Maternal preconception stress produces sex-specific effects at the maternal:fetal interface to impact offspring development and phenotypic outcomes†.

Entering pregnancy with a history of adversity, including adverse childhood experiences and racial discrimination stress, is a predictor of negative maternal and fetal health outcomes. Little is known about the biological mechanisms by which preconception adverse experiences are stored and impact future offspring health outcomes. In our maternal preconception stress (MPS) model, female mice underwent chronic stress from postnatal days 28-70 and were mated 2 weeks post-stress. Maternal preconception stress dams blunted the pregnancy-induced shift in the circulating extracellular vesicle proteome and reduced glucose tolerance at mid-gestation, suggesting a shift in pregnancy adaptation. To investigate MPS effects at the maternal:fetal interface, we probed the mid-gestation placental, uterine, and fetal brain tissue transcriptome. Male and female placentas differentially regulated expression of genes involved in growth and metabolic signaling in response to gestation in an MPS dam. We also report novel offspring sex- and MPS-specific responses in the uterine tissue apposing these placentas. In the fetal compartment, MPS female offspring reduced expression of neurodevelopmental genes. Using a ribosome-tagging transgenic approach we detected a dramatic increase in genes involved in chromatin regulation in a PVN-enriched neuronal population in females at PN21. While MPS had an additive effect on high-fat-diet (HFD)-induced weight gain in male offspring, both MPS and HFD were necessary to induce significant weight gain in female offspring. These data highlight the preconception period as a determinant of maternal health in pregnancy and provides novel insights into mechanisms by which maternal stress history impacts offspring developmental programming.

Chemogenetic activation of CRF neurons as a model of chronic stress produces sex-specific physiological and behavioral effects.

Trauma and chronic stress exposure are the strongest predictors of lifetime neuropsychiatric disease presentation. These disorders often have significant sex biases, with females having higher incidences of affective disorders such as major depression, anxiety, and PTSD. Understanding the mechanisms by which stress exposure heightens disease vulnerability is essential for developing novel interventions. Current rodent stress models consist of a battery of sensory, homeostatic, and psychological stressors that are ultimately integrated by corticotropin-releasing factor (CRF) neurons to trigger corticosteroid release. These stress paradigms, however, often differ between research groups in the type, timing, and duration of stressors utilized. These inconsistencies, along with the variability of individual animals' perception and response to each stressor, present challenges for reproducibility and translational relevance. Here, we hypothesized that a more direct approach using chemogenetic activation of CRF neurons would recapitulate the effects of traditional stress paradigms and provide a high-throughput method for examining stress-relevant phenotypes. Using a transgenic approach to express the Gq-coupled Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor hM3Dq in CRF-neurons, we found that the DREADD ligand clozapine-N-oxide (CNO) produced an acute and robust activation of the hypothalamic-pituitary-adrenal (HPA) axis, as predicted. Interestingly, chronic treatment with this method of direct CRF activation uncovered a novel sex-specific dissociation of glucocorticoid levels with stress-related outcomes. Despite hM3Dq-expressing females producing greater corticosterone levels in response to CNO than males, hM3Dq-expressing males showed significant typical physiological stress sensitivity with reductions in body and thymus weights. hM3Dq-expressing females while resistant to the physiological effects of chronic CRF activation, showed significant increases in baseline and fear-conditioned freezing behaviors. These data establish a novel mouse model for interrogating stress-relevant phenotypes and highlight sex-specific stress circuitry distinct for physiological and limbic control that may underlie disease risk.

Extracellular vesicles are dynamic regulators of maternal glucose homeostasis during pregnancy.

Homeostatic regulation of the maternal milieu during pregnancy is critical for maternal and fetal health. The placenta facilitates critical communication between maternal and fetal compartments, in part, through the production of extracellular vesicles (EVs). EVs enable tissue synchrony via cell-cell and long-distance communication and are at their highest circulating concentration during pregnancy. While much work has been done investigating how physiological challenges in pregnancy affect the fetus, the role of placental communication in maternal health has not been well examined. We previously identified placental O-glycosyl transferase (OGT), a glucose-sensing enzyme, as a target of maternal stress where OGT levels and activity affected the O-glycosylation of proteins critical for EV cargo loading and secretion. Here, we hypothesized that placental OGT plays an essential role in maternal homeostatic regulation during pregnancy via its regulation of maternal circulating EV concentrations. Our studies found that changes to key metabolic factors over the circadian cycle, including glucocorticoids, insulin, and glucose, were significantly associated with changes in circulating EV concentration. Targeting placental OGT in mice, we found a novel significant positive relationship between placental OGT and maternal circulating EV concentration that was associated with improving maternal glucose tolerance during pregnancy. Finally, an intravenous elevation in EVs, matching the concentration of EVs during pregnancy, shifted non-pregnant female glucose sensitivity, blunted glucose variance, and improved synchrony of glucose uptake. These data suggest an important and novel role for circulating EVs as homeostatic regulators important in maternal health during pregnancy.

What the hippocampus tells the HPA axis: Hippocampal output attenuates acute stress responses via disynaptic inhibition of CRF+ PVN neurons.

The hippocampus exerts inhibitory feedback on the release of glucocorticoids. Because the major hippocampal efferent projections are excitatory, it has been hypothesized that this inhibition is mediated by populations of inhibitory neurons in the hypothalamus or elsewhere. These regions would be excited by hippocampal efferents and project to corticotropin-releasing factor (CRF) cells in the paraventricular nucleus of the hypothalamus (PVN). A direct demonstration of the synaptic responses elicited by hippocampal outputs in PVN cells or upstream GABAergic interneurons has not been provided previously. Here, we used viral vectors to express channelrhodopsin (ChR) and enhanced yellow fluorescent protein (EYFP) in pyramidal cells in the ventral hippocampus (vHip) in mice expressing tdTomato in GABA- or CRF-expressing neurons. We observed dense innervation of the bed nucleus of the stria terminalis (BNST) by labeled vHip axons and sparse labeling within the PVN. Using whole-cell voltage-clamp recording in parasagittal brain slices containing the BNST and PVN, photostimulation of vHip terminals elicited rapid excitatory postsynaptic currents (EPSCs) and longer-latency inhibitory postsynaptic currents (IPSCs) in both CRF+ and GAD + cells. The ratio of synaptic excitation and inhibition was maintained in CRF + cells during 20 Hz stimulus trains. Photostimulation of hippocampal afferents to the BNST and PVN in vivo inhibited the rise in blood glucocorticoid levels produced by acute restraint stress. We thus provide functional evidence suggesting that hippocampal output to the BNST contributes to a net inhibition of the hypothalamic-pituitary axis, providing further mechanistic insights into this process using methods with enhanced spatial and temporal resolution.

Elevated MeCP2 in Mice Causes Neurodegeneration Involving Tau Dysregulation and Excitotoxicity: Implications for the Understanding and Treatment of MeCP2 Triplication Syndrome.

Expression of MeCP2 must be carefully regulated as a reduction or increase results in serious neurological disorders. We are studying transgenic mice in which the MeCP2 gene is expressed at about three times higher than the normal level. Male MeCP2-Tg mice, but not female mice, suffer motor and cognitive deficits and die at 18-20 weeks of age. MeCP2-Tg mice display elevated GFAP and Tau expression within the hippocampus and cortex followed by neuronal loss in these brain regions. Loss of Purkinje neurons, but not of granule neurons in the cerebellar cortex is also seen. Exposure of cultured cortical neurons to either conditioned medium from astrocytes (ACM) derived from male MeCP2-Tg mice or normal astrocytes in which MeCP2 is expressed at elevated levels promotes their death. Interestingly, ACM from male, but not female MeCP2-Tg mice, displays this neurotoxicity reflecting the gender selectivity of neurological symptoms in mice. Male ACM, but not female ACM, contains highly elevated levels of glutamate, and its neurotoxicity can be prevented by MK-801, indicating that it is caused by excitotoxicity. Based on the close phenotypic resemblance of MeCP2-Tg mice to patients with MECP2 triplication syndrome, we suggest for the first time that the human syndrome is a neurodegenerative disorder resulting from astrocyte dysfunction that leads to Tau-mediated excitotoxic neurodegeneration. Loss of cortical and hippocampal neurons may explain the mental retardation and epilepsy in patients, whereas ataxia likely results from the loss of Purkinje neurons.

Experiences accompanying postpartum weight loss: benefits, successes, and well-being.

Obesity is a growing problem in the United States, and research has supported the theory that pregnancy contributes to long-term weight gain. This phenomenological study investigated the postpartum weight loss experiences of 24 women. Women ranged in age from 25 to 35 years, were mostly Caucasian with adequate resources, and about half worked either full or part time. Women described both positive and negative experiences associated with weight loss. Themes included issues related to exercise, weight struggles, pregnancy contributions to weight gain, eating, breastfeeding, motivation for weight loss, time issues, miscellaneous struggles, realizing benefits, social support, quick weight loss, personal well-being, and successes. The overarching theme that represents these women's experiences was the need to balance weight loss activity with other responsibilities, which resulted in challenges and triumphs in women's pursuit of returning to their prepregnancy weights. Realizing benefits, successes, and personal well-being are addressed in this article.

Postpartum weight loss: weight struggles, eating, exercise, and breast-feeding.

Twenty-four women with children 5 years old or younger were interviewed regarding their experiences in losing weight during the postpartum period. Phenomenological interviews were conducted according to Husserl's perspective. Women who participated in the study revealed the issues related to postpartum weight loss: weight struggles, exercise, breast-feeding, eating, and pregnancy contributions to weight gain. The overall theme that resulted from these in-depth interviews was that women struggle to balance their successes and setbacks in losing weight during the postpartum period.

Men's Perceptions of Pregnancy-Related Weight Gain: A Psychosocial Firestorm (Upheaval) Intertwined With Supportive Intentions.

In-depth interviews were conducted with 16 men who had a significant other who had given birth within the last 5 years. Men were asked about their perceptions of pregnancy-related weight gain, and content analysis was used to identify themes from the interviews. Men described nine themes related to perinatal weight gain: (a) negative perceptions, (b) eating behaviors, (c) exercise habits, (d) health impact, (e) body changes, (f) weight-loss success, (g) "it bothered her more than me," (h) "the weight gain wasn't a problem," and (i) intimacy. Together, these themes offer a glimpse into men's experiences and highlight the discord and balance between experiencing negative feelings/perceptions and being a supportive partner. This information on how men perceive pregnancy-related weight gain can be used to develop interventions to assist men to support their significant others in meeting weight loss goals following pregnancy.

Women's challenges with postpartum weight loss.

UNLABELLED: This study was designed to examine women's experiences of weight loss during the postpartum period. Understanding women's positive and negative experiences can assist health care providers to successfully intervene in helping women lose weight following pregnancy and avoid long-term weight gain and obesity development. DESIGN: Phenomenology, according to Husserl's perspective. SETTING: Private location of the women's choosing. PARTICIPANTS: Twenty-six women, who ranged in age from 25 to 35 years, and had given birth within the last 5 years, were interviewed regarding their experiences with postpartum weight loss. The majority of the sample was Caucasian. Interviews were transcribed and themes were identified from each of the interviews. Comparisons were made between interviews to identify common experiences between women. Data were analyzed according to the Giorgi method. The women in the study had a wide range of experiences. Themes that emerged from the interviews related to women's challenges with return to prepregnancy weight. These included: time and motivation issues, the need for support, and weight and other struggles. This study provides a look inside the lives of women faced with the reality of losing weight after childbirth. Losing weight after delivery is multi-faceted and influenced by many factors. Interventions to assist women with weight loss should target the challenges described in this paper. When effective strategies are developed, education can be done during pregnancy to prepare for the postpartum period. Ultimately, future research efforts can help us to eliminate pregnancy as a risk factor for obesity in women.

Maternal obesity from all sides.

This column features excerpts from a recent series of articles from the Lamaze International research blog, Science & Sensibility. The eight-part series examined the issue of maternal obesity from various perspectives, incorporating writings from Kimmelin Hull, a physician assistant, a Lamaze Certified Childbirth Educator, and the community manager of Science & Sensibility; Kristen Montgomery, a nursing professor at the University of North Carolina-Charlotte; Pamela Vireday, a childbirth educator and blogger; and Kathleen Kendall-Tackett, a health psychologist, lactation consultant, and writer/speaker. The authors of the blog series, titled "Maternal Obesity from All Sides," reviewed current research about risks associated with maternal obesity as well as the humanistic issues and lived experiences of pregnant women of size.

Women's Desire for Pregnancy.

Descriptive qualitative interviews were conducted with 16 women who had given birth in the previous 5 years to identify factors that influenced their desire to become pregnant. All interviews were audiotaped. Following the interviews, the texts were transcribed verbatim and analyzed using Giorgi's method. Five themes emerged from the interviews: (1) timing; (2) spacing; (3) meeting personal criteria; (4) desire for the experience of pregnancy, birth, and parenting; and (5) extended family in close proximity. The study's findings offer an initial step in understanding the attitudes, motivations, and beliefs of healthy childbearing women and their desire for pregnancy. Increased understanding may help health-care providers develop interventions that not only assist women to conceive as desired but also prevent unplanned pregnancies.

Does relaxation education in anxious primigravid Iranian women influence adverse pregnancy outcomes?: a randomized controlled trial.

UNLABELLED: Maternal anxiety and stress are found to be predictors of adverse pregnancy outcomes, including low birth weight and prematurity. OBJECTIVE: The aim of the study was to determine whether relaxation education in anxious pregnant Iranian women in their first pregnancy affects selected pregnancy outcomes, including birth weight, preterm birth, and surgical delivery rate. SUBJECTS: A total of 110 obstetrically and medically low-risk primigravid women in Iran with a high anxiety level demonstrated by Spielberger's State-Trait Anxiety Inventory were randomly assigned into experimental and control groups. METHOD: In this randomized controlled trial, the experimental group received routine prenatal care along with 7-week applied relaxation training sessions, while the control group received only routine prenatal care. Anxiety and perceived stress were measured by pre-educational and post-educational intervention. Data related to pregnancy outcomes include birth weight, gestational age at birth, and type of delivery. RESULTS: Significant reductions in low birth weight, cesarean section, and/or instrumental extraction were found in the experimental group compared with the control group. No significant differences were found in the rate of preterm birth. CONCLUSION: The findings suggest beneficial effects of nurse-led relaxation education sessions during the prenatal period. This intervention could serve as a resource for improving pregnancy outcomes in women with high anxiety.

Continuing education module-maternal calcium intake and metabolism during pregnancy and lactation.

Calcium is an essential nutrient during pregnancy and lactation. Calcium contributes to bone development in the fetus and neonate and is considered a critical nutrient. Physiological changes in calcium metabolism occur during pregnancy and lactation. Some women may lose some of their bone density during pregnancy and/or lactation, and then regain it after the cessation of lactation. Implications for childbirth educators include content regarding the topic of calcium in their classes.

Childbirth education for multiple pregnancy: part 1: prenatal considerations.

Women with a multiple pregnancy have unique learning needs in preparing for birth. This paper explores the issues relevant to women with a multiple pregnancy to support a positive birth experience. One of the foundations of childbirth education and nursing care is to provide the individual woman and her family with knowledge regarding the birth process, what to expect, and how to cope with labor and birth. Education also focuses on caring for the newborns after birth and how to manage in the early days at home. However, traditional childbirth education classes, which meet in a series of evenings or Saturdays, may not meet the needs of women with a multiple pregnancy. In addition, because of the differences in care that exist for women with a multiple pregnancy, new paradigms for childbirth education are needed to meet the learning needs of these families. The purpose of this paper is to provide information to the childbirth educator on the differences in care women with a multiple pregnancy can expect and to suggest strategies to meet the childbirth education needs of these families.

Childbirth education for multiple pregnancy: part 2: intrapartum and postpartum considerations.

Women with a multiple pregnancy can expect a different labor and birth course than those with a singleton pregnancy. While the postpartum period is similar to that of families with a singleton, it is likely to be more hectic in families with multiple infants. In addition, a multiple pregnancy increases both maternal and neonatal risks; therefore, women with a multiple pregnancy may experience slight differences in care due to these potential risks, including additional monitoring and treatment. This article discusses the intrapartum and postpartum considerations families with a multiple pregnancy/birth may experience. This information is provided so that the childbirth educator can incorporate this content into courses, as appropriate, and assist families with a multiple pregnancy to anticipate a realistic birth and postpartum experience.

Web Sites that Address Prematurity.

Families of preterm infants need a tremendous amount of support. This resource column highlights several Web sites that may be useful to health care providers and childbirth educators, as well as to parents of premature infants and their families.

New Resource from the CDC to Prevent Obesity: Perinatal Implications.

Research has identified pregnancy as a trigger to obesity among women; therefore, childbirth educators are encouraged to include the topic of weight gain in their classes. The Centers for Disease Control and Prevention recently published a guide on obesity that may serve as an excellent resource for both educators and their clients.

Planned adolescent pregnancy: themes related to the pregnancy.

Health-care providers need to recognize that not all adolescent pregnancies occur as a result of error. A small subset of adolescents intentionally plan their pregnancy. The purpose of this phenomenological study was to describe the experiences of 14- to 17-year-old pregnant females who had planned their pregnancies. Participants were recruited from one prenatal clinic at a large tertiary medical center in the eastern region of the United States. Three themes emerged from participant interviews that were related to the adolescents' pregnancies. Themes included living environment issues, adjustment to the pregnancy, and an increased motivation to do well in school and work to provide a good life for their infants. Understanding the phenomena of planned adolescent pregnancy can provide a basis for health-care providers to provide support to adolescent females in this life transition. Understanding the common experience of these adolescents can assist health-care providers to develop individualized interventions to best meet these young women's needs and to improve birth outcomes among this population.

Web Sites that Address Epidural Anesthesia for Childbirth.

Epidural analgesia has become a popular way to reduce pain during labor. Because epidural use is not limited to women who plan its use, but extends to some who originally planned a nonmedicated birth, it is important for the childbirth educator to provide information on this topic to all women. In this column, the authors provide examples of Web sites that address epidural anesthesia. Web sites for professionals and consumers are included. Encouraging the use of such resources by expectant parents can provide them with good information and allow the class time on this topic to be that of clarification.