Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, is characterized by long-term maternal stress, undernutrition and dehydration. While maternal stress and malnutrition of pregnancy are linked to poor neonatal outcome and associated with poor adult health, long-term outcome of fetal exposure to HG has never been explored. The purpose of this study is to determine whether long-term emotional and behavioral diagnoses may be associated with fetal exposure to HG. Emotional and behavioral diagnoses of adults born of a pregnancy complicated by HG were compared to diagnoses from non-exposed controls. Offspring exposed to HG in utero were significantly more likely to have a psychological and behavioral disorder (OR = 3.6, P < 0.0001) with diagnoses primarily of depression, bipolar disorder and anxiety. In utero exposure to HG may lead to increased risks of psychological and behavioral disorders in the offspring.

Our previous work suggests that stressors that impact placental vascular growth result in a deformed chorionic surface shape, which reflects an abnormal placental three-dimensional shape. We propose to use variability of placental disk thickness as a reflector of deviations in placental vascular growth at the finer level of the fetal stems. We hypothesize that increased variability of thickness is associated with abnormal chorionic surface shape, but will be a predictor of reduced placental functional efficiency (smaller baby for a given placental weight) independent of shape. These measures may shed light on the mechanisms linking placental growth to risk of adult disease. The sample was drawn from the Pregnancy, Infection and Nutrition Study. In all, 94.6% of the cohort consented to placental examination. Of the 1023 delivered at term, those previously sectioned by the Pathology Department were excluded, leaving 587 (57%) cases with intact placentas that were sliced and photographed. The chorionic surface shape and the shape of a central randomly oriented placental slice were analyzed and measures were compared using correlation. Lower mean placental disk thickness and more variable disk thickness were each strongly and significantly correlated with deformed chorionic plate shapes. More variable disk thickness was strongly correlated with reduced placental efficiency independent of abnormal chorionic surface shape. Variability of placental disk thickness, simple to measure in a single randomly oriented central slice, may be an easily acquired measure that is an independent indicator of lowered placental efficiency, which may in turn program the infant and result in increased risk for development of adult diseases.

There is evidence that fetal exposure to maternal stress is associated with adverse birth outcomes. Less is known about the association between fetal responses to a stressor and indicators of fetal maturity and developmental outcomes. The purpose of the present study was to determine whether fetal heart rate (FHR) patterns in response to a startling stimulus at ∼30 weeks of gestation were associated with gestational age at birth and birth weight. FHR was measured in 156 maternal–fetal dyads following a vibroacoustic stimulus. All pregnancies were singleton intrauterine pregnancies in English-speaking women who were primarily married, middle class, White and at least 18 years of age. Group-based trajectory modeling identified five groups of fetuses displaying distinctive longitudinal trajectories of FHR response to the startling stimulus. The FHR group trajectories were significantly associated with birth weight percentile (P < 0.01) even after controlling for estimated fetal weight at the time of assessment and parity, which are the known factors influencing birth weight (P < 0.01). Post hoc analyses indicated that two groups accounted for the association between FHR patterns and birth weight. The group (n = 23) with the lowest birth weight exhibited an immediate FHR deceleration followed by an immediate acceleration that does not recover. An FHR pattern characterized by immediate and fast acceleration to the peak and a slow discovery to baseline was associated with the highest birth weight. This is the first direct evidence showing that low birth weight and the resulting neurological consequences may have their origins in early fetal development.

Young people who are born very preterm exhibit a narrower arterial tree as compared with people born at term. We hypothesized that such arterial narrowing occurs as a direct result of premature birth. The aim of this study was to compare aortic and carotid artery growth in infants born preterm and at term. Observational and longitudinal cohort study of 50 infants (21 born very preterm, all appropriate for gestational age, 29 controls born at term) was conducted. Diameters of the upper abdominal aorta and common carotid artery were measured with ultrasonography at three months before term, at term and three months after term-equivalent age. At the first assessment, the aortic end-diastolic diameter (aEDD) was slightly larger in very preterm infants as compared with fetal dimensions. Fetal aortic EDD increased by 2.6 mm during the third trimester, whereas very preterm infants exhibited 0.9 mm increase in aEDD during the same developmental period (P < 0.001 for group difference). During the following 3-month period, aortic growth continued unchanged (+0.9 mm) in very preterm infants, whereas postnatal growth in term controls slowed down to +1.3 mm (P < 0.001 v. fetal aortic growth). At the final examination, aEDD was 22% and carotid artery EDD was 14% narrower in infants born preterm compared with controls, also after adjusting for current weight (P < 0.01). Aortic and carotid artery growth is impaired after very preterm birth, resulting in arterial narrowing. Arterial growth failure may be a generalized vascular phenomenon after preterm birth, with implications for cardiovascular morbidity in later life.

Maternal undernutrition (MUN) results in growth-restricted newborns with reduced nephron numbers that is associated with increased risk of hypertension and renal disease. The total adult complement of nephrons is set during nephrogenesis suggesting that MUN affects the staged development of nephrons in as yet unknown manner. A possible cause may be the increased renal apoptosis; therefore, we investigated whether apoptotic signaling and cell death were increased in MUN rat kidneys. Pregnant rat dams were fed an ad libitum diet [control] or were 50% food restricted (MUN) starting at embryonic day (E) 10. Male offspring kidneys (n = 5 each, MUN and control) were analyzed for mRNA using quantitative PCR (E20) and for protein expression using Western blotting and immunohistochemistry (E20 and postnatal day 1, P1). Apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Upregulation of pro-apoptotic protein expression was detected at E20 (Fas receptor, caspase 9) and at P1 (caspase 3, Bax). The anti-apoptotic factor Bcl2 was significantly decreased in P1 kidneys. Kidney TUNEL showed apoptotic nuclei significantly increased in the P1 nephrogenic zone (MUN 3.3 + 0.3 v. C 1.6 + 0.5, P = 0.002). The majority of apoptotic nuclei co-localized to mesenchyme and pretubular aggregates in the nephrogenic zone. Differential regulation of apoptosis in mesenchyme and pretubular aggregates following parturition suggests a mechanism for nephropenia in gestational programming of the kidney.

Unbalanced nutrition during critical windows of development is implicated in determining the susceptibility to hypertension and cardiovascular disease in adult life, but the underlying mechanisms during fetal life have not been fully elucidated. We investigated the effects of moderate nutritional restriction during critical windows in gestation on late gestation fetal sheep growth, cardiovascular and renal renin-angiotensin system function. Ewes were fed 100% nutrient requirements (control), or 40–50% nutrient requirements during the peri-implantation period (1–31 days gestation (dGA), PI40 and PI50), or 50% nutrient requirements in late gestation (104–127 dGA). At 125 ± 2 dGA, fetal cardiovascular and renal function were measured at baseline, and during frusemide, angiotensin II (Ang II), phenylephrine and hypoxia challenges. Maternal undernutrition had no effect on fetal biometry, kidney weight, nephron number, basal cardiovascular function or cardiovascular and renal responses to frusemide. Fetal blood pressure response to Ang II was blunted in PI50 (P < 0.05), but not in PI40 groups. There was no difference between groups in the cardiovascular or endocrine response to hypoxia. The lack of effect of moderate undernutrition within key developmental windows of fetal kidney development on fetal renal structure and function suggests that renal mechanisms do not underlie our previous observations of cardiovascular dysfunction in adulthood following early-life undernutrition.

Impaired flexibility in the use of substrates for energy production in the heart is implicated in cardiomyopathy. We investigated the effect of maternal protein restriction during pregnancy in rats on the transcription of key genes in cardiac lipid and carbohydrate metabolism in the offspring. Rats were fed protein-sufficient or protein-restricted (PR) diets during pregnancy. Triacylglycerol concentration in adult (day 105) heart was altered by maternal protein intake contingent on post-weaning fat intake and sex. mRNA expression of peroxisomal proliferator-activated receptor (PPAR)-α and carnitine palmitoyltransferase-1 was increased by the maternal PR diet in adult, but not neonatal, offspring. PPARα promoter methylation was lower in adult and neonatal heart from PR offspring. These findings suggest that prenatal nutrition alters the future transcriptional regulation of cardiac energy metabolism in the offspring through changes in epigenetic regulation of specific genes. However, changes in gene functional changes may not be apparent in early life.