Maternal periconceptional biochemical and hematological parameters,vitamin profiles and pregnancy outcome

OBJECTIVES: To evaluate periconceptional maternal biochemical and hematological parameters and vitamin profiles in relation to the risk of early pregnancy loss and birth weight. DESIGN: Prospective longitudinal study. SETTING: University Medical Centre Nijmegen, Academic Medical Centre, Amsterdam, Maria and Elisabeth Hospitals, Tilburg, and Catharina Hospital, Eindhoven, The Netherlands. SUBJECTS: A cohort of 240 women recruited before pregnancy. INTERVENTIONS: Blood samples were taken preconceptional and at 6 and 10 weeks amenorrhea in which the concentrations of hemoglobin, hematocrit, creatinin, uric acid, total protein, serum iron, total iron-binding capacity, ferritin, and the concentrations of retinol, tocopherol, thiamine, riboflavin, pyridoxal-5'-phosphate, cobalamin and folate were analyzed. MAIN OUTCOME MEASURES: Risk of early pregnancy loss and birth weight. RESULTS: The risk of early pregnancy loss increased with increasing prepregnancy weight, and when the periconceptional decline in hematocrit, creatinin and uric acid was less profound (slope: P<0.01). Maternal smoking was negatively associated with birth weight (mean reduction of 183 g, P<0.05). Maternal age and prepregnancy weight were positively associated with birth weight (P<0.01). No significant associations were found between vitamin concentrations and risk of early pregnancy loss or birth weight. CONCLUSIONS: Several periconceptional biochemical parameters are significantly associated with early pregnancy loss. The effects of maternal periconceptional health on embryonic development and subsequent pregnancy outcome should be further explored. SPONSORSHIP: Dutch Prevention fund, grants no. 28.1358 and 28.1006.     

Decreased relative brain tissue levels of inositol in fetal hydrocephalus

OBJECTIVE: Inositol seems to play a role in the development of the central nervous system. In this study, the brain tissue level of inositol in fetal hydrocephalus was compared with that of healthy control subjects. STUDY DESIGN: Proton magnetic resonance spectroscopy was used to examine the inositol over creatine ratio in the brain of 10 hydrocephalic human fetuses and 36 normal control subjects. RESULTS: Resolved signals for inositol and creatine were detected successfully in six hydrocephalic fetuses and in all control subjects. The inositol over creatine ratio was significantly lower in fetuses with hydrocephalus (P <.01). CONCLUSION: This result supports speculations concerning the role of inositol in central nervous system development.     

Maternal and fetal levels of methionine and homocysteine in early human pregnancy

Objective To investigate methionine metabolism during normal human embryonic development by measuring levels of methionine and total homocysteine in samples of maternal serum, extra-embryonic coelomic fluid, and amniotic fluid.
Design Cross-sectional observational study.
Setting Collaboration between St Bartholomew's Hospital, London, and the University Hospital of Nijmegen in The Netherlands.
Participants Twenty-three women with uncomplicated pregnancies between 8 and 12 weeks of gestation before surgical termination of an ultrasonographically normal fetus.
Methods Maternal serum samples were collected prior to surgery. Samples of extra-embryonic fluid and amniotic fluids were obtained by transvaginal ultrasound-guided coelocentesis and amniocentesis. Methionine was measured using an aminoacid analyser and total homocysteine by high performance liquid chromatography.
Results Levels of methionine were four times higher in extra-embryonic coelomic fluid and twice as high in amniotic fluid compared with maternal serum. In contrast, the total homocysteine concentrations were much lower in both extra-embryonic coelomic fluid and amniotic fluid than in maternal serum. All differences were significant (   P 0.01  ).
Conclusions The comparatively high concentrations of methionine in extra-embryonic coelomic fluid and amniotic fluid, and the concomitant low levels of total homocysteine in these fluids, suggest a role for methionine metabolism during early human pregnancy.     

The maternal Mediterranean dietary pattern is associated with a reduced risk of spina bifida in the offspring

Objective  The objective of this study was to test the hypothesis whether a maternal dietary pattern is associated with the risk of spina bifida (SB) in the offspring.
Design  Case–control study.
Setting  Eight clinic sites in the Netherlands, 1999–2001.
Sample  A total of 50 mothers of children with SB and 81 control mothers.
Methods  Maternal food intakes were obtained by food frequency questionnaires at the standardised study moment of 14 months after the birth of the index child. Principal component factor analysis (PCA) and reduced rank regression (RRR) were used to identify dietary patterns.
Main outcome measures  Maternal biomarkers were used as response measures in the RRR analysis and composed of serum and red blood cell (RBC) folate, serum vitamin B12 and total plasma homocysteine. The strength of the use of the dietary pattern in association with SB risk was estimated by odds ratios and 95% CI with the highest quartiles of the dietary pattern as reference.
Results  A predominantly Mediterranean dietary pattern was identified by both PCA and RRR. Those dietary patterns were highly correlated ( r = 0.51, P < 0.001) and characterised by joint intakes of fruit, vegetables, vegetable oil, alcohol, fish, legumes and cereals and low intakes of potatoes and sweets. We observed a significantly increased risk of SB offspring in mothers with a weak use of the Mediterranean dietary pattern, OR 2.7 (95% CI 1.2–6.1) and OR 3.5 (95% CI 1.5–7.9). The Mediterranean dietary pattern was correlated with higher levels of serum and RBC folate, serum vitamin B12 and lower plasma homocysteine.
Conclusion  The Mediterranean dietary pattern seems to be associated with reduction in the risk of offspring being affected by SB.     

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

Parent-of-origin (PofO) effects, such as imprinting are a phenomenon where the effect of variants depends on parental origin. Conventional association studies assume that phenotypic effects are independent of parental origin, and are thus severely underpowered to detect such non-Mendelian effects. Risk of orofacial clefts is influenced by genetic and environmental effects, the latter including maternal-specific factors such as perinatal smoking and folate intake. To identify variants showing PofO effects in orofacial clefts we have used a modification of the family-based transmission disequilibrium test to screen for biased transmission from mothers and fathers to affected offspring, biased ratios of maternal versus paternal transmission, and biased frequencies of reciprocal classes of heterozygotes among offspring. We applied these methods to analyze published genome-wide single-nucleotide polymorphism (SNP) data from ∼2500 trios mainly of European and Asian ethnicity with non-syndromic orofacial clefts, followed by analysis of 64 candidate SNPs in a replication cohort of ∼1200 trios of European origin. In our combined analysis, we did not identify any SNPs achieving conventional genome-wide significance (P<5 × 10⁻⁸). However, we observed an overall excess of loci showing maternal versus paternal transmission bias (P=0.013), and identified two loci that showed nominally significant effects in the same direction in both the discovery and replication cohorts, raising the potential for PofO effects. These include a possible maternal-specific transmission bias associated with rs12543318 at 8q21.3, a locus identified in a recent meta-analysis of non-syndromic cleft (maternal-specific P=1.5 × 10⁻⁷, paternal-specific P=0.17). Overall, we conclude from this analysis that there are subtle hints of PofO effects in orofacial clefting.     

A derangement of the maternal lipid profile is associated with an elevated risk of congenital heart disease in the offspring

Background and aimsMaternal hyperglycaemia and hyperhomocysteinaemia are risk factors for congenital heart disease (CHD). These metabolic derangements and deranged lipid levels are associated with adult cardiovascular disease. We examined whether maternal lipid levels are associated with the risk of CHD offspring.Methods and ResultsFrom 2003 onwards, a case-control study was conducted. Participants were mothers of children with (n = 261) and without (n = 325) CHD. At around 16 months after the index-pregnancy, maternal lipid levels were determined. Maternal characteristics and lipid levels were compared by Student’s t-test. In a multivariable logistic regression model, risk estimates were calculated for associations between CHD and lipid levels. Adjustments were made for maternal age, diabetes, ethnicity, body mass index (BMI), parity, periconception folic acid use and total homocysteine levels. Outcome measures are presented in (geometric) means (p5–p95) and odds ratios (ORs) with 95% confidence intervals (CIs).Case mothers showed higher cholesterol (4.9 vs. 4.7 mmol l^?1, P < 0.05), low-density lipoprotein (LDL)-cholesterol (3.2 vs. 3.0 mmol l^?1, P < 0.05), apolipoprotein B (84.0 vs. 80.0 mg dl^?1, P < 0.01) and homocysteine (10.8 vs. 10.2 μmol l^?1, P < 0.05) than controls. LDL-cholesterol above 3.3 mmol l^?1 (OR 1.6 (95%CI, 1.1–2.3)) and apolipoprotein B above 85.0 mg dl^?1 were associated with an almost twofold increased CHD risk (OR 1.8 (95%CI, 1.2–2.6)). This was supported by elevated CHD risks per unit standard deviation increase in cholesterol (OR 1.2 (95% CI 1.03–1.5)), LDL-cholesterol (OR 1.3 (95%CI, 1.1–1.6) and apolipoprotein B (OR 1.3 (95% CI 1.1–1.6)). Apolipoprotein B was most strongly associated with CHD risk.ConclusionA mildly deranged maternal lipid profile is associated with an increased risk of CHD offspring.     

The impact of calcium, magnesium, zinc, and copper in blood and seminal plasma on semen parameters in men

To investigate the impact of calcium, magnesium, zinc, and copper in blood and seminal plasma on semen parameters, 107 fertile and 103 subfertile males provided a standardized blood and semen specimen. Total calcium and magnesium concentrations were determined with colorimetric end point assay procedures. Zinc and copper were determined by flame atomic absorption spectrophotometer (AAS). Semen analysis was performed according to World Health Organization guidelines (1992). The concentrations of calcium, magnesium, zinc, and copper in blood and seminal plasma were not different between the subfertile and fertile group. Weak correlations were demonstrated between blood plasma zinc concentrations and sperm count (rs = 0.18), sperm motility (rs = 0.15), and abnormal sperm morphology (rs = 0.13). Zinc and magnesium concentrations in seminal plasma correlated weakly with sperm count (rs = 0.17 and rs = 0.16, respectively), and copper concentrations in blood plasma with motility (rs = 0.25). Strong correlations were found between calcium, magnesium, and zinc in seminal plasma. Although calcium, magnesium, zinc, and copper play an essential role in spermatogenesis and fertility, the determination of these elements in blood and seminal plasma does not discriminate on the basis of fertility in this group of men.     

Early pregnancy exposure to antihistamines and risk of congenital heart defects: results of two case–control studies

We aimed to study the association between use of antihistamines in early pregnancy and congenital heart defects (CHD) in the offspring. Design: Two case–control studies. Setting: HAVEN study, Erasmus MC, University Medical Centre, Rotterdam, and Eurocat Northern Netherlands (NNL), University Medical Center Groningen, Groningen, the Netherlands. We studied 361 children with CHD and 410 controls without congenital malformations from the HAVEN study and replicated the analyses in 445 children with CHD and 530 controls from the Eurocat NNL registry. Information about antihistamine use in early pregnancy and potential confounders was obtained from questionnaires postpartum. We calculated the association between antihistamines and CHD risk by multivariable logistic regression analysis. Main outcome measures: Odds ratios (OR) with 95 % confidence intervals (CI). In the HAVEN study, 25 of 771 mothers used antihistamines that were associated with an increased CHD risk (OR 3.0, 95 % CI 1.2–7.3), particularly atrioventricular septal defects (AVSD) (OR 5.1, 95 % CI 1.3–20.5) and perimembranous ventricular septal defects (pVSD) (OR 5.1, 95 % CI 1.8–14.4). Mothers with severe nausea who did not use antihistamines had a reduced risk (OR 0.7, 95 % CI 0.5–0.98), whereas nauseous mothers using antihistamines showed an almost fivefold increased risk of pVSD (OR 4.8, 95 % CI 1.1–21.8). The association between antihistamines and AVSD was confirmed in the Eurocat cohort (OR 3.5, 95 % CI 1.4–8.7), but we could not replicate the association with overall CHD risk. We found a positive association between antihistamine use in early pregnancy and CHD risk, particularly AVSD, which seemed to be independent of nausea/vomiting.