M. J. Whittle

Early placental development occurs in an environment of relative hypoxia. Hypoxia promotes angiogenesis and up-regulates vascular endothelial growth factor (VEGF) expression while it down-regulates placenta growth factor (PIGF) that possess 53% homology with VEGF. Morphological studies show poor placental vascular development and an increase in the mitotic index of cytotrophoblasts in intrauterine growth restriction (IUGR). We hypothesized that the reported relatively high oxygen level in the intervillous space in contact with IUGR placental villi will limit angiogenesis by changes in VEGF and PIGF expression and function. Western immunoblot analysis demonstrates a diametric expression of PIGF and VEGF proteins throughout pregnancy with PIGF levels increasing and VEGF levels decreasing, consistent with placental oxygenation. In IUGR placentae, the ratio of PIGF/GAPDH mRNA was increased by 2.3-fold (p < 0.03) and PIGF protein levels were also increased, (p < 0.05) as compared with gestationally-matched normal placentae. PIGF mRNA and protein were localized to the trophoblast bilayer and villous mesenchyme of the human placenta throughout gestation. In vitro studies demonstrated that increasing oxygen tension (hyperoxia) up-regulated PIGF protein in term placental villous explants, whereas hypoxic culture of a term trophoblast choriocarcinoma cell line (BeWo) down-regulated PIGF mRNA and protein and VEGFR-1 (Flt-1) autophosphorylation. The addition of PIGF-1 to a spontaneously transformed first trimester cytotrophoblast cell line stimulated DNA synthesis while PIGF-2 had little effect. VEGF and PIGF exert their biological actions by means of a common receptor VEGFR-1. In the first trimester trophoblast cells, PIGF-1 increased the association of phosphorylated extracellular signal-related kinase (ERK) with VEGFR-1 immunoprecipitates while both PIGF-1 and PIGF-2 also potentiated endogenous VEGF mediated association of phosphorylated extracellular related kinase (ERK) with VEGFR-2 (KDR). More importantly, the addition of PIGF-1 had little effect while PIGF-2 inhibited cell growth in cultured endothelial cells derived from human umbilical vein. Nitric oxide (NO) is reported to promote angiogenesis and PIGF-2 inhibited the basal release of NO from the first trimester trophoblast. The tissue expression and functional studies support the hypothesis of "placental hyperoxia" in early-onset IUGR because hypoxia down-regulates trophoblast PIGF levels, PIGF expression is increased in IUGR, and PIGF-2 inhibits endothelial cell growth. Taken together, these changes provide a cellular explanation for the observed poor angiogenesis in the pathogenesis of IUGR and show that the two PIGF isoforms may modulate trophoblast and endothelial cell function differently, possibly through potentiation of VEGF mediated activation of VEGF-2.

Abstract Objectives : Analysis of incidence and characteristics of congenital abdominal wall defects, with special reference to the differences between the incidence of gastroschisis and exomphalos (omphalocele). Design : Retrospective analysis using data from the Office of Population Censuses and Surveys (recoded to differentiate exomphalos and gastroschisis) and the National Congenital Malformation Notification Scheme. Setting : England and Wales, 1987 to 1993. Results : 1043 congenital anterior abdominal wall defects were notified within the seven year study period. Of these, 539 were classified as gastroschisis, 448 as exomphalos, 19 as “prune belly syndrome,” and 37 as “unclassified.” Gastroschisis doubled in incidence from 0.65 in 1987 to 1.35 per 10 000 total births in 1991, with little further change; the incidence of exomphalos decreased from 1.13 to 0.77 per 10 000 births. The overall incidence of notified congenital abdominal wall defects was 2.15 per 10 000 total births. Gastroschisis was associated with a lower overall maternal age than exomphalos and with a significantly lower proportion of additional reported congenital malformations (5.0%) than in the cohort with exomphalos (27.4%) (odds ratio 0.14, 95% confidence interval 0.09 to 0.22; P&lt;0.001). The sex ratio of the two cohorts was the same. The incidence of gastroschisis and exomphalos was higher in the northern regions of England than in the south east of the country. Conclusions : The national congenital malformation notification system showed an increasing trend in the incidence of fetuses born with gastroschisis and a progressive decreasing incidence of exomphalos in England and Wales between 1987 and 1993. Although the reasons for this are likely to be multifactorial, a true differential change seems likely. The observed increase in incidence of gastroschisis relative to exomphalos and the differentiation in maternal age have implications for resource management within the NHS and warrant further epidemiological monitoring. Regional differences may be due to a dietary or environmental factor, which requires further study. Key messages Gastroschisis was also associated with a significantly lower proportion of additional reported congenital malformations Younger mothers are significantly more likely than older mothers to have a child with gastroschisis The incidence of congenital abdominal wall defects seemed to be higher in the regions in the north than in the south east of England

Objectives : To identify the etiology and pregnancy outcome of hydrops fetalis in a cohort of pregnancies referred to a tertiary maternal fetal medicine center in the UK. These data allow the review of a large series of pregnancies affected by hydrops fetalis and emphasize the importance of investigation and then treatment of individual cases. This provides parents with improved information and especially specific prognostic information. Methods : A retrospective review of 63 consecutive cases of hydrops fetalis managed between September 1996 and March 1999. Results : Of the pregnancies, 12.7% ( n = 8) were associated with an 'immune' etiology. Of these, 62.5% ( n = 5) had fetal anemia due to anti-D, 25% ( n = 2) anti-Kell and 12.5% ( n = 1) anti-c antibodies. The remaining 55 cases (87.3%) had a non-immune cause. Eight (14.5%) were due to human parvovirus B19 infection. Fourteen cases (25.5%) were associated with aneuploidy and, in four (7.3%), a primary hydrothorax was the cause of the non-immune hydrops fetalis. A cardiac cause was found in five (9.1%) cases. Three of these had supraventricular tachycardia and one had congenital complete heart block. Cystic hygroma was associated with hydrops fetalis in six cases. Twin-twin transfusion syndrome was the cause for hydrops in two cases. Massive transplacental hemorrhage was identified in one case. Fetal akinesia and muscular dystrophy caused hydrops in one case each. In 14.5% (8/55) of cases no obvious cause was identified and these were classified as 'idiopathic'. Three other cases could not be classified because parents declined investigations (unclassified). In the pregnancies with non-immune hydrops fetalis, the outcome was favorable in 27.3% (15/55) of cases. Conclusion : The prognosis of hydrops fetalis differs markedly between different etiological groups. Etiologies range from treatable causes with a good outcome and probably no long-term side-effects (as in case of parvovirus B19), to others which are incompatible with life or are associated with considerable perinatal morbidity and mortality.