Horst Halle

Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1)

The MDR1 gene product P-glycoprotein in the human placenta is important for protecting the fetus from unintended, harmful drug exposure, but also for limiting the access of therapeutic drugs to the fetus after maternal drug intake. A polymorphism in exon 26 of the MDR1 gene (C3435T) has previously been shown to be associated with reduced P-glycoprotein expression in the small intestine, kidney and lymphocytes. In the present study, we examined systematically whether MDR1 polymorphisms also have an impact on P-glycoprotein expression in the human placenta. MDR1 mRNA and P-glycoprotein were analysed in 73 full-term human placentas of Caucasians, as well as respective MDR1 genotypes/haplotypes, for the C3435T and G2677T/A polymorphisms of mothers and infants. MDR1 mRNA levels were not different between these genotype groups. However, P-glycoprotein expression was significantly lower when both mother and infant were homozygous for the 3435T allele (TT/tt) compared to maternal and fetal homozygotes for the C-allele (0.40 +/- 0.18 a.u. for TT/tt versus 0.66 +/- 0.30 a.u. for CC/cc, P = 0.01). Moreover, placentas from mothers carrying both polymorphisms (3435T and 2677T; TT/TT) also had a significantly lower P-glycoprotein expression (0.31 +/- 0.12 a.u.) compared to placentas of wild-type individuals (CC/GG, 0.71 +/- 0.31 a.u., P = 0.02). Taken together, the MDR1 polymorphisms C3435T and G2677T are associated with altered P-glycoprotein expression in the human placenta, and may have clinical consequences due to genetically determined, variable drug exposure of the fetus.

Association of maternal G protein β3 subunit 825T allele with low birthweight

Weight at birth has been associated with an increased risk for cardiovascular disease and type 2 diabetes in adult life. We found an association between the maternal G protein beta3 subunit 825T allele and low birthweight in babies born to women without other risks for reduced fetal growth.

Nitroglycerin to facilitate fetal extraction during cesarean delivery.

Objective To determine the long-term outcomes of children exposed in utero to maternal parvovirus B19 infection. Methods All pregnant women with serologic evidence of recent parvovirus B19 infection and a comparison group with serologic evidence of past infection from January 1988 to December 1994 were sent questionnaires or contacted by phone about the health and development of their children. Information requested included: pregnancy complications, date of delivery, birth weight, sex, birth defects, need for special care, significant health problems, and developmental delays. All women had serology done at either the Centers for Disease Control and Prevention or the virology laboratory of the Connecticut Department of Health. The data were analyzed using descriptive statistics, χ2 analysis with Fisher exact test, or Student t test in appropriate cases. P < .05 was considered significant. Results Outcome information was obtained from 113 of 117 immunoglobulin-M positive women. The 113 respon-dents had 103 term singletons, two sets of twins (of which one neonate died of complications of prematurity), one hydropic stillborn, four spontaneous abortions, and one ectopic pregnancy. The mean gestational age at time of exposure was 15.6 weeks. The median age of the liveborn infants in study and comparison groups was 4 years. Eight of the 108 (7.3%) surviving children, one set of twins (exposed at 27 weeks), and six singletons (exposed at 7, 8, 9, 20, 27, and 35 and 35 weeks) had developmental delays in speech, language, information processing, and attention. Outcomes were obtained for 99 of 110 patients with past infection; they had 83 liveborn singletons, five sets of twins, two stillborns, and five spontaneous abortions. Seven of the 93 (7.5%) children had developmental delays, similar to the study group. Post-hoc power analysis revealed that 712 infected patients would be needed to find a twofold difference in the risk of abnormal neurologic development; our study had 30% power to find such a difference. Conclusion There is no apparent increase in the frequency of developmental delays in children with exposure in utero to parvovirus, but larger studies are needed.

Impact of maternal body mass index on neonatal outcome

IntroductionMaternal body mass index has an impact on maternal and fetal pregnancy outcome. An increased maternal BMI is known to be associated with admission of the newborn to a neonatal care unit. The reasons and impact of this admission on fetal outcome, however, are unknown so far.ObjectiveThe aim of our study was to investigate the impact of maternal BMI on maternal and fetal pregnancy outcome with special focus on the children admitted to a neonatal care unit.MethodsA cohort of 2049 non-diabetic mothers giving birth in the Charite university hospital was prospectively studied. The impact of maternal BMI on maternal and fetal outcome parameters was tested using multivariate regression analysis. Outcome of children admitted to a neonatal ward (n = 505) was analysed.ResultsIncreased maternal BMI was associated with an increased risk for hypertensive complications, peripheral edema, caesarean section, fetal macrosomia and admission of the newborn to a neonatal care unit, whereas decreased BMI was associated with preterm birth and lower birthweight. In the neonatal ward children from obese mothers are characterized by hypoglycaemia. They need less oxygen, and exhibit a shorter stay on the neonatal ward compared to children from normal weight mothers, whereas children from underweight mothers are characterized by lower umbilical blood pH and increased incidence of death corresponding to increased prevalence of preterm birth.ConclusionPregnancy outcome is worst in babies from mothers with low body mass index as compared to healthy weight mothers with respect to increased incidence of preterm birth, lower birth weight and increased neonate mortality on the neonatal ward. We demonstrate that the increased risk for neonatal admission in children from obese mothers does not necessarily indicate severe fetal impairment.

Low Birth Weight, a Risk Factor for Cardiovascular Diseases in Later Life, Is Already Associated With Elevated Fetal Glycosylated Hemoglobin at Birth

Background— It remains unclear whether the association between low birth weight and insulin resistance in adulthood has its origin in utero or whether it develops later in life depending on predisposition and exogenous factors. Methods and Results— Total glycosylated hemoglobin (TGH) was quantified at delivery in 1295 mother/child pairs serving as a surrogate of maternal and fetal glycemia. Multivariable regression analysis considering gestational age at delivery, the child’s sex, maternal body mass index, and smoking during pregnancy revealed that an increase in TGH by 1% in the child was significantly associated with a mean birth weight reduction of 135 g (P<0.0001), whereas the same increase in the mother was associated with a mean birth weight increase of 88 g (P<0.0001). The ratio of fetal/maternal TGH suggests that lighter newborns have a higher percentage of TGH than would be expected from maternal TGH. Conclusions— The study demonstrates for the first time in a large population that there is an inverse association between TGH of a newborn and its birth weight. This might be due to increased insulin resistance in newborns with lower birth weight. Our data suggest that the pathophysiological mechanisms linking prenatal growth and postnatal sensitivity to insulin are present as early as before birth.

Pregnancy on Intensified Hemodialysis: Fetal Surveillance and Perinatal Outcome

Objectives: To evaluate the effect of intensive fetal surveillance via Doppler ultrasound and fetal non-stress test on the perinatal outcome of pregnant women undergoing an intensified hemofiltration scheme. Methods: Five consecutive pregnancies of women undergoing intensified hemodialysis were analyzed due to the following parameters: maternal background, hemodialysis schedule during pregnancy, blood pressure, occurrence of fetal complications, occurrence of obstetric complications, gestational week at delivery, mode of delivery, and newborn outcome and follow-up. Results: All pregnancies resulted in a live birth, mean gestational age was 32 weeks. Intrauterine growth restriction occurred in 4 fetuses, pathological umbilical artery flow velocity waveforms in 2. The mean birth weight was 1,764 g (range 1,274–2,465 g). Cesarean section was performed in 3 patients because of fetal distress. None of the patients developed severe complications like pre-eclampsia. Conclusions: Although intensified dialysis enables the maintenance of stable uteroplacental and fetal perfusion, intensive fetal monitoring is mandatory to reduce perinatal morbidity and mortality in pregnant women on maintenance dialysis.

Fetal sex determines the impact of maternal PROGINS progesterone receptor polymorphism on maternal physiology during pregnancy.

Background Recent evidence from very rare human diseases suggests that variation in the fetal genome can modify maternal physiology during pregnancy. Here, we tested the hypothesis that fetal sex as a major genetic variant of the fetal genome may affect maternal physiology during pregnancy in genetically susceptible pregnant women. Methods We analyzed the impact of fetal sex on maternal physiology during pregnancy in relationship with the maternal PROGINS progesterone receptor gene polymorphism. Two thousand and eighty-nine (2089) Caucasian women without preexisting diabetes and preexisting hypertension with singleton pregnancies delivering consecutively at the Charité obstetrics department participated in this study. Results The maternal PROGINS progesterone receptor polymorphism on its own had no effect on blood pressure, new onset of proteinuria, and total glycated hemoglobin at delivery. However, by considering the offsprings sex, the AA variant of the PROGINS progesterone receptor polymorphism was associated with profound cardiovascular/metabolic effects; mothers carrying both A alleles (AA genotype) delivering a boy had significantly lower systolic blood pressure during the first trimester of pregnancy versus AA mothers delivering girls (107.9±10.2 vs. 116.6±15.1 mmHg, P = 0.044). Diastolic blood pressure was similarly lower during the first trimester of pregnant AA women delivering boys in comparison with AA women delivering girls (63.4±5.7 vs. 68.2±10.9 mmHg, P = 0.032). Total glycated hemoglobin at delivery was significantly (P = 0.002) higher in AA mothers delivering boys (6.6±0.7%) versus AA mothers delivering girls (5.9±0.6%). Conclusion Our study indicates that fetal sex may substantially affect maternal blood pressure as well as glycemic control during pregnancy in genetically susceptible mothers.

Endothelin system in normal and hypertensive pregnancy.

Pre-eclampsia complicates approximately 5-7% of pregnancies and it may be deleterious to both maternal and fetal health. In a prospective study, we investigated plasma endothelin (ET)-1 concentration within the 24th and 36th gestational week in non-smoking pregnant women. Thirty women fulfilled the criteria for the diagnosis of pre-eclampsia according to the American College of Obstetricians and Gynaecologists: de novo arterial hypertension after the 20th gestational week in at least two separate measurements and proteinuria of more than 300 mg/l in a random specimen. For comparison, we analysed blood samples from 125 non-pre-eclamptic pregnant women. ET-1 concentrations were higher in pre-eclamptic pregnancies at both time points (mean+/-S.D.: 1.07+/-2.00 versus 0.54+/-0.56 pg/ml, P=0.045 at 24th week; 0.75+/-1.20 versus 0.44+/-0.45 pg/ml, P=0.023 at 36th week). Receiver operating characteristic (ROC) curves revealed a significant interaction between ET-1 plasma concentrations at the 36th week and the diagnosis of pre-eclampsia [area under the curve (AUC)+/-S.E.M.: 0.657+/-0.049, P=0.008] and a cut-off value at 0.30 pg/ml. Multivariate analysis showed a 4.6-fold higher chance (95% confidence interval: 1.7-12.1, P=0.002) for the diagnosis of pre-eclampsia in pregnant women with ET-1 plasma concentration higher than 0.30 pg/ml at the 36th week. Interaction between ET-1 plasma concentration at the 24th week and diagnosis of pre-eclampsia was not significant in ROC curve analysis (AUC+/-S.E.M.: 0.594+/-0.071, P=0.278). Interestingly, we found a strong positive correlation between ET-1 concentration in the 24th and 36th week in linear regression analysis in pre-eclamptic (r=0.99, P<0.001) and non-pre-eclamptic pregnancies (r=0.61, P<0.001) with a slightly, non-significant decrease from the 24th to 36th week (for group means see above), indicating individual plasma ET-1 levels even in non-pre-eclamptic pregnancies. Linear regression analysis showed no correlation between blood pressure or urine protein excretion and ET-1 plasma concentration in non-pre-eclamptic pregnant women. In conclusion, our prospective study indicates that the ET system is, in contrast to most other forms of human hypertension, activated in pre-eclamptic pregnant women.

Preconceptional factors associated with very low birthweight delivery in East and West Berlin: a case control study

BackgroundVery low birthweight, i.e. a birthweight < 1500 g, is among the strongest determinants of infant mortality and childhood morbidity. To develop primary prevention approaches to VLBW birth and its sequelae, information is needed on the causes of preterm birth, their personal and social antecedents, and on conditions associated with very low birthweight. Despite the growing body of evidence linking sociodemographic variables with preterm delivery, little is known as to how this may be extrapolated to the risk of very low birthweight.MethodsIn 1992, two years after the German unification, we started to recruit two cohorts of very low birthweight infants and controls in East and West Berlin for a long-term neurodevelopmental study. The present analysis was undertaken to compare potential preconceptional risk factors for very low birthweight delivery in a case-control design including 166 mothers (82 East vs. 84 West Berlin) with very low birthweight delivery and 341 control mothers (166 East vs. 175 West).ResultsMultivariate logistic regression analysis was used to assess the effects of various dichotomous parental covariates and their interaction with living in East or West Berlin. After backward variable selection, short maternal school education, maternal unemployment, single-room apartment, smoking, previous preterm delivery, and fetal loss emerged as significant main effect variables, together with living in West Berlin as positive effect modificator for single-mother status.ConclusionVery low birthweight has been differentially associated with obstetrical history and indicators of maternal socioeconomic status in East and West Berlin. The ranking of these risk factors is under the influence of the political framework.

Impact of maternal angiotensinogen M235T polymorphism and angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure, protein excretion and fetal outcome in pregnancy

Objective To test the hypothesis that genetically determined alterations of the renin–angiotensin system are associated with hypertensive disorders in pregnancy. Methods A genetic association study was conducted at the obstetrics department of the Charité university hospital, Berlin, Germany. A total of 1068 Caucasian women were consecutively included after delivery and genotyped for the angiotensinogen M235T polymorphism and the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism. Results Women homozygous for the angiotensinogen T allele have significantly elevated mean systolic and diastolic blood pressures in the third trimester (118.4 ± 1.1/71.5 ± 0.7 versus 116.9 ± 0.3/70.4 ± 0.2 mmHg, n = 128 versus 940; P < 0.05). This finding is especially pronounced in the subgroup of primigravid women. The ACE polymorphism is not associated with blood pressure during pregnancy. None of the polymorphisms is associated with urinary protein excretion or oedema during pregnancy. Maternal polymorphisms do not influence fetal growth and birth weight. There is, however, an interesting trend towards an increased incidence of circulatory system malformations in newborns carrying alleles that are known to be associated with decreased intrinsic renin–angiotensin system activity. Conclusion We demonstrate for the first time in a large Caucasian population that a common maternal polymorphism of the angiotensinogen gene is related to a blood pressure increase during pregnancy. The angiotensinogen M235T polymorphism might contribute to the multifactorial pathogenesis of gestational hypertension and pre-eclampsia.