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Second-trimester maternal serum marker screening: maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, estriol, and their various combinations as predictors of pregnancy outcome.

OBJECTIVE: We evaluated the value of all 3 common biochemical serum markers, maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, and unconjugated estriol, and combinations thereof as predictors of pregnancy outcome. STUDY DESIGN: A total of 60,040 patients underwent maternal serum screening. All patients had maternal serum alpha-fetoprotein measurements; beta-human chorionic gonadotropin was measured in 45,565 patients, and 24,504 patients had determination of all 3 markers, including unconjugated estriol. The incidences of various pregnancy outcomes were evaluated according to the serum marker levels by using clinically applied cutoff points. RESULTS: In confirmation of previous observations, increased maternal serum alpha-fetoprotein levels (>2.5 multiples of the median) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, intrauterine growth restriction, intrauterine fetal death, oligohydramnios, and abruptio placentae. Increased beta-human chorionic gonadotropin levels (>2.5 multiples of the median [MoM]) were significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, and intrauterine fetal death. Finally, decreased unconjugated estriol levels (<0.5 MoM) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, intrauterine growth restriction, and intrauterine fetal death. As with increased second-trimester maternal serum alpha-fetoprotein levels, increased serum beta-human chorionic gonadotropin and low unconjugated estriol levels are significantly associated with adverse pregnancy outcomes. These are most likely attributed to placental dysfunction. CONCLUSION: Multiple-marker screening can be used not only for the detection of fetal anomalies and aneu-ploidy but also for detection of high-risk pregnancies.

Abruptio Placentae↗

Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival.

Mild-to-moderate zinc deficiency may be relatively common worldwide, but the public health importance of this degree of zinc deficiency is not well defined. The purpose of this review was to provide a conceptual framework for evaluating the public health importance of maternal zinc deficiency as it relates to fetal growth and development, complications of pregnancy, labor and delivery, and maternal and infant health. The mechanisms through which zinc deficiency could influence health outcomes are well described. The results of experimental studies conducted in animal models have motivated concern about the potential health effects of mild-to-moderate maternal zinc deficiency. Observational studies in human populations have produced strong associations between poor maternal zinc status and various indicators of poor pregnancy outcome, but supplementation trials have not produced strong, or even consistent results. Supplementation trials are needed to define the public health importance of maternal zinc deficiency worldwide.

Brain↗

Genotypic effects, maternal effects and grand-maternal effects of immobilized derivatives of the transposable element mariner.

The baseline rate of spontaneous integration of the autonomous mariner element Mos1 into the germline of Drosophila melanogaster is estimated as 16 +/- 5% (mean +/- SE) among fertile G0 flies. However, the transformation rate is reduced approximately 20-fold in Mos1 constructs with exogenous DNA in the size range 5-12 kb inserted into the SacI site. To provide alternative Mos1 helper plasmids for transformation experiments, two types of Mos1-promoter fusions were constructed: hsp-70:Mos1 and hsp26-Sgs3:Mos1. The former has the Mos1 coding region driven by the hsp70 heat-shock promoter; the latter has it driven by the basal Sgs3 promoter under the control of the hsp26 female-germline specific transcriptional regulator. When introduced into D. melanogaster by P-element-mediated germline transformation, these elements are unable to transpose or excise in the presence of autonomous Mos1-related elements (they are "marooned") because the 5' inverted repeat of Mos1 is missing. As expected, the hsp26-Sgs3:Mos1 fusions exhibit a significantly greater rate of germline excision of a target mariner element than do the hsp70:Mos1 fusions. Unexpectedly, the rate of excision of target mariner elements induced by hsp26-Sgs3:Mos1 is the same in the male germline as in the female germline. Both hsp:Mos1 fusions show strong germline expression and a maternal effect of the mariner transposase. A significant grand-maternal effect of the hsp:Mos1 fusions was also detected as a result of a maternal effect on the germline of the F1 progeny. Among flies carrying the promoter fusions inherited maternally, about three-quarters of the overall rate of germline excision derives from the direct genotypic effect and about one-quarter results from the grand-maternal effect. Despite the strong somatic expression of the hsp:Mos1 fusions, mariner transformants carrying a white+ reporter gene at the SacI site remained stable in the soma.

Animals↗

Effect of maternal dietary restriction during pregnancy on maternal weight gain and fetal birth weight in the rat.

The effects of the following dietary regimes on maternal body weight and weights of the products of conception were investigated in the laboratory rat: 50% dietary restriction during the catabolic phase (days 15--21) of gestation; 50% dietary restriction during the anabolic phase (days 1--14) but adequate nutrition during the catabolic phase, and 50% dietary restriction throughout gestation. Total body weight and net maternal weight at term were significantly reduced in all three test groups. Restricting dietary intake during the anabolic phase resulted in decreased maternal weight gain. Feeding an adequate diet during the catabolic phase, following restriction during the anabolic phase, caused only a slight decrease in net maternal weight, while term fetal weight approximated that of controls. Dietary restriction during the catabolic phase, or throughout gestation, caused increased net maternal weight loss. Term fetal weight in both groups was significantly lower than that of the controls, but not different from each other. The results indicate that the dam is able to mobilize nutrients stored during the anabolic phase of pregnancy. Mobilization of these nutrients did not significantly increase fetal growth, however, supporting the hypothesis that the dam is able to compartmentalize available nutrients during malnutrition and prevent serious depletion of these stores by the fetus.

Animals↗

Maternal cigarette smoking, regular use of multivitamin/mineral supplements, and risk of fetal death: the 1988 National Maternal and Infant Health Survey.

Data from the 1988 National Maternal and Infant Health Survey were used to examine whether regular use of multivitamin/mineral supplements could modify the relation between maternal smoking and fetal death. Maternal smoking was defined as the self-reported average number of cigarettes smoked after recognition of pregnancy. Regular supplement use was defined as use of multivitamin/mineral supplements for at least 3 days per week during the 3 months before and/or after recognition of pregnancy. The sample comprises 12,465 singleton pregnancies, including 9,402 livebirths and 3,063 fetal deaths. Odds ratios were derived from logistic regression analyses after adjustment for a number of demographic and reproductive variables. Major findings are that 1) smoking increased the risk of fetal death; 2) regular supplement use either before or after recognition of pregnancy did not affect the risk of fetal death in the absence of maternal smoking; 3) odds ratios for fetal death among smoking women who regularly used supplements were generally smaller than those for women who did not regularly use supplements but who smoked a comparable number of cigarettes; and 4) a significant negative excess risk due to interaction was observed among women who regularly used supplements before recognition of pregnancy and smoked 20 or more cigarettes a day. These findings suggested that regular multivitamin/mineral supplement use might reduce the risk of fetal death associated with maternal smoking.

Adult↗

The effect of maternal weight on maternal serum alpha-fetoprotein levels.

In 902 singleton pregnancies, maternal serum alpha-fetoprotein (AFP) levels between 15 and 20 weeks of pregnancy were significantly related to maternal weight (r = 0.24, p less than 0.0001). Lighter women had on average higher AFP levels than heavier women, perhaps on account of the greater concentration of AFP in their relatively smaller volume of blood. The mean AFP level for women weighing less than 45 kg was 68% higher than the mean level for women weighing 85 kg or more. Maternal weight was found to be an important factor which could account for false positive AFP results in antenatal screening for open neural tube defects. A policy of adjusting maternal serum AFP values according to maternal weight among women with borderline positive results could reduce the number having a diagnostic amniocentesis with only a negligible loss of detection for open spina bifida. With such a policy, using a cut-off level of 2.5 x normal median, the false positive rate in the 902 women screened would have been reduced fom 2.8% to 2.0%.

Body Weight↗

Identification of interstitial maternal uniparental disomy (UPD) (14) and complete maternal UPD(20) in a cohort of growth retarded patients.

The association of uniparental disomy (UPD) and short stature has been reported for different chromosomes and in several conditions. Therefore, we investigated a cohort of 21 patients referred because of intrauterine and postnatal growth retardation for UPD of chromosomes 2, 7, 9, 14, 16, and 20. Typing of short tandem repeats showed maternal UPD(14) and maternal UPD(20) in two cases. In the first case, an interstitial UPD(14) was detected and the growth retarded newborn showed some additional clinical signs in common with the putative "maternal UPD(14) syndrome". The maternal UPD(20) patient showed minor features. However, since it is only the second maternal UPD(20) case it is too early to delineate a specific syndrome and the role of this constitution in growth remains to be investigated. Our data suggest that searching for UPD in growth retarded patients is a helpful approach to getting more information on the role of UPD in growth retardation. Based on our results, general considerations and indications for UPD testing are discussed.

Chromosome Aberrations↗

Twin-to-twin transfusion syndrome: polyhydramnios-associated changes in maternal plasma volume and maternal plasma aldosterone concentrations. A preliminary study.

OBJECTIVE: Our aim was to evaluate the consequences of polyhydramnios on maternal plasma volume and maternal serum aldosterone and atrial natriuretic peptide (ANP) concentrations in monochorionic twin pregnancies complicated by twin-to-twin transfusion syndrome (TTTS). METHODS: The maternal plasma volume, ionograms as well as plasma ANP and aldosterone concentrations were compared in normal monochorionic diamniotic twin pregnancies and in TTTS. RESULTS: The maternal plasma volume was normal in TTTS despite severe polyhydramnios. The plasma aldosterone concentration was higher in pregnancies complicated by TTTS. CONCLUSION: The high plasma aldosterone concentration is likely to maintain normal plasma volume despite progressive extravascular volume enhancement. This suggests that TTTS is present early in pregnancy as a chronic phenomenon starting before its clinical expression and may trigger compensatory maternal hyperaldosteronism.

Aldosterone↗

Fat-soluble vitamins in the maternal diet, influence of cod liver oil supplementation and impact of the maternal diet on human milk composition.

BACKGROUND/AIMS: To investigate lactating mothers' intake of fat-soluble vitamins in free-living subjects and to what extent cod liver oil supplementation influences the maternal intake in a population with common intake of cod liver oil. The impact of maternal diet on the concentration of fat-soluble vitamins in human milk was studied. METHODS: Dietary intake of 77 lactating women was investigated by 24-hour diet recalls and breast-milk samples were taken at the same occasions. Breast milk samples were analyzed for fat-soluble vitamins. RESULTS: The median intakes were 927 microg/day for vitamin A, 5.5 mg/day for vitamin E and 3.3 microg/day for vitamin D. Maternal vitamin A, E and D intakes were higher when the diet was supplemented with cod liver oil. Icelandic breast milk was found to have high contents of vitamin A and E. Only vitamin D was too low in breast milk to meet the recommended intake for infants. Retinylpalmitate in relation to lipids correlated with maternal vitamin A intake (r = 0.23, p < 0.05). The group with cod liver oil supplementation had significantly lower levels of gamma-tocopherol in breast milk (p < 0.01), whereas the supplementation did not affect other fat-soluble vitamins. CONCLUSION: The recommended intake of fat-soluble vitamins for lactating women can more easily be met with a cod liver oil supplementation than diet alone. Only vitamin D in human milk cannot meet the recommended intakes for infants, with normal breastfeeding. There is a relationship between the content of vitamins A and E in human milk and the maternal diet.

Adult↗

Allowing for missing data at highly polymorphic genes when testing for maternal, offspring and maternal-fetal genotype incompatibility effects.

Genes can be associated with disease through an individual's inherited genotype, the maternal genotype or the interaction between these two. When the gene is highly polymorphic, it is more difficult to identify the gene's functional role than for less polymorphic loci, because different alleles at the locus may be associated with the disease through separate and joint effects from maternal and offspring genotypes. Family-based studies are used to test genetic associations because of their robustness to population stratification. However, parental genotype data are often missing, and omitting incompletely genotyped families is inefficient. Methods have been proposed to accommodate incomplete families in family-based association studies. They are not easily generalized to allow simultaneous examination of offspring allelic, maternal allelic and maternal-fetal genotype (MFG) incompatibility effects. Since many MFG incompatibility effects occur through matching between maternal and offspring's genotypes, we present an identity-by-state (IBS) framework to incorporate incomplete families in the MFG test when modeling genetic effects produced by a polymorphic gene. Using simulations, we examine the MFG test's performance with incomplete parental genotype data and an IBS framework. The MFG test using the IBS framework is immune to population stratification and efficiently uses information from incomplete families.

Algorithms↗

The relationship between maternal and fetal effects following maternal organophosphate exposure during gestation in the rat.

Organophosphates, a widely used class of insecticidal compounds, have been shown to cross the placental barrier, and thus potentially affect the developing fetus. This study compared the maternal and fetal effects, including cholinesterase inhibition, following gestational exposure to six organophosphates: tribufos, oxydemeton-methyl, azinphos-methyl, fenamiphos, isofenphos, and fenthion in the Sprague-Dawley rat. All test compounds were administered via oral gavage on gestation days 6-15. Maternal cholinesterase activities (plasma, PChe; erythrocyte, RChe; and brain, BChe) were measured on gestation days 16 and 20, and fetal brain cholinesterase activity was measured on gestation day 20. Effects on gestational parameters (clinical signs, food consumption, and body weight) in adult rats, when observed, were only observed at the highest dose tested for each compound. The inhibition of maternal cholinesterase activities associated with these clinical findings was, for all compounds, always greater than 20%. Moreover, cholinesterase activities were inhibited at dose levels below that which elicited clinical effects. Statistically significant inhibition of at least two of the three cholinesterase enzymes (PChe, RChe, or BChe) was observed on gestation day 16, 24 h following exposure, with all of the organophosphates tested. By gestation day 20, the inhibition of cholinesterase activity was reduced; however, the high dose for all test compounds (except BChe in fenamiphos-treated dams) continued to demonstrate statistically significant inhibition of RChe and BChe. Despite significantly affected cholinesterase activity in the dams, no remarkable effects on fetal BChe were observed with any test compound. No embryotoxicity or teratogenicity were observed with any of the test compounds. These results demonstrate that for the six organophosphates tested: (1) inhibition of maternal cholinesterase activity was the most sensitive indicator of organophosphate exposure; (2) the level of cholinesterase inhibition associated with clinical findings was always greater than 20%; and (3) no effect on fetal cholinesterase activity (BChe) was observed, even at dose levels that continued to demonstrate significant inhibition of maternal cholinesterase activity.

Administration, Oral↗

Congenital heart disease in maternal phenylketonuria: report from the Maternal PKU Collaborative Study.

The frequency and types of congenital heart disease in offspring from pregnancies in women with hyperphenylalaninemia were examined in the international prospective Maternal Phenylketonuria Collaborative Study. Relationships of congenital heart disease in offspring to the basal blood phenylalanine level in the mother, metabolic control through diet during pregnancy, and phenylalanine hydroxylase mutations in mother and offspring were determined. The 416 offspring from 412 maternal phenylketonuria pregnancies that produced live births and 100 offspring from the 99 control pregnancies were included in this examination. Thirty-four of the 235 offspring (14%; 95% CI, 10.2 to 19.6%) from pregnancies in phenylketonuric women with a basal phenylalanine level > or = 900 microM (15 mg/dL) [normal blood phenylalanine < 120 microM (2 mg/dL)] and not in metabolic control [phenylalanine level < or = 600 microM (10 mg/dL)] by the eighth gestational week had congenital heart disease compared with one control offspring (1%) with congenital heart disease. One offspring among the 50 (2%) from mothers with non-phenylketonuria mild hyperphenylalaninemia also had congenital heart disease. Coarctation of the aorta and hypoplastic left heart syndrome were overrepresented compared with expected percentages among those with congenital heart disease in the general population. A basal maternal phenylalanine level > 1800 microM (30 mg/dL) significantly increased the risk for bearing a child with congenital heart disease (p = 0.003). Phenylalanine hydroxylase mutations in the mothers and offspring did not have an independent relationship to congenital heart disease but were related through the basal maternal phenylalanine levels. The data in this study indicate that a basal maternal phenylalanine level of 900 microM may be a threshold for congenital heart disease, that women with the most severe degree of phenylketonuria are at highest risk for bearing such a child, and that prevention of the congenital heart disease requires initiation of the low phenylalanine diet before conception or early in pregnancy with metabolic control no later than the eighth gestational week.

Female↗

Chronic maternal fluoxetine infusion in pregnant sheep: effects on the maternal and fetal hypothalamic-pituitary-adrenal axes.

Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor, fluoxetine (FX). FX increases serotonergic neurotransmission and serotonin plays a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. We have therefore investigated the effect of chronic administration of FX to the pregnant ewe on the maternal and fetal HPA axes. Nineteen late-gestation sheep were surgically prepared for chronic study of the fetus. FX (n = 7, 98.5 microg/kg/d) or sterile water (control, n = 8) was administered to the ewe for 8 d by constant rate i.v. infusion with an initial FX bolus dose of 70 mg. Maternal and fetal plasma ACTH and cortisol concentrations were determined at 0700 h each day. Maternal plasma ACTH concentrations fell on infusion d 2, but no changes were observed in maternal plasma cortisol concentrations. Fetal plasma ACTH concentrations increased on infusion d 7, and fetal plasma cortisol concentrations increased on infusion d 6, 7, and 8 in the FX group. In addition, the regression coefficient for the relationship between fetal ACTH and cortisol levels was significantly greater in the FX group compared with the control group. Thus, maternal FX treatment increased fetal plasma cortisol concentration. These results are of particular interest in the context that exposure of the fetus to excess glucocorticoids at critical windows during development has been shown to increase the risk of poor health outcomes in later life.

Adrenocorticotropic Hormone↗

[Maternal plasma beta-endorphin levels during labor in relation to maternal obesity].

The relationship between maternal plasma levels of beta-endorphin (beta-Ep) during labor and various obstetrical factors was investigated in 115 healthy pregnant women. beta-Ep was determined by radioimmunoassay using double-antibody RIA kit (INCSTAR Corporation, Stillwater, M'S.). The results were as follows: (1) The primiparous women showed a significant increase of maternal plasma levels of beta-Ep at delivery compared with the multiparous women. In addition, the group of women whose Bishop's score at the onset of labor was 5 points or less showed a significant increase of maternal plasma levels of beta-Ep at delivery compared with that in the group of women whose Bishop's score was 6 points or more. (2) The increase in maternal plasma levels of beta-Ep during the first and the second stage of labor was significantly higher in obese women (pre-pregnancy BMI > or = 24) than in normal weight women (pre-pregnancy BMI < 24). In normal weight women in pre-pregnancy, the group of women whose weight gain during pregnancy was 11kg or more showed a significantly higher increase of beta-Ep compared with that in the group of women whose weight gain was less than 11 kg. These results suggest that a stressful delivery caused a significant increase of maternal plasma levels of beta-Ep during labor. Moreover, obesity and marked weight gain during pregnancy caused a remarkable increase in beta-Ep probably due to latent dystocia.

Female↗

The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report.

OBJECTIVE: The objective of this study was to describe drug use by pregnant women participating in the 4-site Maternal Lifestyle Study of in utero cocaine and/or opiate exposure. METHODS: Meconium specimens of 8527 newborns were analyzed by immunoassay with GC/MS confirmation for metabolites of cocaine, opiates, cannabinoids, amphetamines, and phencyclidine. Maternal self-report of drug use was determined by hospital interview. RESULTS: The prevalence of cocaine/opiate exposure in the 4 sites was 10.7% with the majority (9.5%) exposed to cocaine based on the combination of meconium analysis and maternal self-report. However, exposure status varied by site and was higher in low birth weight infants (18.6% for very low birth weight and 21.1% for low birth weight). Gas chromatography/mass spectrometry (GC/MS) confirmation of presumptive positive cocaine screens was 75.5%. In the cocaine/opiate-exposed group, 38% were cases in which the mother denied use but the meconium was positive. There was 66% agreement between positive meconium results and positive maternal report. Only 2% of mothers reported that they used only cocaine during pregnancy and mothers were 49 times more likely to use another drug if they used cocaine. CONCLUSION: Accurate identification of prenatal drug exposure is improved with GC/MS confirmation and when the meconium assay is coupled with a maternal hospital interview. However, the use of GC/MS may have different implications for research than for public policy. We caution against the use of quantitative analysis of drugs in meconium to estimate the degree of exposure. Our study also highlights the polydrug nature of what used to be thought of as a cocaine problem.

Adolescent↗

Prenatal and postnatal maternal contributions to reproductive, maternal, and size-related traits of beef cattle.

Brown Swiss-Hereford (BS-H) reciprocal cross embryos were transferred to BS and H recipient cows and Red Poll-Angus (RP-A) reciprocal cross embryos were transferred to RP and A recipient cows to estimate the relative contributions of ovum cytoplasm and uterine influences to prenatal maternal effects. Calves resulting from embryo transfers (ET) were weaned early (3 to 5 d). Reciprocal cross mating also were made by natural service (NS) between BS and H and between RP and A breeds; part of the offspring were weaned at 3 to 5 d, and the remainder nursed their dams to an age of 150 to 180 d. This was done to estimate breed differences in prenatal and postnatal effects combined and to separate the effects of prenatal maternal influences from postnatal maternal influences of these breeds. Females produced in both ET and NS parts of the experiment were retained to produce three calf crops to an age of about 4.5 yr. The following traits were analyzed: percentage of conception rate; percentage of calf survival; percentage of calves produced per cow exposed; birth and weaning weights of calves produced; and periodic weights, heights, and condition scores of females to an age of 4.5 yr. Neither breed of donor (cytoplasmic influence) nor breed of recipient (uterine influence) had consistently important effects on the traits evaluated. In NS matings, differences between reciprocal crosses were small for most of the traits evaluated. Method of rearing (nursed vs weaned at 3 to 5 d) had no effect on reproductive and maternal traits for RP-A reciprocal cross females, but females that nursed generally were heavier, were taller, and had higher condition scores at most ages than early-weaned females. For the BS-H reciprocal cross, early-weaned females were favored over females reared by their dams in percentage of calves produced per cow exposed, but the method of rearing did not affect other reproductive or maternal traits. BS-H reciprocal cross females that nursed their dams were heavier at 550 d and were heavier and had higher condition scores at an age of 34 mo than early-weaned females.

Animals↗

The inadequacy of the current correction for maternal weight in maternal serum alpha-fetoprotein interpretation.

The application of correction factors for maternal serum alpha-fetoprotein (MSAFP) is expected to increase the accuracy of this screening tool. Correction for maternal weight compensates for the dilution effect of a larger plasma volume in women of greater weight. We analyzed the effect of a previously published linear correction formula for weight on the frequency of abnormal MSAFP results. Serum samples from 8276 patients were studied for AFP and were grouped according to maternal weight in 50-lb increments. Abnormal results were defined as 0.4 or less or 2.5 or more multiples of the median for gestational age. Without correction, the highest rate (15%) of low MSAFP results was obtained in the obese population. Conversely, the rate of elevated MSAFP was highest (3.8%) in the lowest maternal weight group. Correction for weight up to 250 lb significantly increased the rate of abnormally high results in the obese group, indicating an overcorrection effect. The number of amniocenteses indicated for abnormal MSAFP was reduced by about 9% with weight correction. We suggest that linear correction of serum AFP results is adequate for maternal weights up to 200 lb. Results in women weighing more than this upper limit should be corrected as if the weight were 200 lb only. This balances the frequency of abnormal results in all weight groups and maintains the reduction in number of procedures performed.

Body Weight↗

Effect of maternal glucose ingestion compared with maternal water ingestion on the nonstress test.

Ninety-three nonstress tests were performed on 57 nondiabetic patients at greater than 34 weeks' gestation. Maternal whole blood glucose levels were measured before beginning the nonstress test and within five minutes of the second fetal heart rate acceleration. There was a significant rise in maternal whole blood glucose levels in the maternal glucose ingestion group but not in the maternal water ingestion group. There was no significant difference in the mean time to reactivity between the two groups. These results suggest that maternal glucose ingestion does not affect time to reactivity or the incidence of reactive nonstress tests.

Blood Glucose↗