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ABSTRACTEmerging trends show declines in maternal and perinatal mortality and morbidity in urban populations might be slower than in rural areas in a variety of contexts. This is happening at a critical juncture in time when urban populations are rapidly increasing and might be partly driven by specifics of vulnerability of the urban poor in Low-income countries and High-income countries alike. Poor maternal and perinatal health outcomes are largely preventable but focusing solely on healthcare interventions misses critical opportunities to reduce ill-health. Social and environmental determinants such as poverty and the impact of climate change must be integrated into policy decisions, especially to benefit poor urban dwellers. Integrating data on the social determinants of health into policy decisions can help multisectoral stakeholders embrace a more Health-in-all-policy approach creating opportunities for better outcomes for these urban poor women and their offspring. We provide examples of two cities – Rotterdam and Kampala – to show that successful multi-sectoral approaches that can address urban maternal and perinatal inequalities should focus on interventions in which healthcare and non-healthcare determinants are integrated.

Existing evidence on the effects of race and ethnicity on pregnancy outcomes is restricted to individual studies done within specific countries and health systems. We aimed to assess the impact of race and ethnicity on perinatal outcomes in high-income and upper-middle-income countries, and to ascertain whether the magnitude of disparities, if any, varied across geographical regions.

Background: Caffeine is a widely used and accepted pharmacologically active substance. The effect of caffeine intake during pregnancy on fetal growth and development is still unclear. Objective: We examined the associations of maternal caffeine intake, on the basis of coffee and tea consumption, with fetal growth characteristics measured in each trimester of pregnancy and the risks of adverse birth outcomes. Design: Associations were studied in 7346 pregnant women participating in a population-based prospective cohort study from early pregnancy onward in the Netherlands (2001-2005). Caffeine intake in the first, second, and third trimesters was on the basis of coffee and tea consumption and was assessed by questionnaires. Fetal growth characteristics were repeatedly measured by ultrasound. Information about birth outcomes was obtained from hospital records. Results: We observed no consistent associations of caffeine intake with fetal head circumference or estimated fetal weight in any trimester. Higher caffeine intake was associated with smaller first-trimester crown-rump length, second- and third-trimester femur length, and birth length (P for trend Conclusions: Our results suggest that caffeine intake of [greater than or equal to]6 units/d during pregnancy is associated with impaired fetal length growth. Caffeine exposure might preferentially adversely affect fetal skeletal growth. Further studies are needed to assess these associations in non-European populations and to assess the postnatal consequences. doi: 10.3945/ajcn.2009.28792.

OBJECTIVE--We examined whether the [PPARγ.sup.2] Ala12 allele influences growth in early life and whether this association is modified by breast-feeding. RESEARCH DESIGN AND METHODS--This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. [PPARγ.sup.2] was genotyped in DNA obtained from cord blood samples in 3,432 children. Information about breast-feeding was available from questionnaires. Weight, head circumference, and femur length were repeatedly measured in second and third trimesters of pregnancy, at birth, and at the ages of 1.5, 6, 11, 14, and 18 months. RESULTS--Genotype frequency distribution was 77.6% (Pro12Pro), 20.7% (Pro12Ala), and 1.7% (Ala12Ala). Growth rates in weight from second trimester of pregnancy to 18 months were higher for Pro12Ala and Ala12Ala than for Pro12Pro carriers (differences 1.11 g/week [95% CI 0.47-1.74] and 2.65 g/week [0.45-4.87], respectively). We found an interaction between genotype and breast-feeding duration (P value for interaction CONCLUSIONS--The [PPARγ.sup.2] Ala12 allele is associated with an increased growth rate in early life. This effect may be influenced by breast-feeding duration. Further studies should replicate these findings, identify the underlying mechanisms, and assess whether these effects persist into later life., Previous studies have shown that common polymorphisms of peroxisome proliferator-activated receptor [γ.sup.2] ([PPARγ.sup.2]) are associated with adipocyte differentiation, lipid metabolism, and insulin sensitivity (1). Recent genome-wide association (GWA) studies found [...]

Background: Knowledge on human fetal amino acid (AA) metabolism, largely lacking thus far, is pivotal in improving nutritional strategies for prematurely born infants. Phenylalanine kinetics is of special interest as is debate as to whether neonates will adequately hydroxylate phenylalanine to the semiessential AA tyrosine. Objective: Our aim was to quantify human fetal phenylalanine and tyrosine metabolism. Design: Eight fasted, healthy, pregnant women undergoing elective cesarean delivery at term received primed continuous stable-isotope infusions of [1-[sup.13]C]phenylalanine and [ring-[D.sub.4]]tyrosine starting before surgery. Umbilical blood flow was measured by ultrasound. Maternal and umbilical cord blood was collected and analyzed by gas chromatography--mass spectrometry for phenylalanine and tyrosine enrichments and concentrations. Data are expressed as medians (25th-75th percentile). Results: Women were in a catabolic state for which net fetal AA uptake was responsible for [greater than or equal to] 25%. Maternal and fetal hydroxylation rates were 2.6 (2.2-2.9) and 7.5 (6.2-15.5) [micro]mol phenylalanine/(kg x h), respectively. Fetal protein synthesis rates were higher than breakdown rates: 92 (84-116) and 73 (68-87) [micro]mol phenylalanine/(kg x h), respectively, which indicated an anabolic state. The median metabolized fraction of available phenylalanine and tyrosine in the fetus was < 20% for both AAs. Conclusions: At term gestation, fetuses still show considerable net AA uptake and AA accretion [converted to tissue [approximately equal to] 12 g/(kg x d)]. The low metabolic uptake (AA usage) implies a very large nutritional reserve capacity of nutrients delivered through the umbilical cord. Fetuses at term are quite capable of hydroxylating phenylalanine to tyrosine.

Background: Despite nutritional intervention, albumin concentrations are often low in critically ill premature neonates. Objective: Our aim was to quantify albumin synthesis rates during early life under physiologic circumstances. Human fetuses thereby reflect the developmentally related optimal condition. Design: Pregnant women undergoing elective cesarean delivery received 3 different labeled amino acid infusions starting at different times before surgery. With the use of mass spectrometry techniques, this novel model enabled us to quantify fetal albumin synthesis from a single blood sample taken from the umbilical cord after cesarean delivery. The fractional synthesis rate reflects the fraction of the albumin pool that is daily renewed. The absolute synthesis rate is the absolute amount of albumin that is daily synthesized. Results are expressed as medians (25th-75th percentile). Results: We studied 8 fetuses at 29.9 (28.4-35.4) weeks of gestation and 8 fetuses around term. Fractional synthesis rates in premature fetuses [17.5 (12.1-24.4) %/d] were higher (P = 0.02) than in mature fetuses [10.4 (9.1-13.7) %/d]. Absolute synthesis rates were also higher (P = 0.02) in premature than in mature fetuses: 280 (227-365) versus 205 (184-238) mg x [kg.sup.-1] x [d.sup.-1]. Conclusions: On a weight basis, albumin synthesis rates in premature fetuses were higher than in fetuses at term and were higher than the rates previously found in neonates after preterm birth. Considering that the premature fetal liver can synthesize albumin at a high rate, the observed hypoalbuminemia in premature infants therefore seems to suggest that current (nutritional) therapies fail to meet requirements necessary to sustain optimum albumin synthesis rates.

A study is undertaken to determine whether the N-acetyltransferase (NAT) phenotype contributes to the susceptibility for the development of preeclampsia. The fast NAT acetylator status, which may result in altered NAT detoxification capacity, is associated with preeclampsia.

The effect of N-acetylcysteine (NAC) on the nitric oxide (NO)-pathway in the human fetoplacental circulation in preeclampsia and control pregnancies is examined. The NO-mediated effects are increased by NAC in the fetoplacental circulation in preeclamptic placentas and in healthy control placentas.

Background: In the Netherlands 73% of cases of neonatal herpes are caused by herpes simplex virus type 1 (HSV-1), whereas in the United States a majority are caused by HSV type 2 (HSV-2). Goal: To understand this difference we undertook a seroepidemiological study on the prevalence of HSV-1 and HSV-2 among pregnant women. Study Design: Type-specific antibodies to HSV-1 and HSV-2 were detected by enzyme-linked immunosorbent assay (ELISA) in serum samples from 1507 pregnant women in Amsterdam, Rotterdam, and Nijmegen. Results: The prevalence of HSV-1 was 61% in Nijmegen, 73% in Amsterdam, and 75% in Rotterdam. The prevalence of HSV-2 was 11% in Nijmegen, 35% in Amsterdam, and 27% in Rotterdam. Conclusion: The seroprevalence of HSV-1 and HSV-2 antibodies among pregnant women in the Netherlands shows significant geographical differences, which were attributed to ethnical variation. However, the epidemiologic differences did not correlate with the incidence of neonatal herpes in the Netherlands.

Measuring blood levels of glutathione S-transferase Alpha 1-1 (GSTA1-1) may allow physicians to diagnose many serious complications of pregnancy sooner. This enzyme is released into the bloodstream during liver damage. Two pregnancy complications that involve liver damage are preeclampsia and the HELLP syndrome. Researchers measured blood levels of GSTA1-1 and another liver enzyme called alanine aminotransferase in 274 pregnant women. GSTA1-1 levels were substantially higher than alanine aminotransferase levels in the women with preeclampsia or HELLP syndrome.

Purpose: To evaluate the effects of preconception care (PCC) consultations by change in lifestyle behaviors.Setting and Intervention: Women in deprived neighborhoods of 14 Dutch municipalities were encouraged to visit a general practitioner or midwife for PCC.Sample: The study included women aged 18 to 41 years who had a PCC consultation.Design: In this community-based prospective cohort study, we assessed initiation of folic acid supplementation, cessation of smoking, alcohol consumption, and illicit drug use.Measures: Self-reported and biomarker data on behavioral changes were obtained at baseline and 3 months later.Analysis: The changes in prevalence were assessed with the McNemar test.Results: Of the 259 included participants, paired analyses were available in 177 participants for self-reported outcomes and in 82 for biomarker outcomes. Baseline self-reported prevalence of no folic acid use was 36%, smoking 12%, weekly alcohol use 22%, and binge drinking 17%. Significant changes in prevalence toward better lifestyle during follow-up were seen for folic acid use (both self-reported, P< .001; and biomarker-confirmed, P= .008) and for self-reported binge drinking (P= .007).Conclusion: Our study suggests that PCC contributes to initiation of folic acid supplementation and cessation of binge drinking in women who intend to become pregnant. Although based on a small sample, the study adds to the limited body of evidence regarding the benefits of PCC in improving periconception health.

Dietary sodium restriction is used in the Netherlands in the prophylaxis of preeclampsia. To study the effects of long-term sodium restriction on the intake of other nutrients and the outcome of pregnancy, 68 healthy nulliparous pregnant women were randomly assigned to either a low-sodium diet (20 mmol/24 h) or an unrestricted diet. The diet was consumed between week 14 of gestation and delivery. The dietary intakes of energy, fat, protein, carbohydrate, sodium, potassium, and calcium were estimated with the dietary-history technique. A low-sodium diet reduced the intake of protein (by[double tilde]15 g/24 h), fat (by 20 g/24 h), and calcium (by 350 mg/24 h) and tended to decrease the energy intake (by[double tilde]0.7 MJ/24 h). The intakes of carbohydrate and potassium did not differ between the groups. The maternal weight gain was less in the low-sodium group (6.0[+ or -]3.7 compared with 11.7[+ or -]4.7 kg). Mean birth weight was not significantly different (3.2[ +or -]0.5 compared with 3.4[+ or -]0.5 kg).

Folate, vitamin B12, and homocysteine concentrations during pregnancy are important factors for early development and may persistently influence kidney function in the offspring. We examined the associations of folate, vitamin B12, and homocysteine concentrations during pregnancy with kidney outcomes in school-aged children.

Gelatin sponges can be used to plug up holes in the uterus and fetal membranes after fetal surgery. The sponge is placed inside the surgical instrument and is kept in the hole by a plunger as the instrument is withdrawn. Surgeons sometimes operate on the fetus to correct certain abnormalities.

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Low birth weight is associated with cardiovascular disease in adulthood. Hemodynamic adaptations related to fetal growth restriction may underlie these associations, through persistent influences on cardiovascular development. We examined the associations of third trimester fetal hemodynamics with cardiovascular outcomes in childhood.

To describe inequalities in perinatal and maternal mortality, and morbidity from an international high-income country perspective. Measures of inequalities are socioeconomic status, ethnic background, and living area.

Aim of this study was to investigate the associations of C-reactive protein levels, as marker of low-grade inflammation, with blood pressure development during pregnancy and the risks of gestational hypertensive complications. We also explored the role of maternal BMI in these associations.

Maternal thyroid function during pregnancy is implicated in the neurodevelopment of the offspring, yet little is known about the effect of maternal thyroid parameters on the behavior of children. We investigated the association of maternal thyroid function during the first half of pregnancy with parent-reported problem behavior of the offspring up to age of 3 y. In the Generation R study, a population-based cohort of 3736 children and their mothers, data on maternal thyroid function and child's behavior were examined. The degree of internalizing and externalizing problems in the children were assessed with the Child Behavior Checklist at ages 1½ and 3 y. Higher levels of maternal TSH during pregnancy predicted a higher externalizing scores in children at 1½ and 3 y (B0.22 per SD of TSH; 95% CI: 0.04, 0.40; B0.10 per SD for internalizing scores; 95% CI: −0.01, 0.21). Maternal free thyroxine (T4) and total T4 were not associated with internalizing or externalizing scores of children. The linear relationship with more externalizing scores was across the range of TSH; this implies that subtle impairments of maternal thyroid function may affect the child. The results suggest that thyroid function is crucial for fetal brain development, which determines problem behavior later in life.

Endocardial cushion defects (ECDs) of the cardiac outflow tract are among the most common congenital heart disease phenotypes. VEGF is essential for endocardial cushion formation and derangements in VEGF synthesis lead to ECD. Three functional single nucleotide polymorphisms (SNPs) in the VEGFgene −2578 C>A, −1154 G>A, and −634 G>C play a role in cardiogenesis. In a Dutch case-control family study of triads, 190 case and 317 control children with both parents, we investigated linkage and association between these VEGFSNPs and ECD. Allele frequencies for the three VEGFSNPs were comparable between ECD children and controls. However, VEGFalleles −2578 C and −1154 G were transmitted more frequently to children with ECD (p0.003 and p0.002), in particular perimembranous ventricular septal defects (p0.012 and p0.006). The −2578A/−1154A/−634G haplotype was associated with a reduced risk of ECD (OR 0.7; 95% CI, 0.6–1.0) and was significantly less transmitted to children with ECD (p0.002). In a Dutch population, we show that the VEGF2578 C, −1154 G alleles, and the AAG haplotype are associated with ECD. Possible VEGFgene-environment interactions exposures are discussed.

Gene–environment interactions in the periconceptional period play an increasing role in the pathogenesis of birth defects, including cleft lip andor cleft palate CLP. The Pglycoprotein, encoded by the ABCB1gene, is suggested to protect the developing embryo from medication and other xenobiotic exposures. Furthermore, maternal medication use during early pregnancy is a significant risk factor for CLP offspring. Therefore, the aim of this study is to investigate the association between the maternal and childs functional ABCB13435C > T polymorphism, periconceptional medication exposure, and the risk of a child with CLP. A case–control study was performed among 175 mothers and 98 of their children with CLP and 83 control mothers and their 65 children. Information on medication and folic acid use was collected. Mothers carrying the 3435TT genotype and using medication showed a 6.2fold 95 CI  1.6–24.2 increased risk of having a child with CLP compared to mothers carrying the 3435CC genotype and not using medication. Periconceptional folic acid use reduced this risk by approximately 30 OR  3.9, 95 CI  0.9–18.0. Mothers carrying the 3435TT genotype, using medication and not taking folic acid showed the highest risk estimate OR  19.2, 95 CI  1.0–369.2. These data suggest that mothers who carry the ABCB13435C > T polymorphism are at significantly increased risk for having offspring with CLP, especially mothers using medication in the periconceptional period. © 2009 WileyLiss, Inc.

BACKGROUND:The methylenetetrahydrofolate reductase MTHFR C677T and A1298C polymorphisms are associated with complex congenital malformations. Whether these polymorphisms are associated with CHDs is not clear. We studied both MTHFR polymorphisms, folate and vitamin B2 by maternal food intake and supplements, and CHD risk. METHODS:A casecontrol family study was conducted in a European population in the Netherlands including 230 case and 251 control children with both parents. Approximately 17 months after the index pregnancy, mothers filled out standardized questionnaires on periconception use of folic acid supplements and a validated food frequency questionnaire on current dietary folate and vitamin B2 intake. All subjects were genotyped for the MTHFR C677T and A1298C polymorphisms. Data were analyzed by logistic regression analysis and ORs and 95 CIs were calculated. For the interaction analysis the dominant model was used. RESULTS:The risk estimates for the MTHFR 677 CT genotypes were 1.4 0.9–2.0 in mothers, 1.1 0.8–1.6 in fathers, and 1.2 0.8–1.7 in children, and for the MTHFR 677 TT genotypes 0.9 0.6–1.2, 1.4 1.0–1.9, and 1.0 0.7–1.3, respectively. The MTHFR 1298 CC genotype in fathers and the MTHFR 1298 AC genotype in children significantly reduced CHD risk, 0.6 0.5–0.9 and 0.6 0.4–0.9, respectively. Of interest is the significant interaction p .008 towards a nearly twofold increased risk in mothers carrying the MTHFR 1298C allele and using a periconception folic acid supplement. CONCLUSIONS:The MTHFR C677T and A1298C polymorphisms are not strong risk factors for CHDs. Birth Defects Research Part A, 2008. © 2008 WileyLiss, Inc.

Cytomegalovirus (CMV) is one of the most common causes of congenital infection without an effective treatment or an effective vaccine available to date. The emphasis has to be on preventive strategies, which rely on the epidemiological situation. The incidence of congenital CMV infections, however, is not known for The Netherlands. Therefore, a prospective virological study was carried out in a population of 7,524 pregnant women and 7,793 newborns. CMV‐specific IgG antibodies were determined in cord blood by ELISA. When CMV antibodies were present, a CMV specific PCR was performed on the throat swab. A positive PCR was confirmed by urine culture. In addition, the seroepidemiology for CMV was investigated in the metropolitan region (Amsterdam and Rotterdam) which has a different ethnic composition. Congenital CMV infection was found in 7 infants (0.9 per 1,000). None had symptoms at birth or during 24 month follow‐up. Carriage or CMV was 41%, with a variation between 35% and 100% depending on ethnicity. The ethnic composition in the south‐eastern region was different from that in large cities, but similar to that in the rest of the country. The incidence of congenital CMV infections in The Netherlands is the lowest described to date, which does not justify special preventive policies. J. Med. Virol. 76:71–75, 2005. © 2005 Wiley‐Liss, Inc.

AbstractPreconception care, a long-established concept for primary prevention of maternal and perinatal morbidity and mortality through detection and reduction of modifiable risks, has been widely propagated for the last decades. This article provides an overview of the various goals and practices described in the literature in different parts of the world, including issues and controversies pertaining to the provision and implementation of preconception care in different health care settings.Copyright © 2002 S. Karger AG, Basel

The function of the glutathione-related detoxification system plays an important role to ensure an uncomplicated pregnancy outcome. This study was performed to investigate whether the components of the glutathione-related detoxification system are equally distributed among the different cotelydons in the human placenta. We measured glutathione, cysteine, glutathione S-transferase (GST) isoenzyme levels (GSTA1+A2, GSTP1, GSTM1 and GSTT1), enzyme activities of glutathione S-transferase and glutathione peroxidases, protein carbonyl levels, and antioxidant capacities at twelve different standardized positions in six placentae from healthy women after uncomplicated pregnancy and vaginal delivery. Data were statistically evaluated with a Friedman two-way ANOVA with Bonferroni correction. ‘Foetal’-side values were not significantly different from those at the ‘maternal’-side. Except for GSTA1+A2, no significant differences were found between different sampling sites indicating that the distribution of all parameters measured was homogenous throughout the placenta. Since levels of GSTA1+A2 were minor compared to those of GSTP1 and GSTT1, the clinical relevance of this heterogeneity may be limited. These results implicate that the location of sampling is not important as long as biopsies are taken from physiological cotelydons.

AbstractObjective:Assessment of anxiety levels in women and men before and after preconception counseling and during the first trimester of pregnancy. Methods:Couples were recruited from the fertility clinic of the University Medical Center Nijmegen, the Netherlands. Anxiety was assessed using the 40-item Spielberger State-Trait Anxiety Inventory (STAI). Results:53 women and 51 men (74%) completed the STAI both before and after counseling. Anxiety levels did not change significantly after counseling or during the first trimester of pregnancy. 83.4% would recommend preconception counseling to others. Conclusion:Preconception counseling is valued by the majority of women and men and does not lead to adverse psychological effects.Copyright © 2002 S. Karger AG, Basel

Cytomegalovirus (CMV) is one of the most common viral causes of congenital infection. A future decision to lower its incidence by vaccination will depend on epidemiological conditions within a country and on the safety of the vaccine to be used, because a life vaccine may cause latency and subsequent reactivation that still may harm the fetus. The aim was to review the epidemiological studies published so far, with respect to factors that affect the incidence of congenital CMV infection, and factors that may influence its outcome, such as preexisting maternal immunity. The study included the data of 19 studies that were retrieved from a MEDLINE search during the period 1977 to 1997. The incidence of congenital CMV infection varied between 0.15 and 2.0 and seemed to correlate with the level of preexisting immunity in the population. Although preexisting maternal immunity was reported to strongly reduce transmission, the severity of congenital CMV infection (symptoms at birth and or sequelae later in life) was not significantly greater after virus transmission due to a primary infection of the mother as compared with recurrence or reinfection. The data indicate that preexisting immunity of the mother does not significantly mitigate the outcome of congenital infection. Moreover, life vaccines may bear a serious risk when transmittable to the fetus.

BACKGROUND: The interaction between decidual natural killer (NK) cells and alloantigens expressed on fetal trophoblast cells are thought to be essential for successful implantation and placentation. Consequently, a disturbed interaction during the first trimester of pregnancy might well lead to a subsequent pregnancy failure. METHODS: We investigated the expression of HLA-G and NK cell markers in tissue sections from recurrent miscarriage (n = 9) and ectopic tubal pregnancies (n = 5), and two hysterectomy specimens of healthy pregnancy as well as decidual biopsies (n = 9) were used as controls. RESULTS: We show in normal pregnancy not only a decrease, but also a morphological change in CD56+ NK cells upon interaction with HLA-G-expressing trophoblasts. The cells appear to be transitioning from a blast-like (activation) state into a state of apoptosis. The number of CD16+ NK cells was low. In contrast, in recurrent miscarriage tissue a sustained NK cell marker expression of both CD56 and CD16 was paralleled by a decreased expression of HLA-G. No morphological changes from the blast-like stage were apparent. Finally, in ectopic pregnancies HLA-G expression in the absence of decidual NK cells was associated with a disturbed trophoblast differentiation. CONCLUSIONS: In pathological pregnancies we show an in-situ altered phenotype of trophoblast and NK cells.

Objective: To measure levels of oxidized and free thiols in whole blood of normotensive pregnant and preeclamptic women and evaluate the role of oxidative stress.

To study the influence of chronic dietary sodium restriction on uteroplacental circulation. In a randomized trial, Doppler flow velocity waveforms of the uterine and umbilical artery were studied at monthly intervals during pregnancy in 59 women on a low-sodium diet and in 68 controls. Pulsatility index (PI), resistance index (RI), and A/B ratio of the uterine artery were significantly lower during sodium restriction, whereas PI, RI, and A/B ratio of the umbilical artery were significantly higher. The lower resistance indices of the uterine artery during sodium restriction might reflect an increase in pulse pressure/impedance ratio as a result of activation of the renin-angiotensin system. The increase in umbilical artery resistance indices supports the hypothesis that fetal circulation might be altered by chronic dietary sodium restriction. J. Matern.-Fetal Med. 9:197–200, 2000. © 2000 Wiley-Liss, Inc.

For diagnostic purposes we assessed peripheral natural killer (NK) cell cytotoxicity and NK and T cell numbers to assess their putative predictive value in recurrent spontaneous abortion (RSA). A total of 43 women with subsequent pregnancy, 37 healthy controls and 39 women successfully partaking in an in-vitro fertilization (IVF) procedure, were included in the study. We show that before pregnancy, levels of NK cytotoxicity and numbers of both single CD56pos and double CD56posCD16pos cells were similar between RSA women and controls. But notably, within the RSA group, NK cell numbers of <12% were strongly associated with a subsequent pregnancy carried to term. Supplementation of folic acid led to an increase of single CD56pos cells, but cytotoxic function appeared unaffected. The expression pattern of killer inhibitory receptors on CD56pos cells was not different between patients and controls. A longitudinal study revealed that, compared with controls, in RSA women higher numbers of double CD56posCD16pos cells were present during early pregnancy, paralleled by an increase in cytotoxic NK cell reactivity. The single CD56pos population decreased in number. In conclusion, the analysis of peripheral NK cell characteristics appears a suitable diagnostic tool in RSA. Immunomodulation aimed at NK cell function appears a promising therapeutic measure.

Defective chorionic villous vascularization has been suggested to be associated with embryonic death. There are no reports, however, describing ch1orionic vascular profiles in spontaneous miscarriage tissue. Therefore, we investigated chorionic villous vascularization by both histopathology and an image analysis system combined with CD34 immunohistochemistry in spontaneous miscarriage tissue of 19 women with recurrent early pregnancy loss (REPL). Subsequently, we studied the vascular profile parameters (median vascular area, perimeter, number of vascular elements per measured chorionic area, and the median area, perimeter and diameter per vascular element) in relation to the maternal plasma total homocysteine concentrations (an independent risk factor for REPL). The histopathological scores and the measured number of vascular elements per mm2 chorionic tissue were not significantly different between women with elevated and those with normal total homocysteine concentrations. However, women with elevated total homocysteine concentrations (fasting >18.3 μmol/l and/or 6 h after methionine load >61.5 μmol/l) showed (per measured chorionic area) significant smaller median vascular areas and perimeters. The single chorionic vascular elements in these women had significant smaller median areas, perimeters and diameters. Furthermore, the fasting total homocysteine was negatively correlated with the perimeter of the vascular element (r = –0.54: P <0.05). In conclusion, in REPL, elevated maternal total homocysteine concentrations are associated with defective chorionic villous vascularization.

Objective: To determine whether genetic variability in biotransformation enzymes contributes to individual differences in susceptibility to preeclampsia or the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP).

Objective: To estimate the relative risk of recurrent early pregnancy loss for different total plasma homocysteine and serum folate concentrations.

Objective: To investigate a possible involvement of glutathione S-transferases, major detoxificating enzymes, in the pathophysiology of preeclampsia.

Maternal folic acid supplementation has been suggested to play a role in the prevention of nonsyndromic orofacial clefts, i.e., cleft lip ± cleft palate. Using a case-control design, we investigated vitamin-dependent homocysteine metabolism in 35 mothers with nonsyndromic orofacial cleft offspring and 56 control mothers with nonmalformed offspring. A standardized oral methionine loading test was performed, in which fasting and afterload plasma total homocysteine, serum and red-cell folate, serum vitamin B12, and whole-blood vitamin B6 levels were determined. We found that both fasting (P &lt; 0.01) as well as afterload (P &lt; 0.05) homocysteine concentrations were significantly higher in cases compared to controls. Hyperhomocysteinemia, defined by a fasting and/or afterload homocysteine concentration above the 97.5th percentile, was present in 15.6% of the cases and in 3.6% of controls (odds ratio, 5.3 (1.1–24.2)). The median concentrations of serum (P &lt; 0.01) and red-cell (P &lt; 0.05) folate were significantly higher, and vitamin B6 concentrations appeared to be significantly lower (P &lt; 0.05), in cases compared with controls. No significant difference was observed between groups for vitamin B12. These preliminary data offer evidence that maternal hyperhomocysteinemia may be a risk factor for having nonsyndromic orofacial cleft offspring. Teratology 60:253–257, 1999. © 1999 Wiley-Liss, Inc.

We studied plasma GSTA1-1 concentrations in preconceptionally recruited epileptic women who received antiepileptic drugs (n = 99) and a control group of healthy women (n = 106). Mean plasma GSTA1-1 concentrations in the control group did not show significant changes preconceptionally and throughout pregnancy. Six weeks postpartum, however, a significant increase in the mean plasma GSTA1-1 concentration (p < 0.001) was found as compared to preconceptional levels and levels during pregnancy. The mean plasma GSTA1-1 concentration in epileptic women was significantly higher in the 4th gestational week compared to those determined in healthy pregnant women (1.68 versus 1.08 μg/l, p < 0.001). Values between the groups in the second and third trimester and postpartum period showed no significant differences.

PurposeWe evaluated new intervention techniques and surgical instruments in a fetal monkey model to determine improvements that would be useful for early intrauterine intervention. Our findings may be helpful in the future for treating select cases of severe prenatal obstructive uropathology.Materials and MethodsIn a series of experiments on 18 pregnant rhesus monkeys (Macaca mulatta) at mid trimester we assessed various endoscopic intra-amniotic access techniques as well as morbidity, mortality and possibilities for fetoscopy.ResultsIn all 18 fetuses adequate fetoscopy was possible with no maternal mortality. Of the 18 pregnancies 14 went to term with no early or late postoperative complications. Technical improvements changed the intrauterine access technique from open placement of trocars to the use of the Seldinger technique, gun introduction of needles with small caliber sheets and small caliber introduction trocars, resulting in minimal amniotic membrane separation. Various rigid and flexible endoscopes were evaluated for fetoscopy and up to 3 cannulas were placed. No change in the fetal growth pattern was observed on postoperative ultrasound. Subsequent pregnancies occurred during this study period, and there were no acceptance problems of the newsborns by the mothers.ConclusionsNew techniques have led to improved intrauterine fetal access. Morbidity mainly depends on the disruption of amniotic membranes, which has an important preterm role. Adapted endoscopes and other instruments offer new possibilities for fetal diagnosis and therapy in the future. Our primate model seems to be suitable for evaluating these new techniques before they are used in a clinical setting.

Objective: To investigate the pathophysiologic involvement of glutathione in pregnancies complicated by preeclampsia or the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome.

To study the presence of homocysteine, methionine and the vitamins folate, B12, and B6in human ovarian follicular fluid (FF).

AbstractOral N-acetylcysteine supplementation in nine young healthy females induced a quick and highly significant decrease in plasma homocysteine levels and an increase in whole blood concentration of the antioxidant glutathione. N-acetylcysteine impresses as an efficient drug in lowering homocysteine concentration and might be beneficial for individuals with hyperhomocysteinemia who are at increased risk of cardiovascular disease.