Janet M. Catov

Maternal Serum 25-Hydroxyvitamin D Concentrations Are Associated with Small-for-Gestational Age Births in White Women

Maternal vitamin D deficiency has been associated with numerous adverse health outcomes, but its association with fetal growth restriction remains uncertain. We sought to elucidate the association between maternal serum 25-hydroxyvitamin D [25(OH)D] concentrations in early pregnancy and the risk of small-for-gestational age birth (SGA) and explore the association between maternal single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene and the risk of SGA. We conducted a nested case-control study of nulliparous pregnant women with singleton pregnancies who delivered SGA infants (n = 77 white and n = 34 black) or non-SGA infants (n = 196 white and n = 105 black). Women were followed from <16 wk gestation to delivery. Womens banked sera at <22 wk were newly measured for 25(OH)D and DNA extracted for VDR genotyping. SGA was defined as live-born infants that were <10th percentile of birth weight according to nomograms based on gender and gestational age. After confounder adjustment, there was a U-shaped relation between serum 25(OH)D and risk of SGA among white mothers, with the lowest risk from 60 to 80 nmol/L. Compared with serum 25(OH)D 37.5-75 nmol/L, SGA odds ratios (95% CI) for levels <37.5 and >75 nmol/L were 7.5 (1.8, 31.9) and 2.1 (1.2, 3.8), respectively. There was no relation between 25(OH)D and SGA risk among black mothers. One SNP in the VDR gene among white women and 3 SNP in black women were significantly associated with SGA. Our results suggest that vitamin D has a complex relation with fetal growth that may vary by race.

Pregnancy Characteristics and Women's Future Cardiovascular Health: An Underused Opportunity to Improve Women's Health?

Growing evidence indicates that women with a history of common pregnancy complications, including fetal growth restriction and preterm delivery (often combined as low birth weight), hypertensive disorders of pregnancy, and gestational diabetes, are at increased risk for cardiovascular disease later in life. The purpose of this paper was to review the associations of parity and these 4 pregnancy complications with cardiovascular morbidity and mortality; to review the role of cardiovascular risk factors before, during, and after pregnancy complications in explaining these associations; and to explore the implications of this emerging science for new research and policy. We systematically searched for relevant cohort and case-control studies in Medline through December 2012 and used citation searches for already published reviews to identify new studies. The findings of this review suggest consistent and often strong associations of pregnancy complications with latent and future cardiovascular disease. Many pregnancy complications appear to be preceded by subclinical vascular and metabolic dysfunction, suggesting that the complications may be useful markers of latent high-risk cardiovascular trajectories. With further replication research, these findings would support the utility of these prevalent pregnancy complications in identifying high-risk women for screening, prevention, and treatment of cardiovascular disease, the leading cause of morbidity and mortality among women.

Health of children born to mothers who had preeclampsia: a population-based cohort study

OBJECTIVE We assessed whether preeclampsia correlates with the long-term postnatal health of the offspring. STUDY DESIGN We conducted a population-based cohort study of 1,618,481 singletons born in Denmark (1978-2004) with up to 27 years of follow-up. We used Cox regression to estimate the associations between preeclampsia and long-term health outcomes of the offspring. RESULTS Children born at term exposed to preeclampsia had an increased risk of a variety of diseases, such as endocrine, nutritional, and metabolic diseases (incidence rate ratio, 1.6; 95% confidence interval, 1.5-1.7), and diseases of the blood and blood-forming organs (incidence rate ratio, 1.5; 95% confidence interval, 1.3-1.8). Children born preterm exposed to preeclampsia had a similar pattern of hospitalizations compared with the children born preterm unexposed to preeclampsia, although they had a decreased risk of cerebral palsy (incidence rate ratio, 0.7; 95% confidence interval, 0.6-0.9). CONCLUSION Preeclampsia was associated with an increased risk of being hospitalized for a number of diseases, especially in the children born at term.

Periconceptional multivitamin use and risk of preterm or small-for-gestational-age births in the Danish National Birth Cohort

BACKGROUND The intake of periconceptional multivitamins may decrease the risk of preterm births (PTBs) or small-for-gestational-age (SGA) births. OBJECTIVE We related the timing and frequency of periconceptional multivitamin use to SGA births and PTBs and its clinical presentations (ie, preterm labor, premature rupture of membranes, and medical induction). DESIGN Women in the Danish National Birth Cohort (n = 35,897) reported the number of weeks of multivitamin use during a 12-wk periconceptional period. Cox regression was used to estimate the relation between any multivitamin use and PTBs (<37 wk) or SGA births (birth weight adjusted for gestational age >2 SDs below the mean on the basis of fetal growth curves). The timing (preconception and postconception) and frequency of use were also analyzed. Regular users (4-6 wk) and partial users (1-3 wk) in each period were compared with nonusers. RESULTS The association between periconceptional multivitamin use and PTBs varied according to prepregnancy overweight status (P-interaction = 0.07). Regular preconception and postconception multivitamin use in women with a prepregnancy BMI (in kg/m(2)) <25 was associated with reduced risks of a PTB (HR: 0.84; 95% CI: 0.73, 0.95) and preterm labor (HR: 0.80; 95% CI: 0.69, 0.94). No similar associations were shown for overweight women. The adjusted risk of an SGA birth was reduced in multivitamin users regardless of their prepregnancy BMI (HR: 0.83; 95% CI: 0.73, 0.95), with the strongest association in regular users in the postconception period. CONCLUSION Regular periconceptional multivitamin use was associated with reduced risk of SGA births and PTBs in nonoverweight women.

Maternal vitamin D status and the risk of mild and severe preeclampsia

Background: We sought to determine the association between maternal vitamin D status at ⩽26 weeks’ gestation and the risk of preeclampsia by clinical subtype. Methods: We conducted a case–cohort study among women enrolled at 12 US sites from 1959 to 1966 in the Collaborative Perinatal Project. In serum collected at ⩽26 weeks’ gestation (median 20.9 weeks) from 717 women who later developed preeclampsia (560 mild and 157 severe cases) and from 2986 mothers without preeclampsia, we measured serum 25-hydroxyvitamin D, over 40 years later, using liquid chromatography–tandem mass spectrometry. Results: Half of women in the subcohort had 25-hydroxyvitamin D (25(OH)D) >50 nmol/L. Maternal 25(OH)D 50 to 74.9 nmol/L was associated with a reduction in the absolute and relative risk of preeclampsia and mild preeclampsia compared with 25(OH)D <30 nmol/L in the crude analysis but not after adjustment for confounders, including race, prepregnancy body mass index, and parity. For severe preeclampsia, 25(OH)D ≥50 nmol/L was associated with a reduction in three cases per 1000 pregnancies (adjusted risk difference = −0.003 [95% confidence interval = −0.005 to 0.0002]) and a 40% reduction in risk (0.65 [0.43 to 0.98]) compared with 25(OH)D <50 nmol/L. Conclusions were unchanged (1) after restricting to women with 25(OH)D measured before 22 weeks’ gestation or (2) with formal sensitivity analyses for unmeasured confounding. Conclusions: Maternal vitamin D deficiency may be a risk factor for severe preeclampsia but not for its mild subtypes. Contemporary cohorts with large numbers of severe preeclampsia cases would be needed to confirm or refute these findings.

Early or Recurrent Preterm Birth and Maternal Cardiovascular Disease Risk

PURPOSE Preterm birth (PTB) has been associated with a later increased risk of maternal cardiovascular disease (CVD). We hypothesized a more pronounced relation between early or recurrent PTB and maternal CVD risk. METHODS We related PTB severity (earlier gestational age at delivery) and recurrence (>/=2) among women with births from 1973-1983 in Denmark (n = 427,765) to maternal CVD morbidity or mortality (1977-2006). Birth data were linked to CVD hospitalizations and deaths identified in national registers and data were analyzed using Cox proportional hazards models. RESULTS Women with a prior PTB had excess CVD after adjustment for age, parity, and education (hazard ratio [HR] = 1.36 [95% confidence interval (CI): 1.31, 1.41]). This was only modestly attenuated when women with preeclampsia or small for gestational age births were excluded, and the relationship was stronger for CVD mortality (HR = 1.98 [1.73, 2.26]). Recurrent PTB was associated with higher CVD morbidity compared to women with one PTB, particularly for ischemic events (HR = 1.78 [1.40, 2.27] vs. 1.22 [1.09, 1.36]). Risk was similarly elevated among women with early, moderate, and late PTB. Sensitivity analysis suggested that confounding by smoking only partly explained these associations. CONCLUSIONS Women with PTB, especially recurrent PTB, were at increased risk for CVD, suggesting common causes of these conditions.

Association of Periconceptional Multivitamin Use With Reduced Risk of Preeclampsia Among Normal-Weight Women in the Danish National Birth Cohort

The timing and frequency of periconceptional multivitamin use may be related to the risk of preeclampsia. Women in the Danish National Birth Cohort (1997-2003) reported multivitamin or folate-only supplement use during a 12-week periconceptional period (from 4 weeks prior to 8 weeks after the last menstrual period). Preeclampsia cases were identified by using International Classification of Diseases, Tenth Revision, codes. Cox regression was used to estimate the association of frequency (weeks of use) and timing (preconception and postconception) of use with preeclampsia risk. Overall, there were 668 cases of preeclampsia (2.3%), and 18,551 women (65%) reported periconceptional multivitamin use. After adjustment, regular use (12 of 12 weeks) was related to a reduced risk of preeclampsia among normal-weight women. Compared with nonusers with a body mass index of 22 kg/m(2), regular multivitamin users with the same body mass index had a 20% reduced risk of preeclampisa (hazard ratio = 0.78, 95% confidence interval: 0.60, 0.99). In addition, regular use in the postconception period only was associated with reduced risk, a relation that also appeared to be limited to women with a body mass index of <25 kg/m(2) (hazard ratio = 0.63, 95% confidence interval: 0.42, 0.93). Folate-only supplement use was unrelated to preeclampsia risk. Regular periconceptional multivitamin use was associated with a reduced risk of preeclampsia among normal-weight women, and the immediate postconception period appeared to be the relevant exposure window.

Chronic hypertension related to risk for preterm and term small for gestational age births.

OBJECTIVE: Evidence relating chronic hypertension to risk of small for gestational age (SGA) births is conflicting. To identify factors associated with SGA that may involve a placental pathogenesis, we related chronic hypertension and other maternal factors that may be markers of endothelial dysfunction to preterm compared with term SGA births. METHODS: Chronic hypertension, diabetes, body mass index, age, and subfertility were related to risk of term and preterm SGA births in the Danish National Birth Cohort (N=81,008). Small for gestational age births were those with a birth weight adjusted for gestational age greater than two standard deviations below the mean based on fetal growth curves. RESULTS: Risk of preterm SGA increased 5.5-fold (95% confidence interval [CI] 3.2–9.4), and risk of term SGA increased 1.5-fold (1.0–2.2) among women with definite chronic hypertension. Risk of preterm SGA but not term SGA was increased among women younger than 20 (odds ratio [OR] 2.8, 95% CI 1.1–6.8) or older than 36 (OR 2.0, 95% CI 1.3–3.1) years of age and among those with at least two early spontaneous abortions (OR 2.0, CI 1.3–3.3). Smoking, parity, time to pregnancy greater than 12 months, and underweight status were similarly related to term and preterm SGA. Overweight status, obesity, and presence of diabetes were unrelated to either SGA subtype. CONCLUSION: Chronic hypertension, young or older maternal age, and recurrent early spontaneous abortions increased risk for preterm SGA. These factors may involve abnormal placentation and likely represent a pathogenesis distinct from that leading to term SGA. LEVEL OF EVIDENCE: II

Preterm delivery and later maternal cardiovascular disease risk.

Background: Women who have delivered a preterm infant are at elevated risk for cardiovascular disease (CVD), but mechanisms for this association are not understood. Methods: In a cross-sectional study we investigated whether older women with a history of preterm birth (<37 weeks) had a higher prevalence of CVD. Participants were 446 women (mean age 80 years; 47% black) enrolled in the Pittsburgh, PA field center of The Health, Aging and Body Composition Study. Women reported preterm status, birth weight, smoking status, and selected complications for each pregnancy. CVD status was determined by self-report and hospital records. Analysis was limited to first births not explicitly complicated by hypertension or preeclampsia. Results: Women who had delivered a preterm infant (on average 57 years in the past) had a higher prevalence of CVD. After adjustment for race, age, blood pressure, pulse wave velocity, interleukin-6, high-density lipoprotein cholesterol, and statin use, the odds ratio for CVD among women who delivered a preterm infant was 2.85 (95% confidence interval = 1.19–6.85) compared with women who had delivered term infants weighing more than 2500 g. This relationship was not altered by lifetime smoking history. There was evidence of negative confounding by statin use and high-density lipoprotein cholesterol. Among women delivering infants who were both preterm and low birth weight (<2500 g), the odds ratio was 3.31 (1.06–10.37) for CVD compared with women with term, normal weight infants. Conclusions: These results suggest that vascular and metabolic factors account for some but not all of the increased prevalence of CVD among women many years after a preterm birth.

Particulate air pollution exposure and C-reactive protein during early pregnancy.

Background: It is not well understood how air pollution leads to adverse pregnancy outcomes. One pathway may be through C-reactive protein, a biomarker of systemic inflammation that has been reported to increase the risk of preterm delivery. We examined whether air pollution influences serum concentrations of C-reactive protein in early pregnancy. Methods: We studied 1696 pregnant women in Allegheny County, PA, from 1997 through 2001. C-reactive protein concentrations were assayed in blood collected before the 22nd week of gestation. We estimated levels of particles of less than 10 &mgr;m (PM10) and less than 2.5 &mgr;m diameter (PM2.5), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone at the maternal zip code using Kriging interpolation for measurements obtained from ambient stations. Associations between air pollution and high C-reactive protein concentrations (≥8 ng/mL) were evaluated using logistic regression. Results: Among nonsmokers, an observed 9.2 &mgr;g/m3 increase in PM10 (averaged over 28 days prior to the blood sample) was associated with an odds ratios of 1.41 for high C-reactive protein concentrations (95% confidence interval = 0.99–2.00). Similarly, a 4.6 &mgr;g/m3 increase in PM2.5 was associated with an odds ratio of 1.47 (1.05–2.06). The odds ratio was 1.49 (0.75–2.96) per 7.9 ppb increase in ozone during summer. There were no associations in smokers or for other air pollutants, and there was no evidence for effect-measure modification by obesity. Conclusions: PM10, PM2.5, and ozone exposures were associated with increased C-reactive protein concentrations in early pregnancy, suggesting that these air pollutants contribute to inflammation and thereby possibly to adverse pregnancy outcomes.