Aviva Lee-Parritz

Prenatal Maternal Stress and Cord Blood Innate and Adaptive Cytokine Responses in an Inner-City Cohort

RATIONALE Stress-elicited disruption of immunity begins in utero. OBJECTIVES Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (n = 557 families). METHODS Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts: individual stressors and ecological-level strains (housing problems and neighborhood problems), which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined, adjusting for sociodemographic factors, parity, season of birth, maternal asthma and steroid use, and potential pathway variables (prenatal smoking, birth weight for gestational age). MEASUREMENTS AND MAIN RESULTS Mothers were primarily minorities (Black [71%], Latino [19%]) with an income less than

Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy

15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, peptidoglycan) stimuli and increased tumor necrosis factor-alpha to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin-induced IFN-gamma. CONCLUSIONS Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs. Stress-induced perinatal immunomodulation may impact the expression of allergic disease in these children.

Changes in Fetal Position During Labor and Their Association With Epidural Analgesia

Increased thromboembolic events occur in women with mechanical prosthetic valves during pregnancy, and selecting an effective and safe anticoagulant is still a challenge. Low molecular weight heparin (LMWH) is a promising alternative, but a recent warning and label change about its use in patients with mechanical prosthetic valves has caused confusion among physicians. The aim of the present study was to review the risks of maternal and fetal complications with mechanical heart valves treated with LMWH during pregnancy. We performed a review of the current medical literature through MEDLINE and EMBASE (1989 to 2004). Additional data sources included abstract proceedings, and reference lists of selected articles. Among 81 pregnancies in 75 women, the proportion of valve thrombosis was 8.64% (7/81; 95% CI, 2.52%-14.76%). The frequency of overall thromboembolic complication (TEC) was 12.35% (10/81; 95% CI, 5.19%-19.51%). Nine of ten patients with TEC received a fixed dose of LMWH and two of these received a fixed low dose of LMWH. Among 51 pregnancies whose anti-factor Xa levels were monitored, only one patient was reported to have a thromboembolic complication. The frequency of live births with LMWH was 87.65% (95%CI, 80.49%-94.81%). In pregnant women with mechanical heart valves, LMWH appears to be a suitable option to a vitamin K antagonist. The use of LMWH warrants monitoring and appropriate dose adjustments to maintain a 4-6 hr post-injection anti-factor Xa level at a minimum of 1.0 U/ml to decrease the incidence of TEC.

Association of rheumatologic disease with preeclampsia.

OBJECTIVE: To evaluate whether epidural analgesia is associated with a higher rate of abnormal fetal head position at delivery. METHODS: We conducted a prospective cohort study of 1,562 women to evaluate changes in fetal position during labor by using serial ultrasound examinations. Ultrasound examinations were performed at enrollment, epidural administration, 4 hours after the initial ultrasonography if epidural had not been administered, and late in labor (> 8 cm). Information about fetal head position at delivery was obtained from the provider. RESULTS: Regardless of fetal head position at enrollment (occiput transverse, occiput posterior, or occiput anterior), most fetuses were occiput anterior at delivery (enrollment position: occiput transverse 78%, occiput posterior 80%, occiput anterior 83%, P = .1). Final fetal position was established close to delivery. Of fetuses that were occiput posterior late in labor, only 20.7% were occiput posterior at delivery. Changes in fetal head position were common, and 36% of women had an occiput posterior fetus on at least one ultrasound examination. Women receiving epidural did not have more occiput posterior fetuses at the enrollment (23.4% epidural versus 26.0 no epidural, P = .9) or the epidural/4-hour ultrasound examination (24.9% epidural, 28.3% no epidural), but did have more occiput posterior fetuses at delivery (12.9% epidural versus 3.3% no epidural, P = .002); the association remained in a multivariate model (adjusted odds ratio 4.0, 95% confidence interval 1.4–11.1). CONCLUSION: Fetal position changes are common during labor, with the final fetal position established close to delivery. Our demonstration of a strong association of epidural with fetal occiput posterior position at delivery represents a mechanism that may contribute to the lower rate of spontaneous vaginal delivery consistently observed with epidural. LEVEL OF EVIDENCE: II-2

Parental Characteristics, Somatic Fetal Growth, and Season of Birth Influence Innate and Adaptive Cord Blood Cytokine Responses

OBJECTIVE: To determine whether maternal rheumatologic disease is associated with an increased risk of adverse obstetric or neonatal outcomes. METHODS: Using an institutional database, we identified all women with diagnosed rheumatologic disease (n = 114) who delivered a baby at our institution during a 33-month period. We compared the incidence of adverse obstetric and neonatal outcomes among these women with the incidence among women without rheumatologic diseases (n = 18,534). RESULTS: Women with rheumatologic diseases were more likely to have preeclampsia than women without rheumatologic disease (8.8% versus 2.3%, P < .001) Women with rheumatologic diseases were also at increased risk of preterm delivery (15.2% versus 7.8%, P = .002) and small-for-gestational-age infants (8.0% versus 3.1%, P = .001) compared with women without rheumatologic disease. CONCLUSION: The finding that women with rheumatologic diseases are at increased risk of adverse obstetric outcomes suggests a need for heightened clinical vigilance and further research into the common pathophysiologic correlates. LEVEL OF EVIDENCE: II-2

Early pregnancy vitamin D status and risk of preeclampsia

BACKGROUND Immunologic responses at birth likely relate to subsequent risks for allergic diseases and wheezing in infancy; however, the influences of parental characteristics and prenatal factors on neonatal immune responses are incompletely understood. OBJECTIVE This study investigates potential correlations between urban parental, prenatal, and perinatal factors on innate and adaptive stimuli-induced cytokine responses. METHODS Five hundred sixty and 49 children of parents with and without allergic disease or asthma, respectively, were enrolled into a prospective birth cohort study (Urban Environment and Childhood Asthma). Cord blood mononuclear cells were incubated with innate and adaptive immune stimuli, and cytokine responses (ELISA) were compared with season of birth, parental characteristics, in utero stressors, and fetal growth. RESULTS Many cytokine responses varied by season of birth, including 2-fold to 3-fold fluctuations with specific IFN-alpha and IFN-gamma responses. Birth weight was inversely associated with IFN-gamma responses to respiratory syncytial virus (R = -0.16), but positively associated with IL-8 responses to a variety of innate stimuli (R = 0.08-0.12). Respiratory syncytial virus-induced cytokine responses were 21% to 54% lower in children of mothers with asthma. Cytokine responses were generally lower in babies born to parents with allergy/asthma. CONCLUSIONS Innate cytokine responses are associated with parental allergic or airway disease, somatic fetal growth, ethnicity, and season of birth. Collectively, these findings suggest that urban prenatal exposures and familial factors affect the development of the fetal immune system.

Obstetric and neonatal outcomes associated with maternal hypothyroid disease.

BACKGROUND Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia. METHODS We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10-18 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (32-38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia. RESULTS Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61-1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD ≥30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.10-0.96). Differential expression of 348 vitamin D-associated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial [VDAART]; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity. CONCLUSIONS Vitamin D supplementation initiated in weeks 10-18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia. TRIAL REGISTRATION ClinicalTrials.gov NCT00920621. FUNDING Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.

Follow-up of gestational diabetes mellitus in an urban safety net hospital: missed opportunities to launch preventive care for women.

Objective: We sought to determine whether women with treated hypothyroid disease were more likely than women without thyroid disease to suffer adverse obstetric or neonatal outcomes or to deliver a child with a congenital anomaly. Methods: Using an institutional database, we identified women with treated hypothyroid disease (n = 482) who delivered a baby at our institution during a 33-month period. We compared the occurrence of adverse obstetric or neonatal outcomes among these women to the occurrence among women without thyroid disease (n = 19,487). Results: Women with treated hypothyroid disease were not at increased risk for delivering a baby with low birth- weight, fetal demise, or congenital anomaly compared to the control group. Women with treated hypothyroid disease were more likely to have chronic hypertension (2.3% vs. 1.2%, p = 0.03) and had an increased risk of pre-eclampsia (4.3% vs. 2.6%, p = 0.03) compared to women without thyroid disease. Conclusion: Women with treated hypothyroid disease are not at higher risk than the general population for adverse neonatal outcomes, but may be at increased risk for pre-eclampsia.

Opioid addiction in pregnancy.

BACKGROUND Our study assessed the follow-up of gestational diabetes mellitus (GDM) in the postpartum period among a racially and ethnically diverse group of women receiving care in a major urban medical center. METHODS We conducted cross-sectional analysis of clinical and administrative data on women aged 18-44 years who gave birth at Boston Medical Center (BMC) between 2003 and 2009, had GDM, and used BMC for regular care. We calculated the rate of glucose testing by 70 days and by 180 days after delivery and used logistic regression to assess the predictors of testing. RESULTS By 6 months postpartum, only 23.4% of GDM-affected women received any kind of glucose test. Among these, over half had been completed by 10 weeks but only 29% were the recommended oral glucose tolerance test (OGTT). After accounting for sociodemographic and health service factors, women aged ≤ 35 years of age and women with a family practice provider were significantly less likely to be tested than their counterparts (odds ratio [OR] 0.51; 95% confidence interval [CI] 0.32, 0.83 and OR 0.36; 95% CI 0.19, 0.71 respectively). Women who attended a primary care visit within 180 days after birth had three times higher odds of being tested than those without such a visit (OR 3.10; 95% CI 1.97, 4.87). CONCLUSIONS Despite widely disseminated clinical guidelines, postpartum glucose testing rates are exceedingly low, marking a critical missed opportunity to launch preventive care for women at high risk of type 2 DM. Failed follow-up of GDM by providers of prenatal and postpartum care also reflects a broader systems failure: the absence of a well-supported transition from pregnancy care to ongoing primary care for women.

Genome-wide DNA methylation associations with spontaneous preterm birth in US blacks: findings in maternal and cord blood samples

The purpose of this review is to discuss the incidence, risks, pregnancy complications, and maintenance options for treatment of opioid addiction in pregnancy. Summary: Opioid dependence in pregnancy carries clear identifiable maternal and fetal risk. Providing care for patients with dependence is best done in a multidisciplinary care model addressing the particular needs of this population. There are limited data on maternal detoxification, with data still emerging surrounding the safety profile of this practice. Historically, methadone has been the recommended maintenance treatment; however, recent data on buprenorphine identify this as a safe and effective option. The majority of births from women with opioid dependence result in neonatal abstinence syndrome requiring prolonged neonatal hospitalization. Intrapartum pain management should not differ from the general obstetric population. Postpartum pain is magnified in this population, and particular attention should be focused on this issue. Breast-feeding is recommended regardless of maintenance dose, unless other conditions restricting breast-feeding are present. Comprehensive postpartum care and transition of care to addiction specialists are highly recommended. Target Audience: Obstetricians and gynecologists, family physicians, addiction specialists Learning Objectives: After completing this CME activity, physicians should be better able to assess the treatment options available to patients with opioid addiction during pregnancy, compare the risk/safety profiles of methadone and buprenorphine, and evaluate the recommendations and current data surrounding breast-feeding while on opioid maintenance treatment.