Thomas F. McElrath

Maternal Preeclampsia Predicts the Development of Bronchopulmonary Dysplasia

OBJECTIVE To test the hypothesis that exposure to preeclampsia is associated with an increased risk of bronchopulmonary dysplasia (BPD). STUDY DESIGN A prospective cohort study of 107 babies born between 23 and 32 weeks gestation, collecting maternal, neonatal, and placental data. RESULTS Of the 107 infants studied, 27 (25%) developed BPD. The bivariate odds ratio (OR) for the relationship between pre-eclampsia and BPD was 2.96 (95% confidence interval [CI] = 1.17 to 7.51; P = .01). When controlling for gestational age, birth weight z-score, chorioamnionitis, and other clinical confounders, the OR of developing BPD was 18.7 (95% CI = 2.44 to 144.76). Including the occurrence of preeclampsia, clinical chorioamnionitis, male sex, and maternal tobacco use in addition to gestational age and birth weight z-score accounted for 54% of the variability of the odds of developing BPD. CONCLUSIONS BPD is increased for infants exposed to preeclampsia. This has possible implications for the prevention of BPD with proangiogenic agents, such as vascular endothelial growth factor.

Environmental Phthalate Exposure and Preterm Birth

IMPORTANCE Preterm birth is a leading cause of neonatal mortality, with a variety of contributing causes and risk factors. Environmental exposures represent a group of understudied, but potentially important, factors. Phthalate diesters are used extensively in a variety of consumer products worldwide. Consequently, exposure in pregnant women is highly prevalent. OBJECTIVE To assess the relationship between phthalate exposure during pregnancy and preterm birth. DESIGN, SETTING, AND PARTICIPANTS This nested case-control study was conducted at Brigham and Womens Hospital, Boston, Massachusetts. Women were recruited for a prospective observational cohort study from 2006-2008. Each provided demographic data, biological samples, and information about birth outcomes. From within this group, we selected 130 cases of preterm birth and 352 randomly assigned control participants, and we analyzed urine samples from up to 3 time points during pregnancy for levels of phthalate metabolites. EXPOSURE Phthalate exposure during pregnancy. MAIN OUTCOMES AND MEASURES We examined associations between average levels of phthalate exposure during pregnancy and preterm birth, defined as fewer than 37 weeks of completed gestation, as well as spontaneous preterm birth, defined as preterm preceded by spontaneous preterm labor or preterm premature rupture of the membranes (n = 57). RESULTS Geometric means of the di-2-ethylhexyl phthalate (DEHP) metabolites mono-(2-ethyl)-hexyl phthalate (MEHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), as well as mono-n-butyl phthalate (MBP), were significantly higher in cases compared with control participants. In adjusted models, MEHP, MECPP, and  Σ DEHP metabolites were associated with significantly increased odds of preterm birth. When spontaneous preterm births were examined alone, MEHP, mono-(2-ethyl-5-oxohexyl) phthalate, MECPP,  Σ DEHP, MBP, and mono-(3-carboxypropyl) phthalate metabolite levels were all associated with significantly elevated odds of prematurity. CONCLUSIONS AND RELEVANCE Women exposed to phthalates during pregnancy have significantly increased odds of delivering preterm. Steps should be taken to decrease maternal exposure to phthalates during pregnancy.

Colonization of second trimester placenta parenchyma

OBJECTIVE The overtly healthy, nonpregnant uterus harbors bacteria, Mycoplasma and Ureaplasma. The extent of colonization remains elusive, as are relationships between isolated microorganisms, preterm labor and fetal inflammation. STUDY DESIGN Biopsy specimens of chorion parenchyma from 1083 placentas delivered before the beginning of the 28th week of gestation were cultured, and the placentas were examined histologically. The frequencies of individual microorganisms and groups of microorganisms were evaluated in strata of processes leading to preterm delivery, routes of delivery, gestational age, and placenta morphology. RESULTS Placentas delivered by cesarean section with preeclampsia had the lowest bacterial recovery rate (25%). Preterm labor had the highest rates, which decreased with increasing gestational age from 79% at 23 weeks to 43% at 27 weeks. The presence of microorganisms in placenta parenchyma was associated with the presence of neutrophils in the fetal stem vessels of the chorion or in the vessels of the umbilical cord. CONCLUSION The high rate of colonization appears to coincide with phenomena associated with preterm delivery and gestational age. The presence of microorganisms within placenta parenchyma is biologically important.

Nutrition in adolescent pregnancy

Prevention of unintended adolescent pregnancy is a primary goal of the American Academy of Pediatrics and of many health providers. Nevertheless, many adolescents become pregnant every year in America. Pediatricians therefore should be aware of nutritional recommendations for pregnant adolescents to provide optimal care. The importance of nutrition during pregnancy is here reviewed from a pediatric perspective. Pregnancy, particularly during adolescence, is a time of extreme nutritional risk. The adolescents most likely to become pregnant are often those with inadequate nutritional status and unfavorable socio-economic background. There is increasing evidence of competition for nutrients between the growing pregnant adolescent and her fetus. Also, the prenatal environment has been implicated in the development of obesity, cardiovascular disease, and diabetes in both the mother and her offspring. Many adolescents have poor diet quality and poor knowledge of appropriate nutrition; these habits may not change during pregnancy. Current knowledge and recommendations regarding the intake of energy, calcium, and folate are discussed in detail.

Relationship Between Neonatal Blood Protein Concentrations and Placenta Histologic Characteristics in Extremely Low GA Newborns.

Amniotic fluid infection with chorioamnionitis is associated with increased risks of morbidity and mortality in children born prematurely. These risks depend on the presence of a fetal inflammatory response. We measured the concentrations of 25 proteins in the blood of 871 infants born before the 28th wk of gestation and examined their placentas for acute inflammation. Newborns who had inflammatory lesions of the placenta were much more likely than their peers (p < 0.01) to have elevated blood concentrations of cytokines (IL-1β, IL-6, and TNF-α), chemokines (IL-8, MIP-1β, RANTES, and I-TAC), adhesion molecules (ICAM-1, ICAM-3, and E-selectin), matrix metalloproteinases (MMP-1 and MMP-9), the angiogenic inflammatory factor VEGF and its receptor VEGF-R2, and acute phase proteins (SAA and CRP) during the first 3 d after birth. In contrast, newborns with poor placental perfusion had lower levels of inflammatory proteins (p < 0.01; IL-6, RANTES, ICAM-1, ICAM-3, VCAM-1, E-selectin, MMP-1, MMP-9, MPO, and VEGF). An inverse pattern was found between newborn levels of VEGF and its competitive inhibitor VEGF-R1 in both the inflamed and poorly perfused placenta categories. These results confirm the predictive value of placental histology for the presence or absence of elevated inflammatory response in newborns.

Preeclampsia : 2-Methoxyestradiol Induces Cytotrophoblast Invasion and Vascular Development Specifically under Hypoxic Conditions

Inadequate invasion of the uterus by cytotrophoblasts is speculated to result in pregnancy-induced disorders such as preeclampsia. However, the molecular mechanisms that govern appropriate invasion of cytotrophoblasts are unknown. Here, we demonstrate that under low-oxygen conditions (2.5% oxygen), 2-methoxyestradiol (2-ME), which is a metabolite of estradiol and is generated by catechol-o-methyltransferase (COMT), induces invasion of cytotrophoblasts into a naturally-derived, extracellular matrix. Neither low-oxygen conditions nor 2-ME alone induces the invasion of cytotrophoblasts in this system; however, low-oxygen conditions combined with 2-ME result in the appropriate invasion of cytotrophoblasts into the extracellular matrix. Cytotrophoblast invasion under these conditions is also associated with a decrease in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha), transforming growth factor-beta3 (TGF-beta3), and tissue inhibitor of metalloproteinases-2 (TIMP-2). Pregnant COMT-deficient mice with hypoxic placentas and preeclampsia-like features demonstrate an up-regulation of HIF-1alpha, TGF-beta3, and TIMP-2 when compared with wild-type mice; normal levels are restored on administration of 2-ME, which also results in the resolution of preeclampsia-like features in these mice. Indeed, placentas from patients with preeclampsia reveal lower levels of COMT and higher levels of HIF-1alpha, TGF-beta3, and TIMP-2 when compared with those from normal pregnant women. We demonstrate that low-oxygen conditions of the placenta are a critical co-stimulator along with 2-ME for the proper invasion of cytotrophoblasts to facilitate appropriate vascular development and oxygenation during pregnancy.

Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth

BACKGROUND Preterm birth is a significant public health problem, affecting over 1 in 10 live births and contributing largely to infant mortality and morbidity. Everyday exposure to environmental chemicals such as phthalates could contribute to prematurity, and may be modifiable. In the present study we examine variability in phthalate exposure across gestation and identify windows of susceptibility for the relationship with preterm birth. METHODS Women were recruited early in pregnancy as part of a prospective, longitudinal birth cohort at the Brigham and Womens Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points during gestation for phthalate measurement, and birth outcomes were recorded at delivery. From this population we selected all 130 cases of preterm birth, defined as delivery before 37 weeks of completed gestation, as well as 352 random controls. RESULTS Urinary phthalate metabolite levels were moderately variable over pregnancy, but levels measured at multiple time points were associated with increased odds of preterm birth. Adjusted odds ratios (aOR) for spontaneous preterm birth were strongest in association with phthalate metabolite concentrations measured at the beginning of the third trimester (aOR for summed di-2-ethylhexyl phthalate metabolites [∑DEHP]=1.33, 95% confidence interval [CI]=1.02, 1.73). Odds ratios for placental preterm birth, defined as delivery with presentation of preeclampsia or intrauterine growth restriction, were slightly elevated in the first trimester for DEHP metabolites (aOR for ∑DEHP=1.33, 95% CI=0.99, 1.78). CONCLUSIONS Pregnant women with exposure to phthalates both early and late in pregnancy are at an increased risk of delivering preterm, but mechanisms may differ based on etiology.

Increased Sensitivity to Angiotensin II Is Present Postpartum in Women With a History of Hypertensive Pregnancy

Pregnancies complicated by new-onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear whether this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high- and low-sodium balance. Ten women had a history of hypertensive pregnancy (5 with preeclampsia; 5 with transient hypertension of pregnancy), and 15 women had a history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone, and soluble fms-like tyrosine kinase 1 levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with a history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 versus 104 mm Hg and 73 versus 65 mm Hg, respectively; P<0.05). Women with a history of hypertensive pregnancy had a pressor response to salt loading, demonstrated by an increase in systolic blood pressure on a high-salt diet. They also had greater systolic pressor response (10 versus 2 mm Hg; P=0.03), greater increase in aldosterone (56.8 versus 30.8 ng/dL; P=0.03), and increase in soluble fms-like tyrosine kinase 1 levels (11.0 versus −18.9 pg/mL; P=0.02) after infusion of angiotensin II in low-sodium balance compared with controls. Thus, women with a history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal, and soluble fms-like tyrosine kinase 1 responses to infused angiotensin II in low-sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women.

Episiotomy, operative vaginal delivery, and significant perineal trauma in nulliparous women

OBJECTIVES The aim of this study was to determine whether choice of obstetric instrument at operative vaginal delivery is associated with any differences in the rate of significant perineal trauma and whether this rate is modified by the use of episiotomy. STUDY DESIGN The occurrence of significant perineal trauma among 323 consecutive operative vaginal deliveries was evaluated according to type of instrument used and performance of episiotomy. These findings were compared with spontaneous vaginal deliveries during the same period. RESULTS Among forceps deliveries the use of episiotomy was not associated with a difference in the occurrence of significant perineal trauma (55% vs 46%; relative risk, 1.2; 95% confidence interval, 0.8-1.9). Among vacuum extraction deliveries an increased rate of such trauma was noted when episiotomy was used (34.9% vs 9. 4%; relative risk, 3.7; 95% confidence interval, 1.2-11.2). There was no difference in the rate of significant perineal trauma according to type of forceps used. In a logistic regression analysis forceps delivery with or without episiotomy was associated with an increase of >10-fold in the rate of significant perineal trauma with respect to vacuum extraction deliveries without episiotomy. CONCLUSIONS Our data suggest that in forceps delivery neither the type of forceps nor episiotomy influences the risk of significant perineal trauma. When vacuum extraction delivery is performed, the use of episiotomy is associated with a higher risk of significant perineal trauma.

Breathing Life Into the Lifecourse Approach: Pregnancy History and Cardiovascular Disease in Women

The lifecourse approach to epidemiology has broadened our understanding of chronic disease as a developmental process that evolves over the entire lifespan. Subclinical syndromes at an early phase in life may offer insights into later health that are not presently recognized. For example, a woman’s reproductive history is an often overlooked predictor of later chronic disease.1 Increasing evidence suggests that pregnancy complications unmask predisposition to cardiovascular disease and may serve as cardiovascular risk markers particular to women.2 Because cardiovascular disease is the leading cause of death among women, an understanding of the ways in which pregnancy complications presage risk, or possibly alter risk, can further the understanding of cardiovascular disease mechanisms. In 2002, Sattar and Greer suggested that pregnancy constitutes a physiological “stress test” that reveals latent chronic disease (Figure, A).3 The authors highlighted the implications for future maternal cardiovascular risk of 4 common pregnancy complications: gestational diabetes, hypertensive disorders, low birthweight delivery (<2500 g), and preterm delivery (<37 weeks). For brevity, we refer here to this group of syndromes as “complicated pregnancies,” recognizing that less prevalent pregnancy complications may also predict cardiovascular risk. As a group, these complicated pregnancies are characterized by inflammation, vasculopathy, altered angiogenesis, thrombosis, and insulin resistance: pathophysiologic processes common to coronary heart disease and stroke. Our intent is to update the growing literature, outline research needs, and question whether it is time to incorporate pregnancy history into cardiovascular risk assessment. Figure. Pregnancy is a “stress test” that can reveal subclinical trajectories and identify new opportunities for chronic disease prevention. A, Women at high risk of future cardiovascular disease are identifiable during pregnancy, at which point subclinical vascular risk may become clinically evident. B, The risk revealed by pregnancy can be used to target high-risk women for screening and early intervention by …