Tamar Wainstock

Stress In Utero: Prenatal Programming of Brain Plasticity and Cognition.

Animal studies confirm earlier anecdotal observations in humans to indicate that early life experience has a profound impact on adult behavior, years after the original experience has vanished. These studies also highlight the role of early life adversaries in the shaping of a disordered brain. Evidence is accumulating to indicate that the epigenome, through which the environment regulates gene expression, is responsible for long-lasting effects of stress during pregnancy on brain and behavior. A possible differential effect of the environment on the epigenome may underlie the observation that only a small fraction of a population with similar genetic background deteriorates into mental disorders. Considerable progress has been made in the untangling of the epigenetic mechanisms that regulate emotional brain development. The present review focuses on the lasting effects of prenatal stress on brain plasticity and cognitive functions in human and rodent models. Although human studies stress the significance of early life experience in functional maturation, they lack the rigor inherent in controlled animal experiments. Furthermore, the analysis of molecular and cellular mechanisms affected by prenatal stress is possible only in experimental animals. The present review attempts to link human and animal studies while proposing molecular mechanisms that interfere with functional brain development.

Prenatal stress and risk of spontaneous abortion.

Objective The aim of this study was to evaluate the association between exposure to life-threatening rocket attacks and spontaneous abortions (SAs). Study Design This is a historical cohort study comparing 1345 pregnancies of female residents of a town exposed to rocket attacks with 2143 pregnancies of female residents of an unexposed town. Demographic and medical data were obtained from hospital records and exposure information from official local databases. Intensity of exposure was calculated for preconception and pregnancy periods. Results Compared with unexposed group, women in the exposed group had higher rates of SA (6.9% versus 4.7%, adjusted odds ratio = 1.59, 95% confidence interval = 1.17–2.2, p = .003). Intensity of preconception and pregnancy exposure were nonlinearly associated with SA risk; both the highest and the lowest quintiles of exposure were associated with increased risk of SA. Conclusions Stress during preconception and pregnancy was associated with increased risk of SA.

Fetal sex modifies effects of prenatal stress exposure and adverse birth outcomes

Abstract Prenatal maternal stress is associated with pregnancy complications, poor fetal development and poor birth outcomes. Fetal sex has also been shown to affect the course of pregnancy and its outcomes. The aim of this study was to evaluate whether fetal sex modifies the association between continuous exposure to life-threatening rocket attack alarms and adverse pregnancy outcomes. A retrospective cohort study was conducted in which the exposed group was comprised of 1846 women exposed to rocket-attack alarms before and during pregnancy. The unexposed group, with similar sociodemographic characteristics, delivered during the same period of time at the same medical center, but resided out of rocket-attack range. Multivariable models for each gender separately, controlling for possible confounders, evaluated the risk associated with exposure for preterm births (PTB), low birthweight (LBW), small for gestational age and small head circumference (HC). In both univariable and multivariable analyses exposure status was a significant risk factor in female fetuses only: PTB (adj. OR = 1.43; 1.04–1.96), LBW (adj. OR = 1.41; 1.02–1.95) and HC < 31 cm (adj. OR = 1.78; 1.11–2.88). In addition, regarding all adverse outcomes, the male-to-female ratio was higher in the exposed group than in the unexposed group. The findings support the hypothesis that male and female fetuses respond differentially to chronic maternal stress.

The association between prenatal maternal objective stress, perceived stress, preterm birth and low birthweight

Abstract Objective: To evaluate the association between prenatal maternal stress, preterm birth (PTB) and low birthweight (LBW). Methods: Forty-seven women exposed to life-threatening rocket attacks during pregnancy were compared to 78 unexposed women. Women were interviewed within 9 months of delivery regarding socio-demographic background, smoking and perceived level of stress prenatally. Clinical data was obtained from hospital records and information regarding rocket attacks was obtained from official local authorities. Results: Women exposed to rocket attacks during the second trimester of pregnancy were more likely to deliver LBW infants than were unexposed women (14.9% versus 3.3%, p = 0.03). No association was found between stress exposure and PTB. A multivariate logistic regression revealed that every 100 alarm increment increased the risk of LBW by 1.97 (adj.OR = 1.97, 95%CI 1.05–3.7). Perceived stress was not associated with LBW. Conclusions: Exposure to rocket attacks during the second trimester of pregnancy was associated with LBW. Objective stress can be used as an indicator of stress. Further studies are required to understand the underlying mechanism.

Placenta accreta is an independent risk factor for late pre-term birth and perinatal mortality

Abstract Objective: This study is aimed to identify the risk factors for the development of placenta accreta (PA) and characterize its effect on maternal and perinatal outcomes. Study design: This population-based retrospective cohort study included all deliveries at our medical center during the study period. Those with placenta accreta (n = 551) comprised the study group, while the rest of the deliveries (n = 239 089) served as a comparison group. Results: The prevalence of placenta accerta is 0.2%. Women with this complication had higher rates of ≥2 previous CS (p < 0.001), recurrent abortions (p = 0.03), and previous placenta accreta [p < 0.001]. The rates of placenta previa and peripartum hemorrhage necessitating blood transfusion were higher in women with placenta accreta than in the comparison group. PTB before 34 and 37 weeks of gestation was more common among women with placenta accreta (p < 0.01), as was the rate of perinatal mortality (p < 0.001). Placenta accreta was an independent risk factor for perinatal mortality (adj. OR 8.2; 95% CI 6.4–10.4, p < 0.001) and late PTB (adj. OR 1.4; 95% CI 1.1–1.7, p = 0.002). Conclusion: Placenta accreta is an independent risk factor for late PTB and perinatal mortality.

Exposure to life‐threatening stressful situations and the risk of preterm birth and low birth weight

To evaluate the association between exposure to life‐threatening rocket attacks and the risks of preterm birth (PTB) and low birth weight (LBW).

Early-term deliveries as an independent risk factor for long-term respiratory morbidity of the offspring

Newborns exhibit the lowest immediate respiratory morbidity rates when born following 39 completed weeks of gestation. We sought to determine whether early‐term delivery (37–38 + 6 weeks’ gestation) impacts on long‐term pediatric respiratory morbidity.

A prior placenta accreta is an independent risk factor for post-partum hemorrhage in subsequent gestations

OBJECTIVE The rate of placenta accreta, a life threatening condition, is constantly increasing, mainly due to the rise in the rates of cesarean sections. This study is aimed to determine the effect of a history of placenta accreta on subsequent pregnancies. STUDY DESIGN A population based retrospective cohort study was designed, including all women who delivered at our medical center during the study period. The study population was divided into two groups including pregnancies with: (1) a history of placenta accreta (n=514); and (2) control group without placenta accreta (n=239,126). RESULTS (1) A history of placenta accreta is an independent risk factor for postpartum hemorrhage (adjusted OR 4.1, 95% CI 1.5-11.5) as were placenta accreta (adjusted OR 22.0, 95% CI 14.0-36.0) and placenta previa (adjusted OR 7.6, 95% CI 4.4-13.2) in the current pregnancy, and a prior cesarean section (adjusted OR 1.7, 95% CI 1.3-2.2); (2) in addition, placenta accreta in a previous pregnancy is associated with a reduced rate of mild preeclampsia in future pregnancies (1.8% vs. 3.4%, RR 0.51, 95% CI 0.26-0.98); (3) however, in spite of the higher rate of neonatal deaths in the study group, a history of placenta accreta was not an independent risk factor for total perinatal mortality (adjusted OR 1.0, 95% CI 0.5-1.9) after adjusting for confounders. CONCLUSION A history of placenta accreta is an independent risk factor for postpartum hemorrhage. This should be taken into account in order to ensure a safety pregnancy and delivery of these patients.

Fertility treatments and pediatric neoplasms of the offspring: results of a population-based cohort with a median follow-up of 10 years

Objective: Studies have questioned the long‐term health effects of offspring conceived after fertility treatments. Methods: We aimed to evaluate whether an association exists between mode of conception (in vitro fertilization, ovulation induction, or spontaneous pregnancy) and neoplasm risk (both benign and malignant tumors) among the offspring; we observed the offspring for up to 18 years. Study Design: A population‐based cohort analysis was performed that compared the risk for neoplasms among children (up to the age of 18 years) based on mode of conception. Neoplasm diagnoses were based on hospital records of the same single tertiary center in the region. All singletons born during from 1991–2013 and discharged alive were included in the study. Offspring with congenital malformations were excluded from the analysis. Kaplan‐Meier survival curves were constructed to compare cumulative neoplasms incidence; multivariable survival analyses were used to control for confounders that included gestational age, pregnancy complications, and maternal factors. Results: During the study period, 242,187 newborn infants met the inclusion criteria: 2603 (1.1%) were conceived after in vitro fertilization; 1721 (0.7%) were conceived after ovulation induction treatments, and 237,863 (98.3%) were conceived spontaneously. During the follow‐up period (median, 10.55 years), 1498 neoplasms(0.6%) were diagnosed. Incidence density rate for neoplasms was higher among children conceived either after in vitro fertilization (1.5/1000 person years) or ovulation induction treatments (1.0/1000 person years), as compared with naturally conceived children (0.59/1000 person years; Kaplan‐Meier log rank, P<.001). The association between in vitro fertilization and total pediatric neoplasms and the association between any fertility treatments and malignancies remained significant; we controlled for confounders such as gestational diabetes mellitus, hypertensive disorders, preterm birth, and maternal age (adjusted hazard ratio, 2.48; 95% confidence interval, 1.71–3.50; and adjusted hazard ratio, 1.96; 95% confidence interval, 1.14–3.36, for all neoplasms and all malignancies, respectively). Conclusion: Children conceived after fertility treatments are at an increased risk for pediatric neoplasms.

Experience-induced transgenerational (re-)programming of neuronal structure and functions: Impact of stress prior and during pregnancy

This review focuses on the inter- and transgenerational effects of stress experience prior to and during gestation. We provide an overview of findings from studies in humans as well as in animal models on brain structural and physiological functions and on the development of cognitive and executive functions. We also discuss the concept of stress-induced (re-)programming in more detail by highlighting epigenetic mechanisms and particularly those affecting the development of monoaminergic transmitter systems, which constitute the braińs reward system. As the majority of studies have focused on male individuals we will emphasize sex-specific differences in stress vulnerability and resilience. Finally, we offer some perspectives on the development of protective and therapeutic interventions in cognitive and emotional disturbances resulting from pre-conception and prenatal stress.