Studies Of Pregnancy Outcomes Research Articles

Exposure assessment in epidemiologic studies of adverse pregnancy outcomes and disinfection byproducts.

A major challenge in studies that examine the association between disinfection byproducts in drinking water and pregnancy outcomes is the accurate representation of a subject's exposure. We used household water samples and questionnaire information on water-use behavior to examine several aspects of exposure assessment: (i) the distribution and correlation of specific disinfection byproducts, (ii) spatial distribution system and temporal variation in byproduct levels, and (iii) the contribution of individual water-use behavior. The level of specific trihalomethanes (THMs) and haloacetic acids (HAAs) was determined for 360 household water samples in Eastern Ontario and Nova Scotia. Subjects were interviewed regarding tap water ingestion and showering and bathing practices. In both provinces, total THMs correlated highly with chloroform (correlation coefficient (r) >0.95) and less so with total HAAs (r = 0.74 in Nova Scotia and r = 0.52 in Ontario). The correlation between total THMs and bromodichloromethane was high in Nova Scotia (r = 0.63), but low in Ontario (r = 0.26). The correlation was between THM level in individual household samples, and the mean THM level during the same time period from several distribution system samples was 0.63, while a higher correlation in THM level was observed for samples taken at the same location 1 year apart (r = 0.87). A correlation of 0.73 was found between household THM level and a total exposure measure incorporating ingestion, showering, and bathing behaviors. These results point to the importance of: measurement of different classes of byproducts; household rather than distribution system sampling; and, incorporation of subject behaviors in exposure assessment in epidemiologic studies of disinfection byproducts and adverse pregnancy outcomes.

Low birth weight in relation to parental occupations—a population-based registry in Singapore (1994–1998)

Objectives: To study the association between parental occupation and low birth weight (LBW) in infants born in Singapore between 1994 and 1998. Other factors that may be related to LBW were also investigated. Methods: A retrospective study. Information was obtained from the Singapore National Registry of Births and Deaths on parental occupations for live births between 1 January 1994 to 31 December 1998. Parental date of birth, ethnic group, and highest educational qualification were also obtained. The associations between these factors and the occurrence of LBW was assessed using descriptive statistics and logistic regression analysis. Results: A total 208,360 live births were studied. Analyses were restricted to singleton births ≥37th week gestation (total of 189,064). No significant differences in LBW risk were found for the different maternal occupational groups, compared with a referent group (“legislators, senior officers, and managers”). However, fathers who were “not working” (OR=2.04; 1.57–2.65), “not classifiable by occupation” (OR=1.34; 1.09–1.65), and “cleaners, laborers, and related workers” (OR=1.32; 1.12–1.55) had the highest risk of LBW infants when compared with “legislators, senior officers, and managers,” after adjustment for maternal occupation, ethnic group, educational level and age, paternal educational level, infant gestational age, sex, and birth order. Conclusion: Certain paternal occupational groups appear to be associated with a higher risk of having LBW infants. This may be linked to socioeconomic status and possible work-related factors. Future studies of pregnancy outcomes should not ignore the potential contributions of fathers.

Transplantation of the uterus

Most women with uterine factor infertility have today no prospect of carrying a pregnancy to term. The development of a method for transplantation of the human uterus would be a means for many of these women to become both genetic and gestational mothers. In this article we review the literature concerning the history and recent development in the area of uterine transplantation. We describe our newly developed model for heterotopic uterine transplantation in the mouse, which we are using for studies of pregnancy outcome and rejection mechanisms. We also address some of the specific questions that need to be solved before attempts to transplant the human uterus should be performed.

Prescription drugs and pregnancy

Prescribing drugs in pregnancy is an unusual risk-benefit situation. Drugs that may be of benefit or even life-saving to the mother can deform or kill the fetus. However, the risk to the fetus should not be exaggerated. There are only ~ 20 drugs or groups of drugs which are known to cause birth defects in humans. For one of these drugs to cause birth defects, a number of criteria must be fulfilled. The drug exposure must take place at a critical stage of pregnancy and the dose must be high enough to cause a threshold of exposure for an appropriate duration of time. For most of the known human teratogens, > 90% of pregnancies exposed during the first trimester result in normal offspring. Although only a few drugs are known to cause birth defects in humans, uncertainty about the safety of the majority may lead to underprescribing for pregnant women and women of childbearing age. Epidemiological studies of pregnancy outcome after specific drug exposures are often superficially reassuring, but most are severely limited in their power to detect adverse outcomes. Safety in animal studies may also be reassuring but species differences demand caution in this interpretation. Concerns about prescription drugs in the first trimester, when they can cause birth defects, are mostly quite different to concerns about use in the second and third trimesters. As the fetal organ systems mature, the fetus can be affected by the pharmacological activity of the drug in the same way as the mother. Many drugs have pharmacological effects on the fetus in the second and third trimesters but in most cases, they are well recognised and can be managed or avoided. The material presented in this paper is mostly concerned with the ‘risks’ associated with drugs in pregnancy. No attempt has been made to quantitate the possible benefits to the mother or fetus. Communicating the risk-benefit situation to the patient is always a challenge for physicians with limited time and sometimes limited knowledge. Fear of litigation is an unfortunate and an unwanted parameter in the assessment. Better knowledge of the parameters that determine teratogenicity may allow physicians to feel more confident in assessing the risks and benefits associated with prescribing in pregnancy.

Selection bias in Teratology Information Service pregnancy outcome studies

Pregnancy outcome studies conducted through Teratology Information Services (TIS) rely on volunteer subjects. If these subjects tend to have different risk profiles than the population from which they are drawn, the results of TIS studies may have limited generalizability. We selected all subjects who enrolled in the California Teratogen Information Service (CTIS) pregnancy outcome study for prenatal exposure to carbamazepine or valproic acid between 1990 and 1997 and who received prenatal care through Kaiser Permanente of Southern California (n = 13). We compared these subjects to Kaiser patients identified through the Maternal Serum Alpha Fetoprotein Program with exposure to carbamazepine or valproic acid but who had not enrolled in the CTIS project. The controls were matched by Kaiser location and pregnancy year using a 2:1 ratio (n = 26). Medical records were reviewed and the prevalence of 14 pregnancy risk factors was compared between the two groups. There were no significant differences between the groups on any one risk factor; however, a notably higher proportion of women who did not enroll in the CTIS study used tobacco or had a positive family history of congenital anomalies. Although the sample was small, and results may not apply to other exposures in different health care environments, these data provide some evidence that women who enroll in TIS pregnancy outcome studies do not have a substantially different pregnancy risk profile than women who do not. Efforts to address possible selection bias should be incorporated in future TIS study design.

Determinants of maternal zinc status during pregnancy

Zinc deficiency in pregnant experimental animals limits fetal growth and, if severe, causes teratogenic anomalies. Although the data from human studies are not consistent, similar outcomes have been observed and were associated with poor maternal zinc status. This paper reviews humans studies of zinc status and pregnancy outcome, describes the physiologic adjustments in zinc utilization during pregnancy to meet fetal needs while maintaining maternal status, and identifies dietary and environmental conditions that may override those physiologic adjustments and put the health of the mother and fetus at risk. Adjustments in intestinal zinc absorption appear to be the primary means by which zinc retention is increased to meet fetal demands. However, transfer of sufficient zinc to the fetus is dependent on maintenance of normal maternal serum zinc concentrations. Conditions that could interfere with zinc absorption include intake of cereal-based diets that are high in phytate, high intakes of supplemental iron, or any gastrointestinal disease. Conditions that may alter maternal plasma zinc concentrations and the transport of zinc to the fetus include smoking, alcohol abuse, and an acute stress response to infection or trauma. Supplemental zinc may be prudent for women with poor gastrointestinal function or with any of these conditions during pregnancy.

Concordance among Measures of Pregnancy Outcome Based on Fetal Size and Duration of Gestation

Epidemiologic and clinical studies of pregnancy outcome often consider a variety of related, overlapping outcome measures. The overlap among these measures was analyzed using data from the Mount Sinai Hospital Perinatal Data Base, New York City, New York. A total of 52,621 births from 1986 through 1996 were included, with information on gender, ethnicity, birth weight, and gestational age assigned based on last menstrual period or early ultrasound. The authors considered very low birth weight (VLBW) (<1,500 g), low birth weight (LBW) (<2,500 g), degrees of preterm delivery (less than 32, 34, and 37 weeks' gestation), and small for gestational age (less than the 10th percentile of weight for gestational age) births. Infants at the extremes of gestational age (<32 or 34 weeks' gestation) were almost always LBW (97.6 and 91.7%, respectively), and those who were VLBW were almost always preterm (99.2%). However, only 69.2% of LBW infants were preterm, and 50.2% of preterm infants were LBW (kappa = 0.54). Only for VLBW and less than 32 weeks' gestation were both measures of overlap at least 70% (kappa = 0.98). The lack of concordance among measures suggests that multiple outcome measures be considered and that results from analyses using disparate measures not be compared directly.

Perinatal and obstetric outcomes of donor insemination using cryopreserved semen in Victoria, Australia.

This study compared the perinatal and obstetric outcomes of 1552 donor insemination pregnancies in Victoria, Australia, with a control group of 7717 normally conceived pregnancies from the general population. Data on the outcomes of pregnancies of at least 20 weeks gestation, for both groups, were obtained from the same population-based birth registry. The study showed that there were no significant differences between the donor insemination and control groups in the incidence of preterm birth, low birthweight, multiple birth, perinatal death and birth defects, or in the sex ratio. Pregnancies conceived by donor insemination were significantly more likely than controls to have an induced labour (OR = 1.6, 95% CI 1. 4-1.8), a forceps delivery (OR = 1.5, 95% CI 1.3-1.8) and/or a Caesarean section (OR = 1.6, 95% CI 1.4-1.9) and to develop pre-eclampsia (OR = 1.4, 95% CI 1.2-1.8) after adjusting for maternal age, multiple birth, parity and presentation. Reasons for the higher rate of induced and operative deliveries are not clear. Overall, the study's findings are reassuring for couples considering infertility treatment with donor insemination. The study illustrates the importance of complete follow-up in studies of pregnancy outcomes after assisted conception and the use of appropriate population-based control groups with comparable ascertainment of outcomes.

Adverse reproductive outcomes from exposure to environmental mutagens

The effect of environmental pollution on reproductive outcomes has been studied in the research project `Teplice Program' analyzing the impact of air pollution on human health. Genotoxicity of urban air particles <10 μm (PM10) in in vitro system was determined by the analysis of DNA adducts. The highest DNA binding activity was observed in aromatic fraction, identifying DNA adducts of carcinogenic polycyclic aromatic hydrocarbons (PAHs) presumably diolepoxide-derived from: 9-hydroxybenzo[ a]pyrene (9-OH-B[ a]P), benzo[ a]pyrene-r-7,-dihydrodiol-t-9,10-epoxide[+] (anti-BPDE), benzo[ b]fluoranthene (B[ b]F), chrysene (CHRY), benz[ a]antracene (B[ a]A), indeno[1,2,3- cd]pyrene (I[ cd]P). Reproductive studies were conducted in both females and males. A study of the effects of PM10 exposure on pregnancy outcomes found the relationship between the intrauterine growth retardation (IUGR) and PM10 levels over 40 μg/m 3 in the first gestational month (Odds Ratio for 40–50 μg/m 3=1.6, >50 μg/m 3=1.9). Selected biomarkers were analyzed in venous blood, cord blood (chromosomal aberrations, comet assay) and placenta (DNA adducts, genetic polymorphisms of GSTM1 and NAT2 genotypes) of women enrolled in a nested case-control study. DNA adduct levels were higher in polluted vs. control districts, in smoking vs. nonsmoking mothers, and in GSTM1 null genotype, which was more pronounced in polluted district. No effect of air pollution was observed by cytogenetic analysis of chromosomal aberrations or by comet assay. The reproductive development of young men was followed by measures of semen quality, adjusted for ambient SO 2 exposure. The analysis identified significant associations with air pollution for <13% morphologically normal sperm, <29% sperm with normal head shape, <24% motile sperm. Analysis of aneuploidy in human sperm by FISH showed, aneuploidy YY8 was associated with season of heaviest air pollution. These findings are suggestive for an influence of air pollution on YY8 disomy. All these results indicate that air pollution may increase DNA damage in human population, which may be even higher for susceptible groups. Biomarkers of exposure (DNA adducts) and susceptibility (GSTM1 and NAT2) may indicate the risk of presumable low environmental exposure. Pregnancy outcome and semen studies imply that relatively low air pollution (higher than 40 μg PM10/m 3) can significantly increase the adverse reproductive outcomes affecting both genders.

Studies of HLA, fertility and mate choice in a human isolate.

The role of human leukocyte antigen (HLA) genes in pregnancy and in human mate choice has been investigated in the Hutterites, an inbred population of European origins. High-resolution HLA haplotypes were defined by alleles at 16 loci in >1000 Hutterites. Prospective studies of pregnancy outcome previously demonstrated increased fetal loss rates among Hutterite couples matching for HLA-B antigens (P = 0.033) or for the entire 16-locus haplotype (P = 0.002). Among living children of couples matching for HLA-B or for the haplotype, there was a non-significant deficit of children who were heterozygous and compatible with the mother; the number of living children who were compatible and homozygous or incompatible and heterozygous was not different than expectations (HLA-B, P = 0.095; haplotype, P = 0.376). Mate choice among 411 couples was non-random with respect to the HLA haplotype, assessed by a variety of methods (P = 0.020 to <0.001). These combined data indicate a role for HLA region genes in both pregnancy outcome and mate choice, and suggest that selection acting on these genes occurs pre-conceptually as well as during pregnancy. This review outlines previously published studies on HLA, fertility and mate choice in the Hutterites.

Serum Caffeine and Paraxanthine as Markers for Reported Caffeine Intake in Pregnancy

PURPOSE: Previous studies of maternal caffeine use and pregnancy outcome have relied on self-reported use. Even if these were perfectly accurate, inter-individual differences in caffeine metabolism result in a relatively weak correlation between caffeine intake and serum concentration. The purpose of this study was to determine whether the serum concentration of caffeine or its primary metabolite, paraxanthine, obtained at an unknown time during working hours, is useful to distinguish between pregnant women who report consuming small and large amounts of caffeine.METHODS: We selected from the Birmingham fetal growth study 60 women with normal pregnancy outcomes who reported consuming ⩽ 0.8 mg/kg/day of caffeine in a 24-hour dietary recall, 60 who consumed 0.81–2.5 mg/kg/day, 60 who consumed 2.51–5.0 mg/kg/day and 59 who consumed ⩾ 5.01 mg/kg/day. These women had serum drawn for storage during regular clinic hours on the same day as the recall interview. Caffeine and paraxanthine were measured in the stored serum using high performance liquid chromatography.RESULTS: The weighted kappa coefficient between strata of caffeine intake and quartiles of serum paraxanthine was 0.58 among smokers and 0.53 among nonsmokers, versus 0.44 and 0.51, respectively, for quartiles of serum caffeine. The Pearson correlation coefficient between intake and paraxanthine was 0.50 for smokers and 0.53 for nonsmokers, and 0.37 and 0.51, respectively, for serum caffeine. These values are comparable to the correlation between reported smoking and serum cotinine in pregnancy.CONCLUSIONS: The serum concentrations of paraxanthine, and to a lesser degree, caffeine are useful to distinguish between women with varying levels of caffeine intake.

Daily demands during pregnancy, gestational age, and birthweight: reviewing physical and psychological demands in employment and non-employment contexts.

Although much research has focused on whether the physical demands of employment during pregnancy affect birth outcomes, this article argues that psychological demands should also be considered. Research published since 1980 is reviewed to examine how physical and psychological demands of employment are related to birth outcomes. Evidence for the effect of specific types of physical activities (e.g., lifting, standing) is equivocal, in part due to methodological limitations. However, studies combining several types of physical activities tend to find an association with more adverse birth outcomes. Too few pregnancy outcome studies have examined psychological demands in the workplace to make conclusions about birth outcomes, but the theoretical basis for further research is discussed. This article also argues that physical and psychological demands occur outside of the workplace and must therefore be considered with respect to responsibilities all women face throughout the day. An integrative model for studying these relationships is proposed.

Clomiphene Citrate and Pregnancy Outcome

Data from Australia and elsewhere have shown consistently that adverse perinatal outcomes such as preterm birth and perinatal mortality are more common in pregnancies resulting from assisted conception with IVF and GIFT than normally conceived pregnancies. Factors that may contribute to the excess of poor outcomes include maternal factors, the assisted conception procedures themselves and possibly the influence of drugs used to induce superovulation. This review examines the medical literature describing pregnancies following ovulation induction with one of the drugs used to induce superovulation, clomiphene citrate, and compares their outcomes with Australian IVF and GIFT pregnancy outcomes. The review shows that whilst some studies have suggested higher rates of ectopic pregnancy, spontaneous abortion and congenital malformations in clomiphene citrate induced pregnancies, the findings are inconsistent and the data are flawed. There are only very poor data available on the incidence of preterm birth. Multiple pregnancy is a well-recognized adverse outcome of clomiphene citrate induced pregnancies. Attempts to improve perinatal outcomes of pregnancies following assisted conception will be helped by a better understanding of the relative contributions of maternal and treatment factors and further studies of pregnancy outcome after ovulation induction are needed.

Modeling maternal weight and height in studies of pregnancy outcome among Hispanic women

The objective of this study was to evaluate methods of using maternal weight and height in studies of pregnancy outcome for Hispanic women. Reference anthropometric data came from 1166 Mexican-American women in the Hispanic Health and Nutrition Examination Survey (HHANES). Prospective data on maternal anthropometry and infant birth weight came from 1362 Hispanic women in the Kaiser-Permanente Contraceptive Drug Study and 12,786 women in the Guatemalan Cooperative Perinatal Study. Five methods of standardizing weight for height were evaluated, including power-type indexes and weights relative to HHANES reference data. In linear- and logistic-regression analyses, these methods were practically interchangeable, with no evident advantage of Hispanic reference data. However, if weight was not height-standardized the effect of height was underestimated; if height was omitted and weight was not height-standardized the effects of weight were exaggerated. Therefore, analyses of pregnancy outcome should include both height and height-standardized weight.

Preface

These studies were initiated by the results of two Danish investigations of infertility clients, which indicated the reduced fecundity of male metal welders. The objective was to refute or corroborate the effects of welding on male reproductive capability and--if there was any effect--to identify the causal exposures. The initial hypothesis postulated reduced spermatogenesis, spontaneous abortion, congenital malformation and childhood malignancy following exposure to hexavalent chromium among stainless steel welders. Subsequently, a hypothesis concerned with the significance of exposure to radiant heat on reduced semen quality was put forward. These studies comprised a case-referent study of infertility, cross-sectional and longitudinal studies of semen quality and historical cohort studies of fertility, pregnancy outcome and cancer in offspring. Exposure to welding was reported with a higher frequency during periods of infertility than prior to conception in the case-referent study (OR 2.0, 95% CI 1.0-4.0). This finding is consistent with the main cross-sectional study showing reduced semen quality in welders [average reduction ranging from 8% (sperm penetration rate in eggwhite) to 28% (total sperm count)] and with the cohort study revealing reduced fertility in relation to welding (OR 0.89, 95% CI 0.83-0.97). However, reduced semen quality and fertility were not attributable to the welding of stainless steel but to the welding of mild steel; and no relationship was found between biological measures of exposure to chromium and parameters of semen quality. If the unexpected association between mild steel welding and reduced fecundity is causal, the biological mechanisms involved are obscure. A separate longitudinal study leaves little doubt that moderate radiant heat exposure may cause reversible deterioration of semen quality, but it is not justified to generalize this observation to the entire population of welders. Male-mediated effects on occurrence of congenital malformation and cancer in offspring from stainless steel welding are not indicated by the studies. Weak indications of an increased risk of spontaneous abortion among partners to stainless steel welders (OR 1.9, 95% CI 1.1-3.2) need to be refuted or corroborated in future studies. Suggested effects of mild steel welding on male fecundity should be corroborated by longitudinal controlled studies of semen quality examined before and during exposure and by prospective studies of fecundability in couples trying to conceive a child. On account of the present knowledge it is not possible to recommend rational preventative measures with the exception of elimination of radiant heat exposure in cases of infertility.(ABSTRACT TRUNCATED AT 400 WORDS)

Potential Sources of Bias and Confounding in Environmental Epidemiologic Studies of Pregnancy Outcomes

Biases familiar to all epidemiologists take on new importance when studying spontaneous abortion because of the significance of the timing of exposure during gestation, and because the gestational age at which the pregnancy is recognized may be related to risk factors under study. In this paper, we systematically review the principal biases that might affect epidemiologic studies of pregnancy loss, in the context of a series of studies that found associations between adverse reproductive outcomes and prenatal use of tap or bottled water. These biases relate to availability of subjects for study, exposure opportunity, recall of exposure, recall of disease, and confounding. In one of the studies, the rate of bottled water use changed dramatically over the course of the study period, providing an opportunity to test indirectly for biased recall of exposure. We conclude that a less complete recall of water intake among women with normal pregnancies, as compared with those with spontaneous abortions, may have produced, or increased the magnitude of, the associations seen in these studies.

Obstetric and neonatal infection

Recent advances in prevention, diagnosis, and treatment of infection-associated preterm labor are discussed. This includes antepartum treatment of vaginal infections, amniocentesis for culture and glucose levels, and adjunctive antibiotic treatment of preterm labor and preterm premature rupture of the membranes. Risk factors for neonatal group B streptococcus sepsis are described and testing for rapid detection of maternal group B streptococcus colonization is discussed, as are recent prospective studies of pregnancy outcome following human parvovirus B19 infection. Studies quantifying the transmission of herpes simplex virus to neonates following vaginal delivery to mothers with recurrent infections are discussed, as well as the results of several studies using rapid detection kits for the virus.

VDTs

As the use of video display terminals (VDTs) has expanded, questions have been raised as to whether working at a VDT affects the risk of adverse pregnancy outcome. A particular focus for these questions has been the very low frequency (VLF) magnetic field produced by a VDT's horizontal deflection coil. VDTs also produce VLF electric fields, extremely low frequency (ELF) electric and magnetic fields, and static electric fields, Ten studies of pregnancy outcome in VDT operators have been conducted in six countries, and with one exception, none has concluded that magnetic fields from VDTs may predispose pregnant operators to spontaneous abortion or congenital malformation. The epidemiologic studies conducted thus far do not provide a basis for concluding that VDT work and adverse pregnancy outcome are associated. Studies of fetal resorptions and malformations in rodents exposed to VLF magnetic fields have produced inconsistent findings. Two laboratories in Sweden that studied mice have reported positive results, one laboratory showing field-related malformations (but not resorptions) and the other showing field-related resorptions (but not malformations). Two Canadian laboratories have reported negative results in rats and mice. Studies of avian embryos have also yielded inconsistent results, but lacking a maternal-fetal placental interface, avian embryos are a questionable model for evaluating human reproductive risks. Finally, VLF electric and magnetic fields measured at the operator position are in compliance with field strength standards and guidelines that have been established around the world.

Effects of cocaine on the human fetus: a review of clinical studies.

The abuse of cocaine in this country has reached epidemic proportions and has generated great concern for the effects of the drug on the fetus when used during pregnancy. Although educational campaigns cite adverse fetal effects as a deterrent to using the drug, there are limited data on which to base a true risk assessment. This paper reviews the published studies of pregnancy outcome in cocaine-abusing mothers, with special focus on structural malformations and other neonatal risks.

Toward a better understanding of the "advanced maternal age" factor.

Women over the age of 30-35 are presumed to encounter more adverse pregnancy outcomes because of their reduced reproductive efficiency. In the vast majority of studies of advanced maternal age and pregnancy outcome, however, researchers have failed to control for important contextual differences surrounding the pregnancy and childbirth experiences of younger and older women. These contextual differences can account for a considerable portion of the differential results mistakenly ascribed to reproductive age. In this article are reviewed research findings that identify three such hidden factors: older women's increasing likelihood of chronic diseases that adversely affect pregnancy outcome; the altered medical management of middle-aged women's pregnancies and labors, with resultant iatrogenically caused complications; and demographic characteristics suggesting that midlife pregnancy in the past has been associated with poverty or subfertility and today is associated with healthy middle-class postponers.