American Journal of Epidemiology Advance Access published August 27, 2009 American Journal of Epidemiology ª The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail:
[email protected].
DOI: 10.1093/aje/kwp211
Original Contribution Metabolic Syndrome in Early Pregnancy and Risk of Preterm Birth
Leda Chatzi, Estel Plana, Vasiliki Daraki, Polyxeni Karakosta, Dimitris Alegkakis, Christos Tsatsanis, Antonis Kafatos, Antonis Koutis, and Manolis Kogevinas Initially submitted March 3, 2009; accepted for publication June 19, 2009.
The authors determined the association between metabolic syndrome in early pregnancy (mean, 11.96 weeks) and the risk of preterm birth in the mother-child cohort study (‘‘Rhea’’ Study) in Crete, Greece, 2007–2009. Maternal fasting serum samples were collected, and blood pressure was measured at the time of the first major ultrasound examination (n ¼ 625). Multivariable log-binomial regression models were used. Women with metabolic syndrome were at high risk for preterm birth (relative risk (RR) ¼ 2.93, 95% confidence interval (CI): 1.53, 5.58), with the highest risk observed for medically indicated preterm births (RR ¼ 5.13, 95% CI: 1.97, 13.38). Among the components of metabolic syndrome, the most significant risk factor was hypertension (RR ¼ 2.32, 95% CI: 1.28, 4.20). An elevation of 10 mm Hg in diastolic blood pressure increased the relative risk for preterm birth by 29% (RR ¼ 1.29, 95% CI: 1.08, 1.53), while a per unit increase in the low density lipoprotein/high density lipoprotein cholesterol ratio increased this risk by 19% (RR ¼ 1.19, 95% CI: 1.02, 1.39). Fetal weight growth restriction was associated with elevated levels of insulin (RR ¼ 1.14, 95% CI: 1.08, 1.20) and diastolic blood pressure (RR ¼ 1.27, 95% CI: 1.00, 1.61) in early pregnancy. These findings suggest that women with metabolic syndrome in early pregnancy had higher risk for preterm birth. fetal growth retardation; metabolic syndrome X; premature birth
Abbreviations: CI, confidence interval; HDL, high density lipoprotein; LDL, low density lipoprotein; RR, relative risk.
A substantial body of epidemiologic evidence suggests that a poor in utero environment elicited by maternal dietary or placental insufficiency may ‘‘program’’ susceptibility in the fetus to later development of cardiovascular and metabolic disease. Moreover, epidemiologic studies suggest that women who deliver preterm (8, 9) or low-birth-weight infants (10, 11) have a higher risk later in life for cardiovascular disease. The metabolic profile of pregnant women who give birth to preterm or fetal growth-restricted neonates is not well investigated. A plausible hypothesis is that pregnant women with characteristics of metabolic syndrome give birth to preterm or fetal growth-restricted neonates that will later develop metabolic syndrome as children or young adults. Previous studies have reported associations between prepregnancy obesity (12–14), chronic hypertension (15–17), dyslipidemia, and inflammation in early pregnancy (18, 19)
The metabolic syndrome is described as a cluster of metabolic abnormalities that appear to directly promote the development of atherosclerotic cardiovascular disease and are characterized by chronic low-grade systemic inflammation (1–3). It is associated with the rising incidence of obesity in developed countries and is reaching epidemic proportions affecting between 24% and 34% of the US population (4) and up to 36% of Europeans aged 40–55 years (5). In a recent study in Greece, the prevalence of metabolic syndrome was 25% in adult men and 15% in women according to the National Cholesterol Education Program, Adult Treatment Panel III, definition (6). Metabolic syndrome is not a universally accepted entity and, although certain cardiovascular risk factors undoubtedly occur together more often than expected by chance, the underlying pathophysiology of the syndrome is unclear (7).
Correspondence to Dr. Leda Chatzi, Department of Social Medicine, Faculty of Medicine, University of Crete, P.O. Box 2208, Heraklion 71003, Crete, Greece (e-mail:
[email protected]).
1
2
Chatzi et al.
and high risk of preterm birth and intrauterine growth restriction. There are no studies, however, on the association between maternal metabolic syndrome in early pregnancy examined as a whole phenotype with birth outcomes. The objective of this study was to determine the association between metabolic syndrome characteristics in early pregnancy and the risk for delivery of a singleton preterm or fetal weight growth-restricted neonate. MATERIALS AND METHODS The mother-child cohort in Crete (Rhea Study)
The mother-child ‘‘Rhea’’ Study in Crete, Greece, is a prospective cohort examining a population sample of pregnant women and their children, at the prefecture of Heraklion. Pregnant women (Greek and immigrants) residents that became pregnant during 1 year starting in February 2007 have been contacted and asked to participate in the study. The first contact was made before 15 weeks’ gestation, at the time of the first major ultrasound examination. Participants were invited to provide blood and urine samples and to participate in a face-to-face interview. Women were then contacted at the sixth month of pregnancy, at birth, and 1 month after birth, and they are currently contacted at 6 months and 2 years after birth. Face-to-face structured questionnaires, together with self-administered questionnaires and medical records, were used to obtain information on several factors including maternal age, education, height, prepregnancy weight, weight at blood collection, reproductive and medical histories, lifestyle (tobacco smoking and environmental tobacco smoke, consumption of medicaments, physical activity, and so on), and hours since last meal at blood collection. The study was approved by the corresponding ethical committees, and all participants provided written, informed consent. During the study period, 1,765 eligible women were approached, 1,610 (91%) agreed to participate, and 1,317 (82%) were followed up until delivery. Only singleton pregnancies were included in this analysis (n ¼ 1,281). A total of 833 participants provided blood samples and, of them, 730 provided fasting blood samples. Women who experienced spontaneous or induced abortions (n ¼ 51) or gave birth to stillborn infants (n ¼ 2) were excluded as were those women with incomplete diagnostic information (n ¼ 39) for any of the following reasons: person moved, person delivered elsewhere, and/or medical records were missing. We also excluded 13 women with preeclampsia (8 in this and 5 in previous pregnancies), because this condition is associated with a higher probability of induced preterm birth. Hence, a cohort of 625 women was available for this analysis. Biochemical analyses
Maternal fasting serum samples were collected at the first prenatal visit at or before 15 weeks’ gestation (mean, 11.96 weeks; standard deviation, 1.49) in 10-mL vacutainer tubes, centrifuged, and then stored in aliquots at 80C until assayed.
Plasma triglycerides, total cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, and glucose concentrations were determined by using standard enzymatic procedures on an automatic analyzer (AU5400 high-volume chemistry analyzer; Olympus America, Inc., Melville, New York). The inter- and intraassay coefficients of variation for all parameters were less than 5%. The insulin concentration was determined by an IMMULITE 2000 immunoassay system (Siemens Healthcare Diagnostics, Inc., Deerfield, Illinois). The inter- and intraassay coefficients of variation were less than 9%. Insulin sensitivity was calculated by a homeostasis model assessment approach (glucose (mg/dl) 3 insulin (mU/ mL/405)) (20). All analyses were performed without knowledge of birth outcomes. Maternal anthropometry
Height, measured at the first prenatal visit, and prepregnancy weight, as reported at the first major ultrasound visit, were used to calculate the prepregnant body mass index (weight (kg)/height (m)2). Maternal blood pressure
Systolic and diastolic blood pressures were measured at the first major ultrasound visit at or before 15 weeks’ gestation. Measurements were taken by using an electronic blood pressure monitor after 10 minutes of rest in a sitting position. Appropriate size cuffs were used with cuff width 40% of the mid-arm circumference. All readings were replicated 3 times in the right arm for each woman. The mean value obtained from the second and third readings was used in the analysis. Definition of metabolic syndrome in early pregnancy
All participants were classified as having metabolic syndrome or not, according to the definitions provided by the recent National Cholesterol Education Program, Adult Treatment Panel III, criteria (1), with some considerations taken into account to adapt to our study population of pregnant women. Abdominal circumference was not considered as a criterion of obesity, although obesity was defined as a body mass index higher than 30 kg/m2 prepregnancy. In particular, the metabolic syndrome was diagnosed if 3 or more of the following risk factors were present: a prepregnancy body mass index of >30 kg/m2; a triglyceride level of 150 mg/dL; a HDL cholesterol level of 30
60
10.6
16
76.2
