In utero exposure to steroid contraceptives and outcome of pregnancy.

A cohort study of women who used steroid contraceptives during pregnancy was conducted in Chiang Mai, northern Thailand, between 1984 and 1987. There were 1,573 pregnancies in which the fetus was exposed to the injectable contraceptive Depo-Provera (The Upjohn Company, Kalamazoo, Michigan) (830 accidental pregnancies and 743 infants conceived before the mother started use of Depo-Provera), 601 accidental pregnancies in women who were using oral contraceptives, and 2,578 planned pregnancies with no steroid exposures (controls). Subjects were followed up for interview, and medical records were traced for birth weight. Women using Depo-Provera had more risk factors for adverse pregnancy outcomes than did the other groups. The adjusted odds ratios for low birth weight were increased for accidental pregnancies with fetal exposure to Depo-Provera (odds ratio (OR) = 1.5, 95% confidence interval (Cl) 1.2-1.9) or oral contraceptives (OR = 1.5, 95% Cl 1.2-2.0). The higher risk of low birth weight among infants exposed in utero to Depo-Provera or oral contraceptives is due in part to self-selection for adverse outcomes among women with unplanned pregnancies. However, among accidental pregnancies with Depo-Provera, the risk of low birth weight was significantly increased when conception was estimated to have occurred within 4 weeks of injection. The odds ratios were 1.9 (95% Cl 1.4-3.2) for injection-to-conception intervals of less than or equal to 4 weeks, 1.5 (95% Cl 0.9-2.3) for intervals of 5-8 weeks, and 1.2 (95% Cl 0.7-1.9) for intervals of greater than or equal to 9 weeks. This trend was highly significant. Thus, the authors conclude that early, high-dose in utero exposures to Depo-Provera may affect fetal growth.     

In utero pesticide exposure and childhood morbidity

In humans, immune development begins early in embryonic life and continues throughout the early postnatal period. Although a number of pesticides have been observed to induce developmental immunotoxicity in mice, few human studies have examined the long term effects of in utero pesticide exposure on childhood morbidity. Empirical evidence suggests that the vulnerable period for toxic insults to the developing immune system extends from early gestation to adolescence in humans and animals. Using data from the Ontario Farm Family Health Study, we examined the relationship between farm couple exposures to pesticides during pregnancy and subsequent health outcomes in their offspring, including: persistent cough or bronchitis, asthma, and allergies or hayfever. No strong associations between pesticide exposures during pregnancy and persistent cough or bronchitis, or asthma were found. There was suggestive evidence that allergies and hayfever appeared to be more common in offspring, especially male offspring, exposed to certain specific pesticides during the period of pregnancy. Nevertheless, given the indirect indicators of pesticide exposure used in this study, and the scarcity of human studies on in utero exposure to pesticides and the development of allergies and other child health outcomes, these findings serve primarily to generate hypotheses for future research.     

Environmental tobacco smoke exposure during infancy.

We collected information about household smoking habits from 518 mothers when they made their first well child visit with a 6 to 8-week old infant. A urine sample was also collected from the infant, the cotinine concentration measured, and the measurement correlated with data provided by the mother. Eight percent of the infant urine cotinine values fell at or above 10 micrograms/L in the 305 households where no smoking was reported. Corresponding rates were 44 percent in the 96 households where a member other than the mother smoked, 91 percent in the 43 households where only the mother smoked, and 96 percent in the 74 households where both the mother and another household member smoked. In households where the mother smoked, infant urine cotinine levels were lower in the summer, and higher when the infant was breast-fed. A screening question about family smoking habits in conjunction with well child care could effectively define a group of infants exposed to environmental tobacco smoke and thus be at greater risk for respiratory diseases.     

In utero exposure to famine and subsequent fertility: The Dutch Famine Birth Cohort Study.

OBJECTIVES: We hypothesized that if prenatal caloric restriction due to nutritional deprivation had affected development of the organs responsible for producing and regulating female reproductive hormones, a woman's fertility would be impaired. METHODS: Women born in Amsterdam from August 1, 1944, through April 15, 1946, a period encompassing a severe 5-month famine, were identified (n = 700; 85% response rate). Date of birth and vital status of all offspring were ascertained by home interview between 1987 and 1991. Famine exposure was inferred from the mother's date of birth. RESULTS: Of the study participants, 74 (10.6%) had no children. The remainder reported 1334 off-spring (1294 singletons, 20 pairs of twins), of whom 14 were stillborn and 22 died in the first 7 days of life. There was no detectable effect of famine exposure on age at menarche, the proportion having no children, age at first delivery, or family size. An excess of perinatal deaths occurred among offspring of famine-exposed women, particularly those exposed in their third trimester. CONCLUSIONS: Acute famine exposure in utero appears to have no adverse consequences for a woman's fertility. The excess perinatal mortality in the second generation is unexplained and should be confirmed by other studies.     

In utero exposure to background concentrations of DDT and cognitive functioning among preschoolers

p,p'-DDT (bis[p-chlorophenyl]-1,1,1-trichloroethane) is a persistent organochlorine compound that has been used worldwide as an insecticide. The authors evaluated the association of cord serum levels of DDT and its metabolite, 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE), with neurodevelopment at age 4 years. Two birth cohorts in Ribera d'Ebre and Menorca (Spain) were recruited between 1997 and 1999 (n = 475). Infants were assessed at age 4 years by using the McCarthy Scales of Children's Abilities. Organochlorine compounds were measured in cord serum. Children's diet and parental sociodemographic information was obtained through questionnaire. Results showed that DDT cord serum concentration at birth was inversely associated with verbal, memory, quantitative, and perceptual-performance skills at age 4 years. Children whose DDT concentrations in cord serum were >0.20 ng/ml had mean decreases of 7.86 (standard error, 3.21) points in the verbal scale and 10.86 (standard error, 4.33) points in the memory scale when compared with children whose concentrations were <0.05 ng/ml. These associations were stronger among girls. Prenatal exposure to background, low-level concentrations of DDT was associated with a decrease in preschoolers' cognitive skills. These results should be considered when evaluating the risk and benefits of spraying DDT during antimalaria and other disease-vector campaigns.     

邻苯二甲酸酯宫内暴露对子代小鼠致肥作用的研究

目的:研究围产期宫内暴露邻苯二甲酸酯(MEHP)对子代小鼠肥胖的程序化作用。方法:不同剂量MEHP(0.05、0.25、0.5mg/kg体重)灌胃处理孕鼠做为低中高剂量组,等体积橄榄油灌胃处理的孕鼠做为对照组。处理周期为孕鼠妊娠第12天直至新生鼠出生后第7天。每周监测仔鼠体重直至第8周,并检测8周龄仔鼠的肝重、脂肪垫质量、血脂和血糖水平。结果:3组剂量MEHP宫内暴露均引起新生仔鼠体重增加(P<0.001);成年后(8周龄)雌性仔鼠体重接近对照组,而低剂量组成年雄性仔鼠体重明显高于对照组(P<0.01),附睾和肾周脂肪垫质量明显增加(P<0.001和P<0.01),血清总胆固醇、甘油三酯和血糖水平明显上升(P<0.01、P<0.05、P<0.001)。中高剂量对成年雄性仔鼠的体重、体脂组成、血脂和血糖水平无明显影响。结论:MEHP可以增加子代雄鼠肥胖发生风险,它可能作为一种潜在的化学诱导因子诱发肥胖及相关疾病发生。     

In utero exposure to tobacco smoke,subsequent cardiometabolic risks,and metabolic syndrome among U.S. adolescents

Purpose

Maternal smoking during pregnancy increases risk of adverse pregnancy outcomes. However, little is known regarding in utero smoke exposure and offspring cardiometabolic risk. Thus, we examined the association between in utero smoke exposure and cardiometabolic risk factors and the metabolic syndrome (MetS) in adolescents.

In utero exposure to background levels of polychlorinated biphenyls and cognitive functioning among school-age children

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants. In utero exposure to background levels of PCBs has been associated with intellectual impairment among children in most, but not all, studies. The authors evaluated prenatal PCB exposure in relation to cognitive test (intelligence quotient (IQ)) scores on the Wechsler Intelligence Scale for Children at age 7 years. Pregnant women were recruited from 12 US study centers from 1959 to 1965, and their children were followed until age 7 years (the Collaborative Perinatal Project). Third trimester serum was analyzed for PCBs in 1997-1999 for 732 women selected at random and for an additional 162 women whose children had either a low or a high IQ score. The PCB-IQ association was examined in multivariate models. Among those in the lowest exposure category (<1.25 microg of PCB/liter of serum), the fully adjusted mean IQ score was 93.6 (standard error: 1.8); among those in the highest category (> or =5 microg of PCB/liter), the mean IQ was 97.6 (standard error: 1.2); and overall the increase in IQ per unit increase in PCB level (microg/liter) was 0.22 (95% confidence interval: -0.28, 0.71). In these data, in utero exposure to background levels of PCBs was not associated with lower IQ at age 7 years.     

In utero exposure to polychlorinated biphenyls and reduced neonatal physiological development from Guiyu, China

Primitive electronic-waste recycling resulted in serious pollution of polychlorinated biphenyls (PCBs) in the environment of Guiyu, China. We aimed to assess body burdens of PCBs and potential health risks for neonates. Umbilical cord blood (UCB) samples were collected from Guiyu, and the control area of Chaonan, China. PCBs in UCB were determined by gas chromatography coupled with mass spectrometry. The median ∑PCBs concentration was 338.56 ng g⁻¹ lipid in UCB samples from Guiyu, vs. 140.16 ng g⁻¹ lipid in samples from Chaonan. Mothers′ involvement in electronic-waste recycling activities and house used as family workshop were the significant factors that contributed to ∑PCBs level. Some individual PCB congeners were found to correlate with reduced neonatal height, weight, Apgar scores, gestational age, and body mass index (BMI). Difference of ∑PCBs level was found between normal birth and adverse birth outcomes. Neonates from Guiyu are exposed to high levels of PCBs; prenatal exposure to PCBs appears to influence neonatal health, but still needs further confirmation.     

In utero exposure to di-(2-ethylhexyl)phthalate and duration of human pregnancy

Di-(2-ethylhexyl)phthalate (DEHP), the most commonly used plasticizer in flexible polyvinylchloride formulations, is a ubiquitous environmental contaminant. To date, no information exists on the potential health hazards from exposure to DEHP and/or its main metabolite, mono-(2-ethylhexyl)phthalate (MEHP), in high-risk conditions, such as pregnancy and during the neonatal period. The aim of this study was to evaluate prenatal exposure to DEHP and/or MEHP and its possible biologic effects. We measured serum DEHP and MEHP concentrations in the cord blood of 84 consecutive newborns by high-performance liquid chromatography. Relationships between DEHP/MEHP and infant characteristics were tested using Fisher's exact test, unpaired t-tests, and univariate linear regression analyses, and significant differences on univariate analysis were evaluated using multiple logistic regression analysis. We found detectable cord blood DEHP and/or MEHP concentrations in 88.1% of the samples. Either DEHP or MEHP was present in 65 of 84 (77.4%) of the examined samples. Mean concentrations of DEHP and MEHP were 1.19 +/- 1.15 microg/mL [95% confidence interval (CI), 0.93-1.44, range = 0-4.71] and 0.52 +/- 0.61 microg/mL (95% CI, 0.39-0.66, range = 0-2.94), respectively. MEHP-positive newborns showed a significantly lower gestational age compared with MEHP-negative infants (p = 0.033). Logistic regression analysis results indicated a positive correlation between absence of MEHP in cord blood and gestational age at delivery (odds ratio = 1.50, 95% CI, 1.013-2.21; p = 0.043). These findings confirm that human exposure to DEHP can begin in utero and suggest that phthalate exposure is significantly associated with a shorter pregnancy duration.     

In utero exposure to the Korean War and its long-term effects on socioeconomic and health outcomes

Prenatal exposure to the disruptions caused by the Korean War (1950–1953) negatively affected the individual socioeconomic and health outcomes at older ages. The educational attainment, labor market performance, and other socioeconomic outcomes of the subjects of the 1951 birth cohort, who were in utero during the worst time of the war, were significantly lower in 1990 and in 2000. The results of difference-in-difference estimations suggest that the magnitude of the negative cohort effect is significantly larger for individuals who were more seriously traumatized by the war. Whereas the 1950 male birth cohort exhibited significantly higher disability and mortality rates at older age, the health outcomes of females are unaffected by the war. Different aspects of human capital (e.g., health and cognitive skills) were impaired by in utero exposure to the war, depending on the stage of pregnancy when the negative shocks were experienced.     

In utero pesticide exposure, maternal paraoxonase activity, and head circumference

Although the use of pesticides in inner-city homes of the United States is of considerable magnitude, little is known about the potentially adverse health effects of such exposure. Recent animal data suggest that exposure to pesticides during pregnancy and early life may impair growth and neurodevelopment in the offspring. To investigate the relationship among prenatal pesticide exposure, paraoxonase (PON1) polymorphisms and enzyme activity, and infant growth and neurodevelopment, we are conducting a prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City. In this report we evaluate the effects of pesticide exposure on birth weight, length, head circumference, and gestational age among 404 births between May 1998 and May 2002. Pesticide exposure was assessed by a prenatal questionnaire administered to the mothers during the early third trimester as well as by analysis of maternal urinary pentachlorophenol levels and maternal metabolites of chlorpyrifos and pyrethroids. Neither the questionnaire data nor the pesticide metabolite levels were associated with any of the fetal growth indices or gestational age. However, when the level of maternal PON1 activity was taken into account, maternal levels of chlorpyrifos above the limit of detection coupled with low maternal PON1 activity were associated with a significant but small reduction in head circumference. In addition, maternal PON1 levels alone, but not PON1 genetic polymorphisms, were associated with reduced head size. Because small head size has been found to be predictive of subsequent cognitive ability, these data suggest that chlorpyrifos may have a detrimental effect on fetal neurodevelopment among mothers who exhibit low PON1 activity.     

Effects of prenatal exposure to dioxin-like compounds on allergies and infections during infancy

Dioxin-like compounds are endocrine disruptors. The effects of prenatal exposure to environmental levels of dioxins on immune function during infancy have not been clarified, although dioxins induce immunosuppression in offspring of animals. Moreover, human studies have not assessed the effects of gender- or congener-specific differences. The purpose of this study was to investigate the association between dioxin levels in maternal blood and the risk of infection and allergies in infancy. We examined 364 mothers and their infants enrolled in a Hokkaido Study on Environment and Children's Health between 2002 and 2005 in Sapporo, Japan. Relevant information was collected from a baseline questionnaire during pregnancy, medical records at delivery, and a follow-up questionnaire when the child was 18 months of age that assessed development of allergies and infections in infancy. Dioxin-like compound levels in maternal blood were measured with high-resolution gas chromatography/high-resolution mass spectrometry. Relatively higher levels of polychlorinated dibenzofuran were associated with a significantly increased risk of otitis media, especially among male infants (odds ratio=2.5, 95% confidence interval=1.1–5.9). Relatively higher levels of 2,3,4,7,8-pentachlorodibenzofuran were also associated with a significantly increased risk of otitis media (odds ratio=5.3, 95% confidence interval=1.5–19). However, we observed a weak association between dioxin-like compound levels and allergic symptoms in infancy. At environmental levels, prenatal exposure to dioxin-like compounds may alter immune function and increase the risk of infections in infancy, especially among males. The compound 2,3,4,7,8-pentachlorodibenzofuran may be responsible for this.     

Monthly injectable steroid contraceptives and cervical carcinoma

The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives is a large multinational hospital-based case-control study of steroid contraceptives and gynecologic, hepatobiliary, and mammary neoplasms. Monthly injectable steroid contraceptives which contained the long-acting progestogen dihydroxyprogesterone acetofenide plus a shorter-acting estrogen (usually estradiol enanthate) were used by women in two of the countries (Chile and Mexico) from which data were collected. In preliminary analyses of data from Chile (1979-1983), a strong association was observed between use of these products and invasive cervical cancer. Therefore, three additional data sets from these two countries were analyzed in further detail for this report. Analyses of additional data from Chile on invasive cervical cancer (1983-1985) and cervical carcinoma in situ (1979-1986) and of data on invasive cervical cancer from Mexico (1979-1986) failed to confirm the initially observed association. The original finding was probably due to chance, but a causal interpretation cannot be confidently ruled out, and additional studies are warranted.     

In utero exposure to dioxins and polychlorinated biphenyls and its relations to thyroid function and growth hormone in newborns

The aim of this study is to examine the association between transplacental exposure to dioxins/polychlorinated biphenyls (PCBs) and thyroid and growth hormones in newborns. We recruited 118 pregnant women, between 25 and 34 years of age, at the obstetric clinic. Personal data collected included reproductive and medical histories and physical factors. Clinicians gathered placental and umbilical cord serum upon delivery and carefully scored the 118 newborns, making both structural and functional assessments. We analyzed placentas for 17 polychlorinated dibenzo-p-dioxins and dibenzofurans and 12 dioxin-like PCB congeners with the World Health Organization-defined toxic equivalent factors, and six indicator PCBs by high-resolution gas chromatography and high-resolution mass spectrometry. We analyzed thyroid and growth hormones from cord serum using radioimmunoassay. Insulin-like growth factor (IGF)-1, IGF-binding globulin-3, and thyroxine x thyroid-stimulating hormone (T4 x TSH) were significantly associated with increased placental weight and Quetelet index (in kilograms per square meter; correlation coefficient r = 0.2-0.3; p < 0.05). Multivariate analyses showed independently and significantly decreased free T4 (FT4) x TSH with increasing non-ortho PCBs (r = -0.2; p < 0.05). We suggest that significant FT4 feedback alterations to the hypothalamus result from in utero exposure to non-ortho PCBs. Considering the vast existence of bioaccumulated dioxins and PCBs and the resultant body burden in modern society, we suggest routine screening of both thyroid hormone levels and thyroid function in newborns.     

Menarche in women with high exposure to persistent organochlorine pollutants in utero and during childhood

In animal studies, exposure to persistent organochlorine pollutants (POPs) in utero and through mother's milk has been suggested to affect the onset of puberty. However, human studies are scarce and ambiguous. In the present study, information on age at menarche was collected from 545 women who had been brought up in a fishing village/family on the Swedish east coast, off the Baltic Sea, and therefore were assumed to have been exposed to POPs in utero, through breast feeding, and/or through dietary habits during their childhood. The average age at menarche for these women was compared to that of three referent groups: (a) 1252 women who also had been brought up in a fishing village/family, but on the Swedish west coast, where the fish had been considerably less contaminated; (b) 634 women from the east coast, but who had not grown up in a fishing village/family; and (c) 869 women from the west coast who had not grown up in a fishing village/family. Based on previous studies, all groups were regarded as having similar socioeconomic circumstances. Data were analyzed using analysis of variance (ANOVA). In an attempt to account for variations in environmental concentrations of POPs over time, all analyses were adjusted for year of birth. Exposed women were found to be slightly older at menarche than referent women from the same coastal area (mean age 13.0 vs 12.8 yr). No differences were found between the exposed women and the two other referent groups (mean age 13.0 yr in all groups).     

In utero exposure to environmental tobacco smoke potentiates adult responses to allergen in BALB/c mice

BACKGROUND: Fetal stress has been linked to adult atherosclerosis, obesity, and diabetes. Epidemiology studies have associated fetal exposure to maternal smoking and postnatal exposure to environmental tobacco smoke (ETS) with increased asthma risk. OBJECTIVE: We tested the hypothesis, in a mouse model of asthma, that in utero ETS exposure alters airway function and respiratory immune responses in adults. METHODS: Pregnant Balb/c mice were exposed daily to ETS or HEPA-filtered air (AIR). Offspring inhaled aerosolized ovalbumin (OVA) or saline in weeks 7-8. Regardless of whether they inhaled OVA or saline, mice were sensitized by OVA injections in weeks 11 and 13 followed by OVA aerosol challenge in weeks 14-15. At three time points, we assessed OVA-specific serum immunoglobins, bronchoalveolar lavage cells and cytokines, lung and nasal histopathology, and airway hyperresponsiveness (AHR). RESULTS: At 6 weeks, we found no significant differences between in utero ETS and AIR mice. At 10 weeks, following OVA aerosol, ETS mice displayed greater AHR than AIR mice (alpha = 0.05), unaccompanied by changes in histopathology, cytokine profile, or antibody levels. At 15 weeks, mice that had inhaled saline in weeks 7-8 developed airway inflammation: eosinophilia (alpha = 0.05), interleukin-5 (alpha = 0.05), and AHR (alpha = 0.05) were greater in ETS mice than in AIR mice. Mice that had inhaled OVA in weeks 7-8 demonstrated no airway inflammation after sensitization and challenge. CONCLUSION: In utero ETS exposure exacerbates subsequent adult responses to initial allergen exposure.     

Use of contraceptives prior to and after conception and exposure to other fetal hazards.

In a large prospective study, set up to determine whether reproductive outcomes are affected by prior contraceptive use, 34,344 women were recruited at their first antenatal visit and followed until pregnancy termination. This paper summarizes the study methods and describes the demographic differences between subjects who used various contraceptives shortly before conception, and those who experienced contraceptive failures. Thirty percent of the women had used oral contraceptives (OCs) during the 5 months prior to conception and 2.4% had continued using them after their LMP. IUDs had been used by 5.8% of women before conception and 1.1% after. If these rates are also true for the whole population of the U.S., they indicate that approximately 70,000 babies are born each year following pill-failures and 30,000 following failures of IUD's. Exposure to other fetal hazards was common, with 48% of pregnant women drinking alcohol, 28% smoking, and 15% receiving diagnostic X-rays. OC use was more common among smokers and drinkers, and OC failures were significantly associated with the use of anti-epileptics, aspirin, and with exposure to radiation.     

Alterations of the antibody response following in utero exposure to diethylstilbestrol.

The antibody response to SRBC and E. coli 0127 lipopolysaccharide were determined in offspring from mice exposed in utero to diethylstilbestrol. The antibody response to SRBC, a T-cell dependent antigen, was similar in control and exposed animals. In contrast, the LPS antibody response was suppressed in treated females and enhanced in treated males. These studies indicated that in utero exposure to DES alters the humoral immune system to T-independent antigens.