Each year, 7.9 million babies are born with birth defects. Seventy percent of those could be prevented, ameliorated, or repaired; yet 3.2 million children still die by the age of three (March of Dimes Global Report 2006). We have found that non-specific maternal immune stimulation with the cytokine interferon-gamma (IFN-gamma) can successfully ameliorate some of these defects in the C57BL/6N mouse model. We have observed a reduction in the distal limb malformations syndactyly, polydactyly, and webbing by 47%, 100%, and 63% respectively when IFN-gamma is given 2 days prior to MNU administration. We have also observed that IFN-gamma works at the placental level to protect against MNU-induced damage. Trophoblast loss and associated cytokine alterations occur in gestation day (GD) 14 placenta following GD9 MNU exposure, showing that fetal-maternal communication can be hindered due to MNU. In the labyrinthine layer of the placenta, we observed multifocal fibrinous necrosis of endothelial cells due to MNU, however IFN-gamma almost completely protected the trophoblast and endothelial cells when given to the dam as an immune stimulant. To determine the genes participating in these processes, gene microarray studies were conducted. Hepatocyte growth factor (HGF), interleukin 1 beta (IL1Β), and insulin-like growth factor 2 (IGF2) were elucidated as genes that were significantly expressed in GD12 placenta. These genes are similar in that they are all connected to the Jak-Stat signaling pathway. These findings provide a possible mechanism for birth defect reduction by maternal immune stimulation with IFN-gamma in MNU-challenged mice. / Master of Science

Background: Spina bifida (SB) is monitored through birth defects surveillance across the United States and in most developed countries. Although much is known about the management of SB and its many comorbid conditions in affected individuals, there are few systematic, longitudinal studies on population-based cohorts of children or adults. The natural history of SB across the life course of persons with this condition is not well documented. Earlier identification of comorbidities and secondary conditions could allow for earlier intervention that might enhance the developmental trajectory for children with SB. Objective: The purpose of this project was to assess the development, health, and condition progression by prospectively studying children who were born with SB in Arizona and Utah. In addition, the methodology used to collect the data would be evaluated and revised as appropriate. Methods: Parents of children with SB aged 3-6 years were eligible to participate in the study, in English or Spanish. The actual recruitment process was closely documented. Data on medical history were collected from medical records; family functioning, child behaviors, self-care, mobility and functioning, and health and well-being from parent reports; and neuropsychological data from testing of the child. Results: In total, 152 individuals with SB were identified as eligible and their parents were contacted by site personnel for enrollment in the study. Of those, 45 (29.6%) declined to participate and 6 (3.9%) consented but did not follow through. Among 101 parents willing to participate, 81 (80.2%) completed the full protocol and 20 (19.8%) completed the partial protocol. Utah enrolled 72.3% (73/101) of participants, predominately non-Hispanic (60/73, 82%) and male (47/73, 64%). Arizona enrolled 56% (28/50) of participants they had permission to contact, predominately Hispanic (18/28, 64%) and male (16/28, 57%). Conclusions: We observed variance by site for recruitment, due to differences in identification and ascertainment of eligible cases and the required institutional review board processes. Restriction in recruitment and the proportion of minorities likely impacted participation rates in Arizona more than Utah.

This study investigated the interactions of facially deformed infants (FD) with their mothers compared to a facially nondeformed control group (FND). All mother-infant dyads were videotaped for 10 minutes during a free play period. Mothers were instructed to spend time with their baby as they normally would. The videotaped interactions of 14 FD dyads and 14 FND dyads were rated by five raters for quality of interactions, amount of vocalization, touch, and face-to-face gaze. The infants were rated on their level of attractiveness from polaroid pictures and videotapes. Mothers also completed a questionnaire which assessed their infants' temperament. Three of the studies' four hypotheses were confirmed. First, the more attractive an infant was, the better his/her interactions with the mother were judged to be. Second, FD infant dyads were rated as significantly poorer in quality of interaction than FND dyads, although FD* dyads did not spend significantly less time vocalizing, touching, or in face-to-face gaze as predicted. A significantly higher percentage of FD infants were judged as having difficult temperament relative to FND infants. Finally, as predicted it was found that infants with difficult temperaments were more likely to exhibit poorer quality interactions than infants with less difficult temperaments. These results have important implications for providing anticipatory guidance to caregivers of FD infants. Without intervention, FD infants appear at risk for subsequent developmental problems stemming from disrupted early mother-infant interactions. Future research should focus on these interactions soon after the infant's birth, attempt to determine if FD infants' emotions can be reliably understood from their facial expressions (as has been found in normal infants) and extend the current research paradigm to include fathers of FD infants.

Congenital diaphragmatic hernia (CDH) results from a defect in the diaphragm through which abdominal contents enter the thorax displacing the heart and the lungs. This causes lung hypoplasia and varying degrees of pulmonary hypertension resulting in high rates of morbidity and mortality. Though CDH has a prevalence rate of 2.61 per 10,000 live births it is an expensive birth defect with an estimated annual cost of nearly $250 million for all CDH survivors. Maternal exposure to air pollutants have not been studied as risk factors for CDH in humans. Ambient ozone has been found to be risk factors for certain birth defects including congenital heart defects, chromosomal anomalies, and limb reduction defects. Cadmium, however, has been found to be a risk factor for diaphragmatic hernia, cleft palate, renal defects, anopthalmia, microphthalmia, anal atresia, undescended testes, and dysplastic ears in animal studies only. The objectives of this study were to: 1) examine the prevalence, temporal trends, and correlates of CDH among live-born infants during 1998–2012; 2) investigate the association between sociodemographic and perinatal characteristics and neonatal and one-year survival among infants with CDH and its subtypes, isolated and complex; 3) examine the role of ambient ozone as a risk factor for CDH; and 4) determine the association between maternal exposure to ambient cadmium in air and CDH and assess if maternal smoking during pregnancy is an effect modifier of the cadmium-CDH association. To answer these questions we used a population-based, retrospective cohort study using data from the 1998–2012 Florida Birth Defects Registry. We classified CDH cases into isolated and complex. A case that was associated with other anomalies listed on the National Birth Defects Prevention Network list of major structural reportable defects was classified as complex CDH. We used Poisson and joinpoint regression models to compute prevalence ratios and assess temporal trends, respectively. Kaplan-Meier survival curves and Cox proportional hazards regression were used to describe neonatal and one-year survival and estimate hazard ratios of neonatal and one-year mortality. We then used multilevel Poisson regression models to examine the association between maternal exposure to ambient ozone and CDH as well as cadmium and CDH. We conducted stratified analyses to test for effect measure modification by maternal smoking status. The study population to answer the first two questions consisted of 3,209,775 live-born infants (including 1,025 cases). To answer the third and fourth questions, the study population consisted of 3,039,685 and 2,591,395 live-born infants (including 981 and 840 cases), respectively. We found a 4% increase in the annual prevalence of CDH among complex cases, but no trend for isolated cases. We observed higher prevalence of CDH among infants born to mothers with high school or less maternal education and for multiple births. Female sex and maternal obesity were found to be associated with decreased risk for CDH. The most important predictor of neonatal and one-year mortality was gestational age

L’objectif de cette thèse était d’étudier les associations potentielles entre les traitements antirétroviraux reçus par les femmes enceintes infectées par le VIH et les complications pouvant survenir au cours de la grossesse ou être diagnostiquées dans la période néonatale. Ce travail est issu en majeure partie des données de l’Enquête Périnatale Française (ANRS-EPF), cohorte nationale multicentrique ayant inclus plus de 20 000 couples mères-enfants depuis 1986. Actuellement, presque toutes les femmes sont traitées par combinaisons antirétrovirales puissantes (cART ; 98% en 2013) et le taux de transmission est inférieur à 1% : 0.6% (IC95% : 0.4%-0.8% pour la période 2005-2013). La première partie portait sur le risque d’accouchement prématuré dont le taux a augmenté significativement entre la période 1990-1993 et 2005-2009, passant de 9.2% à 14.3%. Le risque d’accouchement prématuré était significativement associé au traitement par cART, par rapport aux monothérapies et bithérapies d’INTI, et au traitement débuté avant la conception par rapport aux traitements débutés en cours de grossesse. La survenue d’une cytolyse hépatique était fréquente (17%), et était liée à la fois à la prématurité, et au type de traitement, plus fréquentes avec les IP qu’avec les inhibiteurs non nucléosidiques de la transcriptase inverse. La perturbation du bilan hépatique pourrait être un facteur intermédiaire dans la relation entre traitements et accouchement prématuré. La seconde partie portait sur les malformations congénitales. D’une part, elle a permis de mettre en évidence une association entre exposition à l’efavirenz au premier trimestre de grossesse et les malformations neurologiques, bien que concernant peu de cas (n=4) et n’atteignant la significativité que dans une analyse de sensibilité. Cette association incite à maintenir une vigilance chez les enfants exposés in utero à cette molécule classée tératogène par la FDA mais prescrite de plus en plus largement. D’autre part, l’exposition au premier trimestre à la zidovudine était associée à la survenue de malformations cardiaques. La troisième partie a complété cette étude par une analyse de la fonction cardiaque, des modifications infracliniques de la contractilité et de l’épaisseur des parois du ventricule gauche ont été mises en évidence chez les enfants exposés in utero à une combinaison de traitement contenant la zidovudine et la lamivudine. Ces résultats ne remettent pas en question l’efficacité majeure des traitements antirétroviraux pour la prévention de la transmission de la mère à l’enfant du VIH, mais incitent à la poursuite d’une surveillance épidémiologique des effets indésirables potentiels, de manière à optimiser les prescriptions pour un meilleur rapport bénéfice/risque. / Our objective was to study potential associations between antiretroviral treatment and obstetrical or neonatal complications in a population of HIV-positive pregnant women. Most of the analyses were conducted with data from the French Perinatal Cohort (ANRS-EPF), an ongoing multicenter national cohort with more than 20 000 mother-infant pairs included since 1986. In the recent years, most women receive combination antiretroviral therapies (cART ; 98% en 2013) and the trasnsmission rate is consistently under 1% : 0.6% (IC95% : 0.4%-0.8% for 2005-2013). Risk of preterm birth was significantly associated with cART, when compared to NRTI monotherapy or dual therapy, and with timing of treatment, higher for women treated at conception than for those initiating treatment during pregnancy. The occurrence of liver enzyme elevation was frequent (17%), and was associated both with preterm birth and with PI-based treatment, when compared to NNRTIs. LEE could be an intermediate factor between cART and preterm birth. The second part of this work was a study of congenital birth defect in the cohort, and showed an association between first trimester-exposure to efavirenz and neurological defects, but this concerned small numbers (n=4), and reached significance only in a sensitivity analysis. This association encourages us to maintain awareness concerning this molecule, considered teratogenic by the FDA but more and more largely prescribed. We also reported an association between first-trimester exposure to zidovudine and congenital heart defects. In a third part, we studied heart function, differences in contractility and septum thickness of the left ventricle was found, among girls exposed to a combination containing zidovudine and lamivudineThese results do not question the great progress of antiretroviral treatment in the prevention of mother-to-child transmission, but they encourage us to continue epidemiologic surveillance of potential side effects, in order to optimize prescriptions for an improved benefit/risk ratio.

Doctor Pharmaceuticae - Dpharm / The use of efavirenz (EFV) in the first trimester of pregnancy remains controversial. In South Africa, the use of EFV-containing antiretroviral therapy (ART) as part of a Fixed Dose Combination (FDC) during the first trimester of pregnancy started in April, 2013. Literature to date has reported conflicting outcomes following the use of EFV-containing ART during the first trimester of pregnancy. The objectives of the study were to determine the prevalence of adverse pregnancy outcomes among HIV-positive pregnant women treated with EFV-containing ART and compare these results with those of pregnant women treated with NVP-containing ART and HIV-negative pregnant women in resource-limited settings. In addition, the study also aimed to determine the effect of the time of initiation of ART on the prevalence of adverse pregnancy outcomes.

Objective: To determine if paternal preconception exposure to ionizing radiation through uranium mining increases the risk of congenital anomaly (CA) in offspring. Methods: A population-based matched case-control study was conducted. Cases were infants with CAs recorded in the Canadian Congenital Anomalies Surveillance System and born alive in Ontario 1979-86 (ICD-9 codes 740-759); controls were liveborn infants without CAs identified from Ontario birth certificates and individually matched to cases (case-control file {CCF}). Exposed fathers were identified through the linkage of the CCF to the Mining Master File or the National Dose Registry file, which include those who worked in Ontario uranium mines 1952-1986. For men who linked with a case or control child, radon, gamma and total gonadal doses were estimated for three preconception periods: entire, 3-months and 6-months. Odds ratios were estimated using conditional logistic regression. Results: Linkage of 28,991 uranium miners and 40,482 case-control pairs of fathers and offspring in the CCF identified 431 discordant pairs. There was no evidence of increased risk of a child having a CA if the father was ever a uranium miner before conception of the child (OR=0.89, 95% CI=0.74–1.08). Since gamma radiation (especially during the 6-month preconception period) is more biologically relevant to gonads than radon, further analyses were performed on 117 discordant pairs where data on gamma exposures were available. When ever/never miner, exposed to gamma (yes/no), and gamma dose-response variables were all in the model, there was no ever/never miner effect (OR=1.20, 95% CI=0.85–1.69, p-value=0.30), an inverse association for exposure to gamma (OR=0.42, 95% CI=0.25–0.71, p-value=0.001), but most importantly, there was no statistically significant dose-response relationship between gamma dose during the 6-month preconception period and all CAs (OR=1.15 per loge {mSv+0.01}, 95% CI=0.83–1.59, p-value=0.40). Similarly, no dose-response relationship was observed for exposure to gamma radiation in the 3-month preconception period, or for radon or total gonadal radiation in the 3- or 6-month preconception periods. Conclusion: There was no increased risk of a CA among liveborn children of Ontario uranium miners who were exposed to radon, gamma or total radiation during the 3- or 6-month periods before conception.

Objective: To determine if paternal preconception exposure to ionizing radiation through uranium mining increases the risk of congenital anomaly (CA) in offspring. Methods: A population-based matched case-control study was conducted. Cases were infants with CAs recorded in the Canadian Congenital Anomalies Surveillance System and born alive in Ontario 1979-86 (ICD-9 codes 740-759); controls were liveborn infants without CAs identified from Ontario birth certificates and individually matched to cases (case-control file {CCF}). Exposed fathers were identified through the linkage of the CCF to the Mining Master File or the National Dose Registry file, which include those who worked in Ontario uranium mines 1952-1986. For men who linked with a case or control child, radon, gamma and total gonadal doses were estimated for three preconception periods: entire, 3-months and 6-months. Odds ratios were estimated using conditional logistic regression. Results: Linkage of 28,991 uranium miners and 40,482 case-control pairs of fathers and offspring in the CCF identified 431 discordant pairs. There was no evidence of increased risk of a child having a CA if the father was ever a uranium miner before conception of the child (OR=0.89, 95% CI=0.74–1.08). Since gamma radiation (especially during the 6-month preconception period) is more biologically relevant to gonads than radon, further analyses were performed on 117 discordant pairs where data on gamma exposures were available. When ever/never miner, exposed to gamma (yes/no), and gamma dose-response variables were all in the model, there was no ever/never miner effect (OR=1.20, 95% CI=0.85–1.69, p-value=0.30), an inverse association for exposure to gamma (OR=0.42, 95% CI=0.25–0.71, p-value=0.001), but most importantly, there was no statistically significant dose-response relationship between gamma dose during the 6-month preconception period and all CAs (OR=1.15 per loge {mSv+0.01}, 95% CI=0.83–1.59, p-value=0.40). Similarly, no dose-response relationship was observed for exposure to gamma radiation in the 3-month preconception period, or for radon or total gonadal radiation in the 3- or 6-month preconception periods. Conclusion: There was no increased risk of a CA among liveborn children of Ontario uranium miners who were exposed to radon, gamma or total radiation during the 3- or 6-month periods before conception.