Geeta K. Swamy

Acute Myocardial Infarction in Pregnancy. A United States Population-Based Study

Background— The purpose of this study was to determine the incidence, mortality, and risk factors for pregnancy-related acute myocardial infarction in the United States. Methods and Results— The Nationwide Inpatient Sample for the years 2000 to 2002 was queried for all pregnancy-related discharges. A total of 859 discharges included a diagnosis of acute myocardial infarction, for a rate of 6.2 (95% confidence interval [CI] 3.0 to 9.4) per 100 000 deliveries. Among these, there were 44 deaths, for a case fatality rate of 5.1%. The odds of acute myocardial infarction were 30-fold higher for women aged 40 years and older than for women <20 years of age. Single independent variables that were statistically and clinically significant, including age, race, and certain medical conditions and obstetric complications, were entered into a multivariable logistic regression model. Hypertension (odds ratio [OR] 21.7, 95% CI 6.8 to 69.1), thrombophilia (OR 25.6, 95% CI 9.2 to 71.2), diabetes mellitus (OR 3.6, 95% CI 1.5 to 8.3), smoking (OR 8.4, 95% CI 5.4 to 12.9), transfusion (OR 5.1, 95% CI 2.0 to 12.7), postpartum infection (OR 3.2, 95% CI 1.2 to 10.1), and age 30 years and older remained as significant risk factors for pregnancy-related acute myocardial infarction. Black race was eliminated as a risk factor in the multivariable analysis, which suggests that the increased incidence among black women is explained by an increased prevalence of other cardiovascular risk factors. Conclusions— Although acute myocardial infarction is a rare event in women of reproductive age, pregnancy increases the risk 3- to 4-fold. Certain medical conditions and complications of pregnancy increase the risk further and are potentially modifiable risk factors.

Cell-free DNA Analysis for Noninvasive Examination of Trisomy

BACKGROUND Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations. METHODS In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing. Participants received the results of standard screening; the results of cfDNA testing were blinded. Determination of the birth outcome was based on diagnostic genetic testing or newborn examination. The primary outcome was the area under the receiver-operating-characteristic curve (AUC) for trisomy 21 (Downs syndrome) with cfDNA testing versus standard screening. We also evaluated cfDNA testing and standard screening to assess the risk of trisomies 18 and 13. RESULTS Of 18,955 women who were enrolled, results from 15,841 were available for analysis. The mean maternal age was 30.7 years, and the mean gestational age at testing was 12.5 weeks. The AUC for trisomy 21 was 0.999 for cfDNA testing and 0.958 for standard screening (P=0.001). Trisomy 21 was detected in 38 of 38 women (100%; 95% confidence interval [CI], 90.7 to 100) in the cfDNA-testing group, as compared with 30 of 38 women (78.9%; 95% CI, 62.7 to 90.4) in the standard-screening group (P=0.008). False positive rates were 0.06% (95% CI, 0.03 to 0.11) in the cfDNA group and 5.4% (95% CI, 5.1 to 5.8) in the standard-screening group (P<0.001). The positive predictive value for cfDNA testing was 80.9% (95% CI, 66.7 to 90.9), as compared with 3.4% (95% CI, 2.3 to 4.8) for standard screening (P<0.001). CONCLUSIONS In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes. (Funded by Ariosa Diagnostics and Perinatal Quality Foundation; NEXT ClinicalTrials.gov number, NCT01511458.).

Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth.

CONTEXT Preterm birth is a major cause of infant morbidity and mortality. Less is known about long-term health among persons born preterm. OBJECTIVE To determine the long-term effects of preterm birth on survival, reproduction, and next-generation preterm birth. DESIGN, SETTING, AND PARTICIPANTS Population-based, observational, longitudinal study using registry data from 1,167,506 singleton births in the Medical Birth Registry of Norway in 1967-1988. The cohort was followed up through 2002 for survival. The cohort was truncated to births from 1967-1976 for assessment of educational achievement and reproductive outcomes through 2004. MAIN OUTCOME MEASURES In relation to sex and gestational age at birth, absolute mortality, risk of fetal, infant, child, and adolescent mortality, and incidence and risk of reproduction and next-generation preterm birth. Singleton term (37-42 weeks) fetal deaths and live births, stratified by sex, served as the reference group for all analyses. RESULTS The percentage who were born preterm was higher among boys (5.6%) than among girls (4.7%). Preterm participants had an increased risk of mortality throughout childhood. For boys born at 22 to 27 weeks, mortality rates were 1.33% and 1.01% for early and late childhood death, with relative risks (RRs) of 5.3 (95% confidence interval [CI], 2.0-14.2) and 7.0 (95% CI, 2.3-22.0), respectively. The mortality rate for girls born at 22 to 27 weeks was 1.71% for early childhood death, with an RR of 9.7 (95% CI, 4.0-23.7); there were no late childhood deaths. For 28 to 32 weeks, the early and late childhood mortality rates among boys were 0.73% and 0.37%, with RRs of 2.5 (95% CI, 1.6-3.7) and 2.3 (95% CI, 1.3-4.1), respectively. Girls born at 28 to 32 weeks did not have a significantly increased risk of childhood mortality. Reproduction was diminished for index participants born preterm. For men and women born at 22 to 27 weeks, absolute reproduction was 29.3[corrected]% and 51.9[corrected]%, with RRs of 0.59 [corrected] (95% CI, 0.45[corrected]-0.79[corrected]) and 0.78 [corrected] (95% CI, 0.65[corrected]-0.93[corrected]), respectively. For 28 to 32 weeks, absolute reproduction was 43.1[corrected]% and 63.6[corrected]% for men and women, with RRs of 0.81[corrected] (95% CI, 0.77[corrected]-0.86[corrected]) and 0.89 [corrected] (95% CI, 0.86 [corrected]-0.93 [corrected]), respectively. Preterm women but not men were at increased risk of having preterm offspring. CONCLUSION In persons born in Norway in 1967-1988, preterm birth was associated with diminished long-term survival and reproduction.

Antenatal Betamethasone for Women at Risk for Late Preterm Delivery

BACKGROUND Infants who are born at 34 to 36 weeks of gestation (late preterm) are at greater risk for adverse respiratory and other outcomes than those born at 37 weeks of gestation or later. It is not known whether betamethasone administered to women at risk for late preterm delivery decreases the risks of neonatal morbidities. METHODS We conducted a multicenter, randomized trial involving women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gestation who were at high risk for delivery during the late preterm period (up to 36 weeks 6 days). The participants were assigned to receive two injections of betamethasone or matching placebo 24 hours apart. The primary outcome was a neonatal composite of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery. RESULTS The primary outcome occurred in 165 of 1427 infants (11.6%) in the betamethasone group and 202 of 1400 (14.4%) in the placebo group (relative risk in the betamethasone group, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P=0.02). Severe respiratory complications, transient tachypnea of the newborn, surfactant use, and bronchopulmonary dysplasia also occurred significantly less frequently in the betamethasone group. There were no significant between-group differences in the incidence of chorioamnionitis or neonatal sepsis. Neonatal hypoglycemia was more common in the betamethasone group than in the placebo group (24.0% vs. 15.0%; relative risk, 1.60; 95% CI, 1.37 to 1.87; P<0.001). CONCLUSIONS Administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications. (Funded by the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01222247.).

Active Mothers Postpartum A Randomized Controlled Weight-Loss Intervention Trial

BACKGROUND Pregnancy may contribute to overweight and obesity. PURPOSE The primary objective of Active Mothers Postpartum was to promote a reduction in BMI through 24-months postpartum via sustainable lifestyle changes. DESIGN Behavioral intervention RCT to enhance postpartum weight loss. SETTING/PARTICIPANTS A total of 450 overweight or obese women, enrolled 6-weeks postpartum, were recruited through obstetrics clinics and community posters in the Durham NC area. INTERVENTION Intervention participants were offered eight healthy-eating classes, ten physical-activity classes, and six telephone-counseling sessions over 9 months. MAIN OUTCOME MEASURES Changes from baseline (6-weeks postpartum) to 1-month post-intervention (12-months postpartum) in: (1) diet (caloric intake, calories from fat, intake of certain foods); (2) physical activity (self-reported physical activity, television time); and (3) weight (collected 2004-2007, analyzed 2007-2008). RESULTS Mean weight loss was 0.90 kg (+/-5.1 kg) in the intervention group and 0.36 kg (+/-4.9 kg) in the control group; this difference was not significant. There were also no significant group differences in improvement of diet or increased physical activity. In secondary analyses, there was a positive bivariate relationship between classes attended and weight loss (p=0.01). CONCLUSIONS There were no significant differences among the arms in diet, physical activity, or weight change. Home-based interventions via mail, telephone, or Internet/e-mail may be more feasible and successful in this population. The postpartum period is an important phase in womens lives with regard to weight retention, but engaging them during this busy period remains a challenge. TRIAL REGISTRATION NCT00212251.

Pregnancy outcomes associated with viral hepatitis

Summary.  The aim of this study was to examine the contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to pregnancy‐related complications including gestational diabetes mellitus (GDM), preterm birth (PTB), intrauterine growth restriction (IUGR), pre‐eclampsia, antepartum haemorrhage and cholestasis. The Nationwide Inpatient Sample was queried for all pregnancy‐related discharges, pregnancy complications and viral hepatitis from 1995 to 2005. Logistic regression was used to examine the association between HBV, HCV, HBV + HCV and pregnancy‐related complications including GDM, PTB, IUGR, pre‐eclampsia, antepartum haemorrhage, cholestasis and caesarean delivery. Model covariates included maternal age, race, insurance status, substance use and medical complications including liver complication, hypertension, HIV, anaemia, thrombocytopenia and sexually transmitted infections. Of 297 664 pregnant women data available for analysis, 1446 had a coded diagnosis of HBV, HCV or both. High‐risk behaviours, such as smoking, alcohol and substance use were higher in women with either HBV or HCV. Women with HBV had an increased risk for PTB (aOR 1.65, CI [1.3, 2.0]) but a decreased risk for caesarean delivery (aOR 0.686, CI [0.53, 0.88]). Individuals with HCV had an increased risk for GDM (aOR 1.6, CI [1.0, 2.6]). Individuals with both HBV and HCV co‐infection had an increased risk for antepartum haemorrhage (aOR 2.82, CI [1.1, 7.2]). There was no association of viral hepatitis with IUGR or pre‐eclampsia. Women with hepatitis have an increased risk for complications during pregnancy. Research to determine the efficacy and cost‐effectiveness of counselling patients about potential risks for adverse outcomes is warranted.

Cadmium exposure and the epigenome: Exposure-associated patterns of DNA methylation in leukocytes from mother-baby pairs

Cadmium (Cd) is prevalent in the environment yet understudied as a developmental toxicant. Cd partially crosses the placental barrier from mother to fetus and is linked to detrimental effects in newborns. Here we examine the relationship between levels of Cd during pregnancy and 5-methylcytosine (5mC) levels in leukocyte DNA collected from 17 mother-newborn pairs. The methylation of cytosines is an epigenetic mechanism known to impact transcriptional signaling and influence health endpoints. A methylated cytosine-guanine (CpG) island recovery assay was used to assess over 4.6 million sites spanning 16,421 CpG islands. Exposure to Cd was classified for each mother-newborn pair according to maternal blood levels and compared with levels of cotinine. Subsets of genes were identified that showed altered DNA methylation levels in their promoter regions in fetal DNA associated with levels of Cd (n = 61), cotinine (n = 366), or both (n = 30). Likewise, in maternal DNA, differentially methylated genes were identified that were associated with Cd (n = 92) or cotinine (n = 134) levels. While the gene sets were largely distinct between maternal and fetal DNA, functional similarities at the biological pathway level were identified including an enrichment of genes that encode for proteins that control transcriptional regulation and apoptosis. Furthermore, conserved DNA motifs with sequence similarity to specific transcription factor binding sites were identified within the CpG islands of the gene sets. This study provides evidence for distinct patterns of DNA methylation or “footprints” in fetal and maternal DNA associated with exposure to Cd.

Immunogenicity of an Inactivated Monovalent 2009 H1N1 Influenza Vaccine in Pregnant Women

BACKGROUND Although pregnant women are at increased risk of severe illness following influenza infection, there is relatively little information on the immunogenicity of influenza vaccines administered during pregnancy. METHODS We conducted a clinical trial that enrolled 120 pregnant women in which participants were randomly assigned to receive an inactivated 2009 H1N1 influenza vaccine containing either 25 μg or 49 μg of hemagglutinin (HA) in a 2-dose series with a 21-day period between administration of the first and second doses. RESULTS Following the first vaccination, HA inhibition (HAI) titers of ≥1:40 were detected in 93% (95% confidence interval [CI], 82%-98%) of subjects who received the 25-μg dose and 97% (95% CI, 88%-100%) of subjects receiving the 49-μg dose. In cord blood samples, HAI titers of ≥1:40 were found in 87% (95% CI, 73%-96%) of samples from the 25-μg dose group and in 89% (95% CI, 76%-96%) from the 49-μg dose group. Microneutralization titers tended to be higher than HAI titers, but the patterns of response were similar. CONCLUSIONS In pregnant women, 1 dose of an inactivated 2009 H1N1 influenza vaccine containing 25 μg of HA elicited an antibody response typically associated with protection against influenza infection. Efficient transplacental transfer of antibody was also documented.

Predictors of Postpartum Weight Change Among Overweight and Obese Women: Results from the Active Mothers Postpartum Study

BACKGROUND The postpartum period may be critical for the development of midlife obesity. Identifying factors associated with postpartum weight change could aid in targeting women for healthy lifestyle interventions. METHODS Data from Active Mothers Postpartum (AMP), a study of overweight and obese postpartum women (n=450), were analyzed to determine the effect of baseline characteristics, breastfeeding, diet, physical activity, and contraception on weight change from 6 weeks to 12, 18, and 24 months postpartum. The repeated measures mixed model was used to test the association of these effects with weight change. RESULTS Although mean weight loss was modest (0.49 kg by 24 months), the range of weight change was striking (+21.5 kg to -24.5 kg, standard deviation [SD] 7.4). Controlling only for baseline weight, weight loss was associated with breastfeeding, hormonal contraception, lower junk food and greater healthy food intake, and greater physical activity. Only junk food intake and physical activity were significant after controlling for all other predictors. CONCLUSIONS Eating less healthy foods and being less physically active put overweight and obese women at risk of gaining more weight after a pregnancy.

Maternal serum cytokines in preterm premature rupture of membranes.

OBJECTIVE: To estimate whether maternal serum interleukin (IL)-6 or granulocyte colony-stimulating factor (G-CSF) obtained daily are elevated in women with preterm premature rupture of membranes who develop funisitis. METHODS: Daily blood samples were obtained from women with preterm premature rupture of membranes and analyzed for IL-6 and G-CSF by enzyme-linked immunosorbent assay. Funisitis was determined by placental examination. Observations were stratified based on the presence or absence of funisitis and analyzed. Proportional hazards models were used to evaluate time-to-delivery on the basis of diagnostic IL-6 and G-CSF levels, determined by receiver operating characteristic curve analysis. RESULTS: Of the 107 patients available for analysis, 54 (50%) had evidence of funisitis after delivery. Patients with funisitis were more likely to deliver at an earlier gestational age (28.5 weeks compared with 31.5 weeks, P<.001) and have Medicaid insurance (57% compared with 39%, P=.04). Serum IL-6 and G-CSF were elevated 24 to 48 hours before delivery in women with preterm premature rupture of membranes with funisitis compared with those without funisitis (IL-6, 7.5 compared with 2.8 pg/mL, P<.001; G-CSF, 121.7 compared with 56.9 pg/mL, P=.002). Using values identified by the receiver operating characteristic curve, elevated serum IL-6 in the interval 24–72 hours before delivery was significantly associated with funisitis (P<.03), even after controlling for gestational age and insurance status. CONCLUSION: Maternal serum IL-6 and G-CSF appear to be biomarkers in the identification of women with preterm premature rupture of membranes likely to develop funisitis. LEVEL OF EVIDENCE: II