Fetal Growth

Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR)=2.97; 95% CI=2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR=1.61; 95% CI=1.31, 1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as ≤ 10 years (OR=1.41 95% CI=0.97, 2.03) than defined as ≤ 11 years (OR=1.16; 95% CI=0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life.

A range of complications of pregnancy, abnormal fetal growth and development, and complications of delivery have been associated with increased risk of schizophrenia. Few studies have been able to adjust for a broad range of potential confounding factors. A national population nested case-control study based on Danish longitudinal registers was conducted to investigate the risk of schizophrenia associated with exposure to a range of obstetric events. The sample included 1039 first admissions to, or contacts with Danish psychiatric services with an ICD-8 or ICD-10 diagnosis of schizophrenia and 24, 826 individually matched controls. Adjusting for the other obstetric factors, family psychiatric history, and socio-economic and demographic factors, risk of schizophrenia was associated with maternal non-attendance at antenatal appointments (Incidence Rate Ratio (IRR) 2.08, 95% CI: 1.0, 4.4), gestational age of 37 weeks or below (IRR 1.51, 95% CI: 1.0, 2.2), maternal influenza (IRR 8.2, 95% CI: 1.4, 48.8), preeclampsia (IRR 2.72, 95% CI: 1.0, 7.3), threatened premature delivery (IRR 2.39, 95% CI: 1.4, 4.1), haemorrhage during delivery (IRR 2.43, 95% CI: 1.1, 5.6), manual extraction of the baby (IRR 2.15, 95% CI: 1.1, 4.4), and maternal sepsis of childbirth and the puerperium (IRR 2.91, 95% CI: 1.1, 7.9). There was no significant interaction between the obstetric factors and either sex or family psychiatric history. The data suggest a modest association between prematurity, indicators of hypoxia, maternal infections, and maternal behaviours and risk of the later development of schizophrenia after adjusting for a number of possible confounding factors.

The regulation of mRNA stability plays a major role in the control of gene expression during cell proliferation, differentiation, and development. Here, we show that inactivation of the RasGAP-associated endoribonuclease (G3BP)-encoding gene leads to embryonic lethality and growth retardation. G3BP-/- mice that survived to term exhibited increased apoptotic cell death in the central nervous system and neonatal lethality. Both in mouse embryonic fibroblasts and during development, the absence of G3BP altered the expression of essential growth factors, among which imprinted gene products and growth arrest-specific mRNAs were outstanding. The results demonstrate that G3BP is essential for proper embryonic growth and development by mediating the coordinate expression of multiple imprinted growth-regulatory transcripts.

Human placental GH (hPGH) replaces pituitary GH during pregnancy. hPGH is correlated to serum IGF-I in normal preg- nancies and in pregnancies complicated by fetoplacental dis- orders. In gestational diabetes and type 2 diabetes no corre- lation between hPGH and IGF-I has been found. The relationship between hPGH and IGF-I in type 1 diabetes mel- litus has not been investigated

Among 95 term infants with benzoylecgonine, the cocaine metabolite, detectable in their meconium, there was an inverse relation between the concentration of benzoylecgonine and birth weight, length, and head circumference. Multiple regression analysis confirmed these relations after controlling for gestational age and maternal use of marijuana, cigarettes, and alcohol. These data suggest a dose-response relation between the magnitude of prenatal cocaine exposure and impaired fetal growth.

More than 3 decades after Jones and Smith (1973) reported on the devastation caused by alcohol exposure on fetal development, the rates of heavy drinking during pregnancy remain relatively unchanged. Early identification of fetal alcohol exposure and maternal abstinence led to better infant outcomes. This study examined the utility of biometry for detecting alcohol-related fetal growth impairment. We obtained fetal ultrasound measures from routine ultrasound examinations for 167 pregnant hazardous drinkers who were enrolled in a brief alcohol intervention study. The fetal measures for women who quit after learning of their pregnancies were compared with measures for women who continued some drinking throughout the course of their pregnancies. Because intensity of alcohol consumption is associated with poorer fetal outcomes, separate analyses were conducted for the heavy (average of >or=5 drinks per drinking day) alcohol consumers. Fetal measures from the heavy-exposed fetuses were also compared with measures from a nondrinking group that was representative of normal, uncomplicated pregnancies from our clinics. Analyses of covariance were used to determine whether there were differences between groups after controlling for influences of gestational age and drug abuse. Nearly half of the pregnant drinkers abstained after learning of their pregnancies. When women reportedly quit drinking early in their pregnancies, fetal growth measures were not significantly different from a non-alcohol-exposed group, regardless of prior drinking patterns. Any alcohol consumption postpregnancy recognition among the heavy drinkers resulted in reduced cerebellar growth as well as decreased cranial to body growth in comparison with women who either quit drinking or who were nondrinkers. Amphetamine abuse was predictive of larger cranial to body growth ratios. Alterations in fetal biometric measurements were observed among the heavy drinkers only when they continued drinking after becoming aware of their pregnancies. Although the reliance on self-reported drinking is a limitation in this study, these findings support the benefits of early abstinence and the potential for ultrasound examinations in the detection of fetal alcohol effects.

Although a suboptimal prenatal environment has been linked with schizophrenia and depression, possible associations with personality disorders remain unclear. The aim of this study was to examine the associations of body size at birth and length of gestation with hospitalization for personality disorders in a cohort study of 6506 men and 5857 women born in Helsinki, Finland, between 1934 and 1944. International Classification of Diseases (-8, -9, -10) diagnoses of personality disorders were extracted from the national Finnish Hospital Discharge Register since 1969. 102 men and 80 women had been hospitalized due to any personality disorder. 41 men and 30 women had dramatic personality disorders. Among men, head circumference showed an inverse J-shaped, nonlinear association with hospitalization for personality disorders. Men with a small head circumference were at increased risk. Also in men, a smaller head-to-length ratio linearly predicted personality disorders. Among women, a smaller placental area predicted increased risk of hospitalization for dramatic personality disorders. Vulnerability to personality disorders may be programmed during fetal life.

Insulin-like growth factor I receptor (Igf1r) signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal life, a function for the Igf pathway during preimplantation development has not been described. We show that abrogating Igf1r signaling with specific inhibitors blocks trophectoderm formation and compromises embryo survival during murine blastocyst formation. In normal embryos total Igf1r is present throughout the membrane, whereas the activated form is found exclusively at cell contact sites, colocalizing with E-cadherin. Using genetic domain switching, we show a requirement for E-cadherin to maintain proper activation of Igf1r. Embryos expressing exclusively a cadherin chimera with N-cadherin extracellular and E-cadherin intracellular domains (NcEc) fail to form a trophectoderm and cells die by apoptosis. In contrast, homozygous mutant embryos expressing a reverse-structured chimera (EcNc) show trophectoderm survival and blastocoel cavitation, indicating a crucial and non-substitutable role of the E-cadherin ectodomain for these processes. Strikingly, blastocyst formation can be rescued in homozygous NcEc embryos by restoring Igf1r signaling, which enhances cell survival. Hence, perturbation of E-cadherin extracellular integrity, independent of its cell-adhesion function, blocked Igf1r signaling and induced cell death in the trophectoderm. Our results reveal an important and yet undiscovered function of Igf1r during preimplantation development mediated by a unique physical interaction between Igf1r and E-cadherin indispensable for proper receptor activation and anti-apoptotic signaling. We provide novel insights into how ligand-dependent Igf1r activity is additionally gated to sense developmental potential in utero and into a bifunctional role of adhesion molecules in contact formation and signaling.

To study the association between umbilical plasma levels of interleukin-6 (IL-6) in relation to fetal growth in subgroups of preeclampsia, and in control pregnancies. Umbilical cord plasma was collected from 12,804 consecutive births. A total of 271 singleton cases of preeclampsia were identified, and classified as mild or severe, and as disease with early or late onset. As controls, 611 singleton pregnancies without preeclampsia were selected, and the ratio between observed and expected birth weight was used as a measure of fetal growth. In the analysis, we also included maternal smoking during pregnancy. Umbilical cord plasma IL-6 concentration was measured with an IL-6 bioassay. Comparing controls with subgroups of preeclampsia (severe and early onset), this study had a statistical power of 90% to detect a difference in cord IL-6 of 10 pg/mL. In severe preeclampsia, cord plasma IL-6 concentration was lower than among controls (P <.001), and there was a sharp decrease in cord plasma IL-6 with decreasing birth weight ratio (P trend <.001). By further dividing the preeclampsia group into early or late onset, the strong association between low IL-6 levels and low birth weight ratio appeared to be present mainly in early-onset disease. These results were not confounded by maternal smoking. Restricted fetal growth related to preeclampsia is associated with reduced umbilical cord plasma IL-6 concentration in cases with early-onset disease. In these cases, fetal growth restriction could be mediated by impaired trophoblast function.

A study was conducted to examine the effects of low dietary Mn on growth performance of pregnant heifers and fetal development of their offspring. Twenty pregnant Angus (n = 9) and Simmental (n = 11) heifers averaging 17 mo of age and 447.6 kg of initial body weight were used in the 267-d study. Heifers were selected from a previous study examining the effects of supplemental Mn on growth and reproductive performance of heifers. Ten pregnant heifers per treatment from the control (analyzed at 15.8 mg of Mn/kg of DM) and supplemental Mn (50 mg/kg of DM) treatments were randomly selected at the conclusion of the previous study to continue on their respective dietary treatments through gestation and early lactation. Serum cholesterol for the 267-d period was not affected by treatment. Whole-blood Mn concentration of heifers on d 267 was not affected by treatment. Whole-blood Mn concentration at birth was lower in calves born to control heifers than in those born to supplemented heifers...

Protein and nucleic acid content, and RNase levels were measured in placentas collected at birth in a randomized controlled trial of prenatal nutritional supplementation in New York City. These biochemical indices were explored to understand better the effects of nutritional supplementation. (With high-protein supplements, gross measures had shown no improvement in outcome at birth and adverse effects on fetal growth.

Leptin is an adipocytokine that is also synthesized by the placenta. Leptin and its receptor, which is also expressed by the placenta, are believed to play an auto- and paracrine role in trophoblast invasion and placental development. The leptin concentration in first trimester maternal serum and its relation to fetal growth disturbances were examined in this study. The study is a case-control study with 36 small-for-gestational-age (SGA) (<5th percentile) pregnancies and 108 appropriate-for-gestational-age (AGA) (> or =5th percentile) pregnancies. The groups were matched by maternal age, gestational age and body mass index (BMI). All were non-smokers. Leptin was measured in maternal serum in weeks 8-13 and was normalized for BMI with concentrations expressed as multiples of the median for the actual BMI. It was found that maternal serum leptin increased strongly (r = 0.7, P < 10(-4))with maternal BMI. There was no significant difference in maternal serum leptin concentrations between SGA and AGA pregnancies. In conclusion, SGA pregnancies are not associated with a lower maternal serum leptin concentration in first trimester. The maternal serum leptin concentration is largely determined by maternal BMI. Variation in the leptin concentration in maternal serum in first trimester does not seem to be associated with impaired fetal growth.

Summary   An adequate increase of uterine blood flow throughout gestation is essential for uterine, placental and fetal growth. Maternal cardiovascular adaptation has to provide the uterine perfusion that is necessary to meet the requirements of the developing and growing fetus by providing transport of nutrients and oxygen to the placenta and the fetus. Thus uterine blood flow is inextricably linked to fetal growth and survival. Reductions of uterine blood flow can occur under acute or chronic conditions or in a combination of both. Chronic reductions of uterine blood flow can be observed in pregnancy induced hyertension (PIH), diabetes mellitus in pregnancy and intrauterine growth restriction (IUGR). Chronic restrictions in uterine blood flow will elicit a placental and fetal response in the form of growth adaptation to the reduced supply of oxygen and nutrients to the conceptus. If compensatory growth restriction reaches its limits intrauterine fetal distress can ensue.