greater risk in BP across pregnancy in women who deliver at term and have no evidence of preeclampsia or existing hypertension. This suggests a continuum of BP risk during pregnancy and that interventions aimed at preventing HDPs should be targeted at all women from early in pregnancy or during preconception counseling.AcknowledgementsThis work was supported by the US NIH (grant number R01 DK077659) and UK Wellcome Trust (grant number WT087997MA). Core support for ALSPAC is provided by the UK Medical Research Council (MRC), the Wellcome Trust and the University of Bristol. The UK MRC provides funding for the MRC CAiTE centre (grant number G0600705). 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A nationally representative study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989–2007. Int J Obesity 2010; 34:420–428. [Context Link] Avon Longitudinal Study of Parents and Children; blood pressure; BMI; parity; pregnancy; smoking; twinsEstablished preeclampsia risk factors are related to patterns of blood pressure change in normal term pregnancy: findings from the Avon Longitudinal Study of Parents and ChildrenMacdonald-Wallis, Corrie; Tilling, Kate; Fraser, Abigail; Nelson, Scott M.; Lawlor, Debbie A.Original papers: Epidemiology929