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Objective: To test the hypothesis that high circulating concen-trations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS). Study Design: This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hyperten-sion and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endo-glin (sEng) in maternal serum were measured at 21–32 weeks of gestation. Results: Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5% vs. 20.9%, p =0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% CI 1.08–4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during midpregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL vs. 7,000 pg/mL, p =0.01). Conclusions: Preterm preeclampsia and gestational hypertension, charac-terized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during midpregnancy were substantially higher in women whose infants developed RDS.

Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B(12) (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case-control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmö and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P=0.01 and P=0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l(-1); P=0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.

Please cite this paper as: Lynch A, Murphy J, Gibbs R, Levine R, Giclas P, Salmon J, Holers V. The interrelationship of complement-activation fragments and angiogenesis-related factors in early pregnancy and their association with pre-eclampsia. BJOG 2010; 117:456–462. Objective To determine the interrelationships during early pregnancy of complement-activation fragments Bb, C3a and sC5b-9, and angiogenesis-related factors placental growth factor (PiGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), and their associations with pre-eclampsia. Design Prospective cohort study. Setting Denver complement study (June 2005–June 2008). Population A total of 668 pregnant women with singleton gestations, recruited between 10 and 15 weeks of gestation. Methods Using univariable and multivariable logistic regression analysis, concentrations of complement-activation fragments and angiogenesis-related factors were compared between 10 and 15 weeks of gestation in women who subsequently did or did not develop pre-eclampsia. Interrelationships between these variables were tested using the non-parametric Spearman rank correlation coefficient. Main outcome measure Pre-eclampsia. The association of complement-activation fragments and angiogenesis-related factors with obesity was also examined. Results The mean (±SD) levels of complement Bb in early pregnancy among women who did and did not develop pre-eclampsia were 0.84 (±0.26) μg/ml and 0.69 (±0.2) μg/ml, respectively (P = 0.001). Concentrations of PiGF were significantly (P = 0.01) lower (31 ± 12 pg/ml) in early pregnancy in the pre-eclamptic group of women, as compared with the normotensive group (39 ± 32 pg/ml). The adjusted odds ratio (AOR) of Bb and PiGF were 2.1 (CI = 1.4–3.1, P

Standard sperm parameters have a limited power for prediction of the chance of natural conception. Recent studies have indicated that the sperm chromatin structure assay (SCSA) DNA fragmentation index (DFI), a measure for the fraction of sperms with DNA damage, is associated with fertility in vivo. The aim of this study was to evaluate the value of this parameter for prediction of infertility. One hundred and twenty-seven men from infertile couples with no known female factor and 137 men with proven fertility were included. Semen analysis was performed as recommended by the WHO. DFI was assessed using SCSA. Logistic binary regression was used to compute the odds ratios (OR) for infertility. As compared with men with a DFI 20% (OR 8.4; 95% CI: 3.0-23). In men with normal standard semen parameters (sperm concentration, motility and morphology) the OR for infertility was increased with DFI >20% (OR 5.1, 95% CI: 1.2-23), whereas if one of the standard semen parameters was abnormal, the OR for infertility was increased already at DFI above 10% (OR 16, 95% CI: 4.2-60). We conclude that SCSA DFI adds to the value of semen analysis in prediction of the chance of natural conception.

Preeclampsia (PE) is diagnosed using clinical criteria and in atypical cases the diagnosis may be inaccurate as there are no specific tests to confirm or exclude PE. This study sought to evaluate the utility of angiogenic biomarkers, sFlt1, sEng and PlGF to distinguish patients with gestational thrombocytopenia and immune thrombocytopenic purpura (ITP) from patients with thrombocytopenia resulting from the HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, a complication of severe PE.Serum was collected and the angiogenic biomarkers of patients with ITP and gestational thrombocytopenia (N = 9) were compared to patients with HELLP (N = 11) and PE (N = 11). Circulating levels of these angiogenic biomarkers were also compared by gestational age to 1564 randomly selected normotensive women from the Calcium for Preeclampsia Prevention study.Patients with non-HELLP thrombocytopenia had lower sFlt1 (7.3 +/- 3.8 ng/ml vs. 15.5 +/- 5 ng/ml, P0.001), lower sEng (8.7 +/- 3.6 vs. 34 +/- 17, P0.001) and higher PlGF (484 +/- 412 vs. 66.3 +/- 44, P = 0.003) than patients with HELLP syndrome. Angiogenic factor abnormalities in patients with PE were similar to patients with HELLP syndrome, suggesting a common pathogenesis. Patients with non-HELLP thrombocytopenia had angiogenic profiles similar to normotensive controls, whereas patients with HELLP syndrome had levels higher than the 90th percentile for sFlt1 and sEng and lower than the 10th percentile for PlGF.Angiogenic biomarkers may be useful in excluding conditions that mimic PE.

Concentrations of soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) increase in maternal blood with the approach of clinical preeclampsia. Although alterations in these circulating antiangiogenic factors herald the signs and symptoms of preeclampsia, in vitro studies suggest they may also play a role in regulating early placental cytotrophoblast functions. Early pregnancy changes in sFlt1 and sEng may thus identify women destined to develop preeclampsia. We performed a nested case-control study of 39 women who developed preeclampsia and 147 contemporaneous normotensive controls each with serum collected in the first (11 to 13 weeks of gestation) and second (17 to 20 weeks) trimesters. Whereas levels of sFlt1 and sEng at 11 to 13 weeks were similar between cases and controls (sFlt1: 3.5±0.3 ng/mL versus 3.0±0.1, P =0.14; sEng 6.9±0.3 ng/mL versus 6.6±0.2, P =0.37, respectively), at 17 to 20 weeks both were elevated in the women destined to develop preeclampsia (sFlt1: 4.1±0.5 ng/mL versus 3.1±0.1, P P delta { d} ] between second and first trimester levels: d sFlt1, 0.63±0.91 ng/mL in preterm PE versus 0.05±0.15 in controls; d sEng, 0.73±0.77 ng/mL versus −1.32±0.18, P

Alterations in circulating soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and placental growth factor (PlGF), a proangiogenic protein, appear to be involved in the pathogenesis of preeclampsia. Since soluble endoglin, another antiangiogenic protein, acts together with sFlt1 to induce a severe preeclampsia-like syndrome in pregnant rats, we examined whether it is associated with preeclampsia in women.We performed a nested case-control study of healthy nulliparous women within the Calcium for Preeclampsia Prevention trial. The study included all 72 women who had preterm preeclampsia (37 weeks), as well as 480 randomly selected women--120 women with preeclampsia at term (ator =37 weeks), 120 women with gestational hypertension, 120 normotensive women who delivered infants who were small for gestational age, and 120 normotensive controls who delivered infants who were not small for gestational age.Circulating soluble endoglin levels increased markedly beginning 2 to 3 months before the onset of preeclampsia. After the onset of clinical disease, the mean serum level in women with preterm preeclampsia was 46.4 ng per milliliter, as compared with 9.8 ng per milliliter in controls (P0.001). The mean serum level in women with preeclampsia at term was 31.0 ng per milliliter, as compared with 13.3 ng per milliliter in controls (P0.001). Beginning at 17 weeks through 20 weeks of gestation, soluble endoglin levels were significantly higher in women in whom preterm preeclampsia later developed than in controls (10.2 ng per milliliter vs. 5.8 ng per milliliter, P0.001), and at 25 through 28 weeks of gestation, the levels were significantly higher in women in whom term preeclampsia developed than in controls (8.5 ng per milliliter vs. 5.9 ng per milliliter, P0.001). An increased level of soluble endoglin was usually accompanied by an increased ratio of sFlt1:PlGF. The risk of preeclampsia was greatest among women in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone.Rising circulating levels of soluble endoglin and ratios of sFlt1:PlGF herald the onset of preeclampsia.

Abnormalities in circulating angiogenic factors have been reported in diseases of abnormal placentation, such as preeclampsia and intrauterine growth restriction. Our objective was to determine whether circulating angiogenic factors are altered in another placental vascular disease, abruptio placentae.In a nested case-control study of nulliparous pregnancies, we examined levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal control subjects. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum angiogenic factors were compared within 3 gestational age windows: early (20 weeks or less), middle (21-32 weeks), and late (33 weeks or more) pregnancy.During early pregnancy women who developed placental abruption had lower PlGF and higher sFlt-1 concentrations and higher sFlt-1/PlGF ratios than women with normal pregnancies. In mid-pregnancy these differences became greater, reaching statistical significance for PlGF concentration (431 versus 654 pg/mL, P.01) and the sFlt-1/PlGF ratio (25.3 versus 2.5, P.01). When the women with placental abruption were subdivided into those who did (n=10) and those who did not (n=21) develop preeclampsia or gestational hypertension, significant alterations in angiogenic factors were noted only in women who later developed hypertension in pregnancy. Among these women, PlGF concentrations were decreased in mid-pregnancy (160 versus 723 pg/mL, P.001), and the mid-pregnancy sFlt-1/PlGF ratio was increased (70.1 versus 2.3, P=.001).Serum levels of the proangiogenic factor PlGF were decreased, and those of the antiangiogenic ratio sFlt-1/PlGF were increased in nulliparous women who subsequently developed hypertension and placental abruption.

Objective The purpose of this study was to determine whether serum fms-like tyrosine kinase 1 (sFlt1) concentration during preeclampsia were associated with mid trimester blood pressure, other maternal characteristics, or pregnancy outcomes. Study design We performed a nested case-control study within the Calcium for Preeclampsia Prevention study cohort. Each woman with preeclampsia (case) was matched to 1 normotensive control. A total of 120 pairs of women was chosen randomly. Serum concentrations of sFlt1 and placental growth factor were measured throughout pregnancy, but before labor and delivery. We focused on data from 40 women with blood specimens that were obtained after the onset of preeclampsia. After logarithmic transformation, we determined mean serum sFlt1 concentrations of all control specimens within gestational age windows during which case specimens had been obtained after the onset of preeclampsia. Within each of these gestational age windows, we computed an upper bound for the control specimens equal to 2 standard deviations above the mean. After the onset of preeclampsia, 16 women with log-transformed serum sFlt1 values greater than the upper bound of the control specimens were considered to have high preeclampsia serum sFlt1 levels. The 24 other women were considered to have low preeclampsia serum sFlt1 levels. Results Women with high or low concentrations of serum sFlt1 during preeclampsia (arithmetic means, 5746 and 3007 pg/mL, respectively) had similar pregnancy outcomes and similar maternal characteristics, except for blood pressure at Calcium for Preeclampsia Prevention study enrollment. Systolic and diastolic blood pressure at enrollment at 13 to 21 weeks of gestation were significantly higher in the 24 women with low serum sFlt1 concentrations during preeclampsia (systolic blood pressure, 114 mm Hg; diastolic blood pressure, 65 mm Hg) than in the 16 women who had preeclampsia at high serum sFlt1 concentrations (systolic blood pressure, 106 mm Hg; diastolic blood pressure, 59 mm Hg). Blood pressure at 13 to 21 weeks among the women with high preeclampsia serum sFlt1 concentrations was identical to the blood pressure among normotensive control subjects. In linear regression analyses of data from all 40 women, both systolic ( P P = .014) blood pressures at enrollment were correlated negatively with natural logarithm serum sFlt1 concentration after onset of preeclampsia. Conclusion Women with higher mid trimester blood pressure had preeclampsia at lower serum sFlt1 concentrations. Because higher blood pressure may reflect occult endothelial damage, these observations may explain increased susceptibility to preeclampsia among women with pre-existing vascular disease.

Objective Women who are carrying a trisomy 13 fetus are more prone to develop preeclampsia. Excess circulating soluble fms-like tyrosine kinase-1 has been implicated recently in the pathogenesis of preeclampsia. Since the fms-like tyrosine kinase-1/soluble fms-like tyrosine kinase-1 gene is located on chromosome 13q12, we hypothesized that the extra copy of this gene in trisomy 13 may lead to excess circulating soluble fms-like tyrosine kinase-1, reduced free placental growth factor level, and increased soluble fms-like tyrosine kinase-1/placental growth factor ratio. This may then contribute to the increased risk of preeclampsia that has been observed in these patients. Our objective was to characterize the maternal circulating angiogenic proteins in trisomy 13 pregnancies. Study design Maternal serum samples of trisomy 13, 18, 21 and normal karyotype pregnancies were obtained from first and second trimester screening programs. We chose 17 cases of trisomy 13 that were matched for maternal age, freezer storage time, and parity with 85 normal karyotype control samples. Additionally, 20 cases of trisomy 18 and 17 cases of trisomy 21 were included. Cases and control samples were assayed for levels of soluble fms-like tyrosine kinase-1 and placental growth factor by enzyme-linked immunosorbent assay in a blinded fashion. Because of the skewed distributions of soluble fms-like tyrosine kinase-1 and placental growth factor, nonparametric analytic techniques were used, and the results are reported as median and ranges. Results In early pregnancy trisomy 13 cases and control samples, the median circulating soluble fms-like tyrosine kinase-1/placental growth factor ratios were 17.0 (range, 1.2-61.3) and 6.7 (range, 0.8-62.9), respectively (P = .003). The median soluble fms-like tyrosine kinase-1/placental growth factor ratios in trisomy 18 and 21 were 4.8 (range, 0.9-53.9) and 5.1 (range, 1.0-18.1), which were not significantly different than the control samples. Furthermore, the differences between trisomy 13 and control samples were more pronounced in the second trimester specimens than in the specimens from the first trimester. Conclusion These data suggest that alterations in circulating angiogenic factors may be involved intimately in the pathogenesis of preeclampsia in trisomy 13. A larger clinical study that measures these factors longitudinally and correlates them with pregnancy outcomes is needed to further establish the link between trisomy 13, altered angiogenic factors, and preeclampsia.

Objective To evaluate levels of 24-hour urine insulin excretion before the onset of pre-eclampsia and gestational hypertension. Design Nested case–control study within the Calcium for Preeclampsia Prevention (CPEP) study cohort. Setting Five university medical centres in the United States. Sample Cases had developed pre-eclampsia (n= 70) or gestational hypertension (n= 142) in the absence of gestational diabetes. Controls (n= 429) had remained normotensive without gestational diabetes. Methods Subjects were required to have had an adequate baseline 24-hour urine collection prior to CPEP enrolment at 13–21 weeks. Controls were matched to cases by enrolment site and specimen storage time, without regard to gestational age or CPEP treatment. Adjusted mean 24-hour urine insulin excretion was, however, calculated using analysis of covariance, with adjustment models for pre-eclampsia considering body mass index, race and smoking status; and for gestational hypertension, gestational age at specimen collection, height, body mass index and smoking. Urine insulin was measured by radio-immunoassay. Main outcome measures Twenty-four-hour urine insulin excretion. Results Adjusted 24-hour urine insulin excretion at baseline (mean 17 weeks of gestation) was greater in women who developed pre-eclampsia than in normotensive controls (mean [SE]: 15.6 [1.5] vs 13.1 [1.2] × 103μIU/24 hour, P= 0.06), but not in women who developed gestational hypertension (14.7 [0.9] vs 15.0 [0.6] × 103μIU/24 hour, P= 0.79, in cases vs controls). Among women who developed pre-eclampsia, adjusted urine insulin excretion was greater than controls only in women with mild pre-eclampsia and not in severe pre-eclampsia (mild pre-eclampsia vs controls: 17.3 [2.0] vs 13.7 [1.6] × 103μIU/24 hour, P= 0.04; severe pre-eclampsia vs controls: 12.3 [2.2] vs 11.5 [1.2], P= 0.69). Conclusion The data suggest that early hyperinsulinaemia, a marker of insulin resistance, may predispose to mild pre-eclampsia.

Seasonal, daylight-dependent variation in human spermatozoa counts, with lowest values during summer, has been suggested. To test this hypothesis, we performed a longitudinal study of semen quality and reproductive hormone levels in Norwegian men living north and south of the Arctic Circle. An ejaculate and a serum specimen were obtained both in summer and in winter from 92 volunteers in Tromsoe (69° north latitude) and 112 in Oslo (60° north latitude). Semen analyses were performed, and serum was assayed for FSH and inhibin B. The median spermatozoa concentration in Tromsoe after adjustment for abstinence period length was 49 10 6 /ml in summer and 54 10 6 /ml in winter. Corresponding values for Oslo were 59 10 6 /ml and 54 10 6 /ml. The seasonal differences in spermatozoa concentration were not statistically significant, nor were significant differences observed in median total spermatozoa count, semen volume, percentage progressive motile spermatozoa, or FSH. In Tromsoe, but not Oslo, inhibin B concentration was slightly, but significantly (P 0.02) higher in winter than summer (229 ng/liter vs. 223 ng/liter). The length of the daylight period may have a slight impact on hormonal markers of spermatogenesis but does not cause substantial changes in spermatozoa numbers and motility. (J Clin Endocrinol Metab 89: 4397– 4402, 2004)

The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role.We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia.During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant.Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia.

An imbalance of pro- and antiangiogenic factors may lead to preeclampsia (PE). In this prospective nested case-control study, we investigated whether first trimester serum levels of placental growth factor (PlGF), a potent angiogenic factor, and its soluble inhibitor, soluble fms-like tyrosine kinase 1 (sFlt1), distinguished women who developed PE (n = 40) from those who developed gestational hypertension (n = 40), delivered a small for gestational age (SGA) newborn (n = 40), or completed a full term normal pregnancy (n = 80). Compared with controls, serum PlGF levels were lower among women who developed PE (23 +/- 24 pg/ml vs. 63 +/- 145 pg/ml; P0.01) or gestational hypertension (27 +/- 19 pg/ml; P = 0.03), or who delivered a SGA newborn (21 +/- 16 pg/ml; P0.01). In contrast, serum sFlt1 levels did not markedly differ between the groups: PE, 1048 +/- 657 pg/ml; gestational hypertension, 942 +/- 437 pg/ml; SGA newborns, 1011 +/- 479 pg/ml; and normal controls, 973 +/- 490 pg/ml. Multivariable analysis adjusting for potential confounders and serum sFlt1 levels demonstrated a 3.7-fold (95% confidence interval, 1.2-12.5) increase in risk for PE for every log unit decrease in serum levels of PlGF compared with controls. Analyses for gestational hypertension and SGA were not significant. Examined in tertiles, the risk for PE was increased 28.7-fold (95% confidence interval, 2.3-351.0) in the third (12 pg/ml) compared with the first (39 pg/ml) PlGF tertile. First trimester serum levels of PlGF and sFlt1 may identify women at high risk for PE.

Objective The purpose of the study was to evaluate the effects of smokeless tobacco use during pregnancy. Study design We examined birth weight, preterm delivery, and preeclampsia in women who were delivered of singleton, live-born infants in Sweden from 1999 through 2000. For each snuff user, 10 cigarette smokers and 10 tobacco nonusers were selected randomly. Results After exclusions, 789 snuff users, 11,240 smokers, and 11,495 nonusers remained. Compared with nonusers, adjusted mean birth weight was reduced in snuff users by 39 g (95% CI, 6-72 g) and in smokers by 190 g (95% CI, 178-202 g). Preterm delivery was increased in snuff users and smokers (adjusted odds ratios, 1.98 [95% CI, 1.46-2.68] and 1.57 [95% CI, 1.38-1.80], respectively). Preeclampsia was reduced in smokers (adjusted odds ratio, 0.63; 95% CI, 0.53-0.75) but increased in snuff users (adjusted odds ratio, 1.58; 95% CI, 1.09-2.27). Conclusion Snuff use was associated with increased risk of preterm delivery and preeclampsia. Snuff does not appear to be a safe alternative to cigarettes during pregnancy.

A prior birth confers a strong protective effect against preeclampsia, whereas a prior abortion confers a weaker protective effect. Parous women who change partners in a subsequent pregnancy appear to lose the protective effect of a prior birth. This study (Calcium for Preeclampsia Prevention Trial, 1992-1995) examines whether nulliparous women with a prior abortion who change partners also lose the protective effect of the prior pregnancy. A cohort analysis was conducted among participants in this large clinical trial of calcium supplementation to prevent preeclampsia. Subjects were nulliparous, had one prior pregnancy or less, delivered after 20 weeks' gestation, and were interviewed at 5-21 weeks about prior pregnancies and paternity. Women without a history of abortion served as the reference group in logistic regression analyses. Women with a history of abortion who conceived again with the same partner had nearly half the risk of preeclampsia (adjusted odds ratio = 0.54, 95 percent confidence interval: 0.31, 0.97). In contrast, women with an abortion history who conceived with a new partner had the same risk of preeclampsia as women without a history of abortion (adjusted odds ratio = 1.03, 95 percent confidence interval: 0.72, 1.47). Thus, the protective effect of a prior abortion operated only among women who conceived again with the same partner. An immune-based etiologic mechanism is proposed, whereby prolonged exposure to fetal antigens from a previous pregnancy protects against preeclampsia in a subsequent pregnancy with the same father.

Demographic indicators such as fertility rates and infant mortality rates are often measured in census surveys by interviewing mothers to obtain their pregnancy histories and child deaths. The validity of such surveys depends upon accurate recall of histories, truthful reporting of events and understanding of the questions posed. To measure the reliability of maternal reporting, two census surveys conducted in a rural Egyptian population were compared. Women between 15 and 55 years of age residing in 20 villages were asked their histories of live births, stillbirths and child deaths. An identical set of questions was posed 2 years later. Twice-monthly home visits were conducted in the intervening 2-year interval to identify accurately any new births, stillbirths and deaths occurring in the population. The maternal reports from the first census were combined with the prospectively identified births, stillbirths and deaths and compared with the maternal reports from the second census. For 1502 women, the discrepancies in the total number of births, stillbirths and child deaths reported between the two surveys were 0.6%, 4% and 0.6% respectively. However, when the consistency of responses was analysed, the proportion of women with discordant responses was 10%, 6% and 7% for the same measures. These results suggest that, despite the large number of births and deaths that women may experience in developing countries, maternal interviews provide reliable responses that can be used to estimate mortality and fertility rates in settings where vital records are incomplete or unreliable.

Objective: This study was undertaken to address the role of oxidative stress in preeclampsia. Study Design: We measured urinary 8,12- iso -iPF 2 α -VI, a chemically stable, free-radical catalyzed product, in a case control study of severe preeclampsia nested within the trial of Calcium for Preeclampsia Prevention. Cases included 29 women who developed severe preeclampsia and from whom urine had been obtained 10 to 20 weeks before the diagnosis of preeclampsia, 3 to 9 weeks before, and 1 day before through delivery. Controls did not develop hypertension or proteinuria and were matched to cases by center, gestational age at each of 3 corresponding urine collections, and date of enrollment. Results: Urinary 8,12- iso -iPF 2 α -VI did not differ significantly between cases and controls before or at diagnosis of preeclampsia, nor did it vary with gestational age. Conclusions: These results call into question the importance of oxidative stress in the disease and the biochemical rationale for clinical trials of antioxidants to prevent and treat preeclampsia. (Am J Obstet Gynecol 2001;185:572-8.)

Whether the consumption of caffeine during pregnancy increases the risk of spontaneous abortion is controversial. Prior studies have determined caffeine consumption by questionnaire. We used a biologic marker, such as serum paraxanthine, a metabolite of caffeine, to measure the dose of caffeine.In a nested case-control study, we measured serum paraxanthine in 591 women who had spontaneous abortions at less than 140 days' gestation and in 2558 matched women from the same clinic who gave birth to live infants at 28 weeks' gestation or later and who had serum drawn on the same day of gestation as the women who had abortions. The women were enrolled in the Collaborative Perinatal Project during the period from 1959 to 1966, and serum paraxanthine was measured over 30 years later.A total of 487 women who had spontaneous abortions (82 percent) and 2087 controls (82 percent) had quantifiable serum paraxanthine concentrations. However, the mean serum paraxanthine concentration was higher in the women who had spontaneous abortions than in the controls (752 vs. 583 ng per milliliter, P0.001). The odds ratio for spontaneous abortion was not significantly elevated in the women who had serum paraxanthine concentrations of 1845 ng per milliliter or lower, corresponding to the 95th percentile of the matched women. However, the adjusted odds ratio for spontaneous abortion among women with serum paraxanthine concentrations higher than 1845 ng per milliliter, as compared with women who had concentrations below 50 ng per milliliter, was 1.9 (95 percent confidence interval, 1.2 to 2.8).Only extremely high serum paraxanthine concentrations are associated with spontaneous abortion. This suggests that moderate consumption of caffeine is unlikely to increase the risk of spontaneous abortion.

Objective: To determine the effect of maternal calcium supplementation during pregnancy on fetal bone mineralization. Methods: Healthy mothers with early ultrasound confirmation of dates and singleton pregnancies were enrolled in a double-masked study and randomized before 22 weeks’ gestation to 2 g/day of elemental calcium or placebo until delivery. Maternal dietary intake at randomization and at 32–33 weeks’ gestation was recorded with 24-hour dietary recalls. Dual-energy x-ray absorptiometry measurements of the whole body and lumbar spine of the neonates were performed before hospital discharge. Results: The infants of 256 women (128 per group) had dual-energy x-ray absorptiometry measurements during the first week of life. There were no significant differences between treatment groups in gestational age, birth weight, or length of the infants, or in the total-body or lumbar spine bone mineral content. However, when bone mineral content was analyzed by treatment group within quintiles of maternal dietary calcium intake, total body bone mineral content (mean ± standard error of the mean) was significantly greater in infants born to calcium-supplemented mothers (64.1 ± 3.2 versus 55.7 ± 2.7 g in the placebo group) in the lowest quintile of dietary calcium intake (less than 600 mg/day). The effect of calcium supplementation remained significant after adjustment for maternal age and maternal body mass index and after normalization for skeletal area and body length of the infant. Conclusion: Maternal calcium supplementation of up to 2 g/day during the second and third trimesters can increase fetal bone mineralization in women with low dietary calcium intake. However, calcium supplementation in pregnant women with adequate dietary calcium intake is unlikely to result in major improvement in fetal bone mineralization.

Objective: The study's aim was to determine whether healthy nulliparous women with abnormal glucose tolerance during pregnancy are at increased risk for development of pregnancy-associated hypertension or preeclampsia. Study Design: A series of 4589 healthy nulliparous women from 5 university centers were evaluated prospectively to determine whether calcium supplementation would prevent preeclampsia. Pregnancy-associated hypertension was a diastolic blood pressure ≥90 mm Hg on 2 occasions 4 hours to 1 week apart. Pregnancy-associated proteinuria was proteinuria ≥1+ by dipstick testing on 2 occasions 4 hours to 1 week apart, proteinuria ≥300 mg/24 h, a protein to creatinine ratio of ≥0.35, or a single dipstick measurement of ≥2+. Preeclampsia was defined as pregnancy-associated hypertension and pregnancy-associated proteinuria documented within 7 days of each other. Normal glucose tolerance was a plasma glucose level Results: Calcium supplementation did not prevent pregnancy-associated hypertension or preeclampsia. Of 3689 women with complete glucose testing data, 227 (6%) had abnormal glucose tolerance and 81 (2%) had gestational diabetes mellitus. Compared with women with normal glucose tolerance, women with abnormal glucose tolerance were significantly older, had greater body mass index, and were more likely to be white non-Hispanic, to smoke, and to have private medical insurance. Among women with gestational diabetes mellitus, after adjustment for clinical center the relative risks of preeclampsia and of all hypertensive disorders were increased (relative risk 1.67, 95% confidence interval 0.92-3.05, and relative risk 1.54, 95% confidence interval 1.28-2.11, respectively). Risk ratios were not substantially reduced after further adjustment for race and body mass index (odds ratios 1.41 and 1.48, respectively). Even within the normal range, multivariate analysis demonstrated that the level of plasma glucose 1 hour after a 50-g oral glucose challenge was an important predictor of preeclampsia. Conclusion: Even within the normal range, the level of plasma glucose 1 hour after a 50-g oral glucose challenge was positively correlated with the likelihood of preeclampsia. Women with gestational diabetes mellitus were at increased risk for hypertensive disorders during pregnancy after adjustment for clinical center, race, and body mass index, although the increase was not statistically significant. These findings suggest that insulin resistance may play a role in the pathogenesis of the hypertensive disorders of pregnancy. (Am J Obstet Gynecol 1998;179:1032-7.)

Background— An imbalance in circulating angiogenic factors plays a central role in the pathogenesis of preeclampsia. Methods and Results— We prospectively studied 616 women who were evaluated for suspected preeclampsia. We measured plasma levels of antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) at presentation and examined for an association between the sFlt1/PlGF ratio and subsequent adverse maternal and perinatal outcomes within 2 weeks. The median sFlt1/PlGF ratio at presentation was elevated in participants who experienced any adverse outcome compared with those who did not (47.0 [25th–75th percentile, 15.5–112.2] versus 10.8 [25th–75th percentile, 4.1–28.6]; P P P =0.001). Delivery occurred within 2 weeks of presentation in 86.0% of women with an sFlt1/PlGF ratio ≥85 compared with 15.8% of women with an sFlt1/PlGF ratio Conclusions— In women with suspected preeclampsia presenting at

A nested case-control study was undertaken to identify the determinants of lung cancer mortality in a cohort of 8147 foundry men among whom an excess of lung cancer deaths was previously observed. The present study consisted of all lung cancer deaths (N = 220) that occurred within this cohort between 1950 and 1989. both living and dead controls, matched on race and attained age, were selected in the ratio of 10:1 (N = 2200) by means of the incidence density sampling procedure. All cases and two controls per case, randomly selected from each case's 10 controls, were included in a smoking history survey. Basic smoking history information was obtained for about 71% of these study subjects. For the purpose of this study, formaldehyde exposure levels were categorized as high, medium, low, and none. Airborne silica exposure was categorized only as high, medium, and low levels, because all foundry workers were known to be exposed to silica. Conditional logistic regression analyses indicated that cigarette smoking was a strong predictor of lung cancer mortality in this cohort. Neither exposure to formaldehyde nor silica exposure level, nor employment in any of the six major work areas within the foundry, showed an association with lung cancer.

Preeclampsia is a clinical syndrome defined as the new onset of hypertension and proteinuria during the second half of pregnancy.1 It afflicts 3% to 5% of pregnancies and is a leading cause of maternal mortality, especially in developing countries.2,3 Because the only known remedy is delivery of the placenta, in developed countries preeclampsia is an important cause of premature delivery, usually medically indicated for the benefit of the mother. This results in infant morbidity and substantial healthcare expenditure.4 Despite the considerable morbidity and mortality, the cause of preeclampsia has remained enigmatic. Both hypertension and proteinuria implicate the endothelium as the target of the disease. The hypertension of preeclampsia is characterized by peripheral vasoconstriction and decreased arterial compliance.5,6 The proteinuria of preeclampsia is associated with a pathognomonic renal lesion known as glomerular endotheliosis, in which the endothelial cells of the glomerulus swell and endothelial fenestrations are lost.7,8 Podocyturia has been recently associated with preeclampsia during clinical disease9; however, whether this is the cause or effect of proteinuria is unknown. The glomerular filtration rate is decreased compared with normotensive pregnant women; in rare cases, acute renal failure may develop. Preeclampsia is a systemic vascular disorder that may also affect the liver and the brain in the mothers. When the liver is involved, women may present with abdominal pain, nausea, vomiting, and elevated liver enzymes. Pathological examination of the liver reveals periportal and sinusoidal fibrin deposition and, in more extreme cases, hemorrhage and necrosis.10 The severe preeclampsia variant HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurs in ≈20% of women with severe preeclampsia,11 and is named not only for the liver involvement, but also for the disorder of the coagulation system that develops.12 Approximately 20% of …

This study utilized a randomized, double-blind, within subject, crossover design to examine the effect of Reiki and LeShan healing in combination on iatrogenic pain experienced after unilateral operative extraction of the lower third molar. Two separate operations were performed on 21 patients with bilateral, asymptomatic, impacted lower third molar teeth. The patients were randomly assigned to the treatment or control condition prior to the first operation. For the second operation, patients crossed over to the opposite condition - i.e. those subjects who were in the treatment group for the first operation became control group subjects for the second operation, and those subjects who were in the control group for the first operation became treatment group subjects for the second operation. All pre-operative and postoperative conditions were identical for the treatment and control groups for both operations, with the exception that the treatment group received Reiki and LeShan healing postoperatively. The patients assessed their pain intensity using a 100 mm visual analogue scale for postoperative hours 3 through 9, and pain relief using a 5 point scale for hours 4 through 9. A statistically significant difference was found between the treatment and control groups in both the level of pain intensity and degree of pain relief experienced for postoperative hours 4 through 9.

Preeclampsia is a systemic syndrome that occurs in 3 to 5% of pregnant women and classically manifests as new-onset hypertension and proteinuria after 20 weeks of gestation. Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. The only known cure is delivery of the placenta. Recent discoveries, however, have led to important advances in understanding the pathogenesis of the condition. Placental antiangiogenic factors are upregulated and disrupt the maternal endothelium. This change in the normal angiogenic balance toward an antiangiogenic state can result in hypertension, proteinuria, glomerular endotheliosis, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and cerebral edema—the clinical signs of preeclampsia and eclampsia. The regulation of these antiangiogenic factors in the placenta is unknown. The recent discoveries of upregulated antiangiogenic factors provide promise for future testing to predict and diagnose preeclampsia as well as therapeutic targets for amelioration of the clinical disease.

In this Case Study, Hladunewich and colleagues describe the case of a woman with a twin pregnancy with a single fetal demise who presented earlier than 20 weeks' gestation with severe nephrotic syndrome, hypertension and renal insufficiency. The authors describe how aberrant levels of anti-angiogenic and angiogenic factors helped confirm the diagnosis of pre-eclampsia in this complex renal presentation, allowing for the rapid discontinuation of unnecessary immunosuppressive agents and the avoidance of the potential risks inherent with diagnostic renal biopsy. Background. An otherwise healthy 31-year-old gravida 2 para 1 woman with a spontaneous dichorionic, diamniotic twin pregnancy presented with hypertension, nephrotic syndrome and renal insufficiency at 19 weeks' gestation. Fetal ultrasound revealed severe intrauterine growth restriction of one fetus and measurement of serum anti-angiogenic and angiogenic factors were consistent with a profound anti-angiogenic state. After one fetus died and the placenta became increasingly echogenic, the patient improved clinically, and weekly ultrasound assessments of the intact co-twin from 22 weeks onwards demonstrated symmetrical fetal growth along the 10th centile. Repeat serum angiogenic factors at 24 weeks' gestation revealed considerable improvement of the anti-angiogenic state and paralleled resolution of the clinical syndrome. Investigations. Physical examination, laboratory evaluations including full blood count, liver function tests, electrolytes, renal function tests, screening for glomerular-based disease, 24-h urine collection for total protein, analysis of serum anti-angiogenic and angiogenic factors, fetal ultrasonography and placental Doppler examination. Diagnosis. Spontaneous resolution of early-onset pre-eclampsia after single fetal demise in a twin pregnancy. Management. Labetalol was given to treat hypertension and furosemide was given as needed for edema. The patient was closely followed up throughout pregnancy in a combined nephrology/obstetrics outpatient clinic.

Preeclampsia, a disorder with prominent cardiovascular manifestations, is a cause of maternal, fetal, and infant morbidity and mortality. Chocolate contains compounds that may promote cardiovascular health. A recent study found chocolate consumption during pregnancy, and, particularly, increasing cord serum concentration of theobromine (the primary methylxanthine alkaloid in chocolate), to be associated with reduced occurrence of preeclampsia.We studied 2769 women who comprised the control group from a case-control study of caffeine metabolites and spontaneous abortion nested within the Collaborative Perinatal Project. These women were pregnant between 1959 and 1966, with liveborn infants of at least 28 weeks' gestation. Serum was drawn at20 weeks and26 weeks' gestation, and assayed for theobromine by high-performance liquid chromatography. Odds ratios (ORs) for preeclampsia were estimated using logistic regression, and adjusted for age, education, prepregnant weight, race, parity, smoking, and gestation at blood draw.Preeclampsia occurred in 68 (2.9%) of 2105 eligible women. Adjusted ORs for preeclampsia were near unity across most third-trimester theobromine concentrations. Adjusted ORs for preeclampsia according to theobromine concentration in serum at20 weeks' gestation increased with increases in concentration, although estimates were imprecise.This study does not support the previous finding that chocolate consumption is associated with a reduced occurrence of preeclampsia. Unmeasured confounding or reverse causation may account for the positive association between early-pregnancy theobromine and preeclampsia.

Objective Our goal was to determine whether obstetric outcomes and serum angiogenic factors are altered in women with gestational proteinuria without hypertension. Study Design We performed a nested case-control study of 108 women with gestational proteinuria and compared them with 1564 randomly selected women with normotension without proteinuria during pregnancy (control subjects) and with 319 women who experienced preeclampsia. Results Women with gestational proteinuria had greater body-mass index and higher blood pressure at study enrollment. Adverse obstetric outcomes were infrequent. Levels of free placental growth factor were lower than control levels beginning early in gestation. Compared with gestational-age matched control subjects, free placental growth factor was reduced beginning 6-8 weeks before proteinuria. Although soluble fms-like tyrosine kinase 1 and soluble endoglin concentrations were elevated 1-2 weeks before proteinuria, these elevations were modest and transient. After the onset of proteinuria, angiogenic factor levels generally did not differ significantly from control levels. Conclusion Gestational proteinuria in healthy nulliparous women appears to be a mild variant of preeclampsia.

Objective Our objective was to investigate whether serum concentrations of a novel anti-angiogenic factor, soluble endoglin (sEng), could predict placental abruption. Methods In a nested case–control study of nulliparous pregnancies, we examined levels of sEng in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal controls. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum sEng was compared within three gestational age intervals: early- (

Accumulating evidence suggests that an imbalance between pro-angiogenic (i.e., vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)) and anti-angiogenic factors (i.e., soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1)) is involved in the pathophysiology of preeclampsia (PE). Endoglin is a protein that regulates the pro-angiogenic effects of transforming growth factor beta, and its soluble form has recently been implicated in the pathophysiology of PE. The objective of this study was to determine if changes in maternal plasma concentration of these angiogenic and anti-angiogenic factors differ prior to development of disease among patients with normal pregnancies and those destined to develop PE (preterm and term) or to deliver a small for gestational age (SGA) neonate.This longitudinal nested case-control study included 144 singleton pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered appropriate for gestational age (AGA) neonates (n = 46); (2) patients who delivered an SGA neonate but did not develop PE (n = 56); and (3) patients who developed PE (n = 42). Longitudinal samples were collected at each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. Plasma concentrations of soluble endoglin (s-Eng), sVEGFR-1, and PlGF were determined by specific and sensitive ELISA.(1) Patients destined to deliver an SGA neonate had higher plasma concentrations of s-Eng throughout gestation than those with normal pregnancies; (2) patients destined to develop preterm PE and term PE had significantly higher concentrations of s-Eng than those with normal pregnancies at 23 and 30 weeks, respectively (for preterm PE: p0.036 and for term PE: p = 0.002); (3) patients destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma concentrations of PlGF than those with a normal pregnancy throughout gestation, and the maternal plasma concentration of this analyte became detectable later among patients with pregnancy complications, compared to normal pregnant women; (4) there were no significant differences in the plasma concentrations of sVEGFR-1 between patients destined to deliver an SGA neonate and those with normal pregnancies; (5) patients destined to develop preterm and term PE had a significantly higher plasma concentration of sVEGFR-1 at 26 and 29 weeks of gestation than controls (p = 0.009 and p = 0.0199, respectively); and (6) there was no significant difference in the increment of sVEGFR-1 between control patients and those who delivered an SGA neonate (p = 0.147 at 25 weeks and p = 0.8285 at 40 weeks).(1) Changes in the maternal plasma concentration of s-Eng, sVEGFR-1, and PlGF precede the clinical presentation of PE, but only changes in s-Eng and PlGF precede the delivery of an SGA neonate; and (2) differences in the profile of angiogenic and anti-angiogenic response to intrauterine insults may determine whether a patient will deliver an SGA neonate, develop PE, or both.

A retrospective cohort mortality study was conducted among 8147 men and 627 women employed in a gray iron foundry for at least 6 months between 1950 and 1979. More than 1700 deaths occurred during a 35-year period of observation. Standardized mortality ratios (SMRs) for all causes were close to expected values based on the US general population as the standard. The mortality of nonwhite men was significantly increased for lung cancer (SMR 132) and ischemic heart disease (SMR 126). Other moderate, but nonsignificant excesses were noted among nonwhite men for cancers of the stomach, pancreas, and prostate, for diabetes mellitus and pulmonary emphysema, and among white men for cancers of the lung and stomach, gastric and duodenal ulcers, pulmonary emphysema, and suicide. Small mortality increases were observed in both racial groups for cerebrovascular disease. The lack of a trend with time since hire and duration of foundry employment suggests that lung cancer mortality may not be associated with exposure to the foundry environment. Utilizing indirect measures of smoking, it appears that virtually all excess lung cancer deaths among whites and at least some of the excess among nonwhites could be explained by smoking habits. Similarly, smoking may have been responsible for the mortality excesses from emphysema, cerebrovascular diseases, and ischemic heart disease.

A deterministic mathematical model has been developed for quantitative reconstruction of historical exposure. The model takes into account the causal variables actually responsible for changes in exposure and the interdependence between mean exposures in consecutive time periods. The effects of causal variables are described by step functions. In contrast, statistical modeling, a popular alternative strategy, often employs ad hoc exploratory variables, presumes independence among exposure levels, and invokes linearity or curvilinearity. Changes in exposure-modifying variables used in the deterministic model are identified from plant records. Available industrial hygiene sampling data are employed to estimate model parameters by the method of weighted least squares. The resulting general solution permits reconstruction of past exposure levels for the entire time period of interest, e.g., in a retrospective epidemiologic study. The method is illustrated by using formaldehyde exposure data from the coremakin...

Reliance on self-reported smoking status among pregnant women can result in exposure misclassification. We used data from the Calcium for Preeclampsia Prevention trial, a randomized study of nulliparous women conducted from 1992 to 1995, to characterize tobacco exposure misclassification among women who reported at study enrollment that they had quit smoking. Urinary cotinine concentration was used to validate quit status, and factors associated with exposure misclassification and the effects of misclassification on associations between smoking and pregnancy outcomes were evaluated using logistic regression. Of 4,289 women enrolled, 508 were self-reported smokers and 771 were self-reported quitters. Of 737 self-reported quitters with a valid cotinine measurement, 21.6% had evidence of active smoking and were reclassified as smokers. Women who reported having quit smoking during pregnancy were more likely to be reclassified than women who reported quitting before pregnancy (p

The purpose of this study was to compare neonatal outcomes of pregnancies with preeclampsia or gestational hypertension with those of normotensive pregnancies that delivered at 35, 36, or 37 weeks of gestation separately.Secondary analysis of neonatal outcomes by week of delivery between 35 and 37 weeks 6 days of gestation to 4293 nulliparous women who were enrolled in a multicenter National Institute for Child Health and Human Development study. Outcomes included the percentage of neonatal intensive care unit admission, duration of neonatal hospitalization, and neonatal complications.As compared with normotensive pregnancies, hypertensive pregnancies that delivered at 35 and 36 weeks of gestation had higher rates of small for gestational age births (17.9% vs 1.7% [P.05] and 33.3% vs 12.2% [P.01], respectively) and neonatal intensive care unit admission (57.1% vs 34.5% [P.05] and 33.3% vs 10.7% [P.001]). The rate of neonatal intensive care unit admission (25.6% vs 8.7%; P.001) and duration of neonatal stay (3.9 vs 2.0 days; P.001) were greater in hypertensive pregnancies that delivered at 37 weeks of gestation. These differences were observed largely in women whose condition required labor induction, regardless of the severity of the hypertensive disease.Pregnancies with preeclampsia or gestational hypertension that delivered between 35 and 37 weeks of gestation had higher rates of neonatal intensive care unit admission, small for gestational age, and longer neonatal stay than normotensive pregnancies, regardless of the severity of the hypertensive disease.

Objective: To determine the stability of immunoglobulin E levels in obstetric sera. Methods: AlaSTAT R and AlaTOP R (Diagnostic Products) were used to assay total and specific IgE levels in obstetric sera collected in Memphis, TN and Portland, OR. The samples were collected from the Collaborative Perinatal Project (CPP) between 1959 and 1965 and stored at −20°C. The assay results were compared with IgE levels found in sera collected at the same locations for the Calcium for Pre-eclampsia Prevention Study (CPEP) and stored since 1992 at −70°C. The samples were also assayed for cockroach (CR) and mouse urine specific IgE using the AlaSTAT R assay (Diagnostic Products). Results: Total IgE and specific IgE to CR and mouse urine were detectable in older and recent samples. The median total IgE for the recent and older Portland samples was 26 IU/ml and 65 IU/ml, respectively. The median total IgE was identical (40 IU/ml) in the recent and older Memphis samples. Conclusion: Long-term storage does not diminish the ability to measure serum IgE. Levels of IgE in sera stored 32–37 years were equal to or greater than levels in sera stored for 5 years.

Maternal smoking reduces the risk of pre-eclampsia, but has been reported to increase the risk of adverse outcomes related to the disease. We used data from the trial of Calcium for Pre-eclampsia Prevention (CPEP) to explore whether clinical manifestations of pre-eclampsia were altered by maternal smoking. CPEP was a randomised study of 4589 nulliparous women conducted in five US medical centres. Smoking history was obtained at study enrolment and women were monitored for the development of hypertension, proteinuria, and other medical complications. Among pre-eclamptic women (n=274), the risk of severe disease was not elevated in smokers (adjusted odds ratio 0.87 [95% confidence interval (CI) 0.30, 2.51]). Compared with non-smokers, gestational age (days, +/-SE) at onset of pre-eclampsia was not reduced in smokers (264.8 +/- 1.5, and 268.2 +/- 5.5, respectively, P=0.48). The smoking-attributable deficit in birthweight was not increased in pre-eclamptic women compared with normotensive women (97 g [95% CI -49, 244] and 185 g [95% CI 141, 229] respectively). In conclusion, among women who developed pre-eclampsia, smoking during pregnancy was not associated with disease severity. We found no evidence that pre-eclampsia and smoking act synergistically to restrict fetal growth.

Gestational diabetes mellitus has been associated with adverse maternal and infant outcomes, including preeclampsia and fetal macrosomia. Although cigarette smoking has been associated with increased insulin resistance, its effect on gestational diabetes mellitus risk is uncertain. The authors evaluated the effects of smoking on glucose tolerance in a cohort of pregnant women who participated in the Calcium for Preeclampsia Prevention trial, a randomized study of nulliparous women conducted in five US medical centers from 1992 to 1995. Results of screening and diagnostic testing for gestational diabetes mellitus were analyzed. For 3,774 of the 4,589 women enrolled, plasma glucose concentration 1 hour after a 50-g oral glucose challenge and complete information on pregnancy outcome were available; for 3,602 of the women, gestational diabetes mellitus status was known. Adjusted mean 1-hour plasma glucose concentration (mg/dl) was elevated in women who smoked at study enrollment (112.6, 95% confidence interval: 110.0, 115.3) compared with women who had never smoked (108.3, 95% confidence interval: 106.7, 109.8; p < 0.01). Women who smoked were at increased risk of gestational diabetes mellitus when criteria proposed by the National Diabetes Data Group were used (adjusted odds ratio = 1.9, 95% confidence interval: 1.0, 3.6). These findings support an association between smoking and gestational diabetes mellitus. diabetes, gestational; glucose tolerance test; pregnancy; smoking

The purpose was to determine whether preeclampsia (PE) is caused by microfragments of syncytial trophoblast shed into the maternal circulation that stimulate an exaggerated inflammatory response.A nested case control study was performed within the Calcium for Preeclampsia Prevention trial cohort of healthy nulliparous women. Each preeclampsia case was matched to 1 normotensive control. One hundred twenty pairs were randomly chosen for analysis of serum cell-free fetal DNA (cffDNA), a marker of placental debris, and C-reactive protein (CRP), a marker of inflammation, in all 658 specimens obtained before labor.At 29 to 41 weeks of gestation, cffDNA concentrations were significantly higher after preeclampsia than before (219 vs 112 genome equivalents [GE]/mL, P.001). Before preeclampsia, cffDNA in cases exceeded controls at 17 to 28 weeks (36 vs 16 GE/mL, P.001), but at 29 to 41 weeks, only within 3 weeks before preeclampsia (176 vs 75 GE/mL, P.001). CRP serum concentrations were neither associated with cffDNA nor elevated before preeclampsia.Preeclampsia is accompanied by a 2-stage elevation of fetal DNA, but not by elevation of CRP. Elevated cffDNA at 17 to 28 weeks may be due to placental necrosis and apoptosis. Subsequent elevations may reflect impaired DNA elimination. The 2-stage elevation suggests the possibility of measurement of fetal DNA both to screen for preeclampsia and to indicate impending clinical disease.

Altered angiogenesis and insulin resistance, which are intimately related at a molecular level, characterize preeclampsia. To test if an epidemiological interaction exists between these two alterations, we performed a nested case-control study of 28 women who developed preeclampsia and 57 contemporaneous controls. Serum samples at 12 weeks of gestation were measured for sex hormone binding globulin (SHBG; low levels correlate with insulin resistance) and placental growth factor (PlGF; a proangiogenic molecule). Compared with controls, women who developed preeclampsia had lower serum levels of SHBG (208±116 versus 256±101 nmol/L, P =0.05) and PlGF (16±14 versus 67±150 pg/mL, P 175 mg/dL), women with low levels of SHBG and PlGF had a 25.5-fold increased risk of developing preeclampsia ( P =0.10), compared with 1.8 ( P =0.38) among women with high levels of SHBG and low levels of PlGF. Formal testing for interaction (PlGF×SHBG) was significant ( P =0.02). In a model with 3 (n−1) interaction terms (high PlGF and high SHBG, reference), the risk for developing preeclampsia was as follows: low PlGF and low SHBG, OR 15.1, 95% CI 1.7 to 134.9; high PlGF and low SHBG, OR 4.1, 95% CI 0.45 to 38.2; low PlGF and high SHBG, OR 8.7, 95% CI 1.2 to 60.3. Altered angiogenesis and insulin resistance are additive insults that lead to preeclampsia.

Objective: Our purpose was to determine whether smoking before pregnancy reduces the risk of gestational hypertension or preeclampsia. Study Design: The trial of Calcium for Preeclampsia Prevention (CPEP) was a randomized study of 4589 nulliparous women conducted in 5 US medical centers during the years 1992 through 1995. Women were classified into 4 exposure groups by smoking history obtained at study enrollment (13-21 weeks' gestation): (1) never smoked, (2) smoked but quit before the last menstrual period (LMP), (3) smoked but quit after LMP but before enrollment, and (4) smoked and still smoking at enrollment. Results: After adjustments were made for maternal age, race, body mass index, type of health insurance, and clinical center, women smoking at enrollment had a reduced risk of hypertension (relative risk=0.8; 95% CI, 0.6-0.9). Women who quit smoking before the LMP did not have reduced risk (relative risk=1.1; 95% CI, 0.9-1.3). Results were similar for gestational hypertension and preeclampsia examined separately. Conclusion: Women who smoke but quit before becoming pregnant do not have a reduced risk for gestational hypertension or preeclampsia. (Am J Obstet Gynecol 2002;186:1035-40.)

Objective: Ethnic differences in birth outcomes are well established, but it is not clear whether differences in nutrition may partly explain unaccounted differences in birth outcomes. Our purpose was to evaluate the relationship of nutrition to ethnic differences in birth outcomes. Study Design: This was a multicenter, prospective study of 4589 healthy nulliparous women who were enrolled in the Calcium for Preeclampsia Prevention trial conducted from 1992 to 1995. Main outcome measures were birth weight, gestational age at delivery, preterm birth, and small for gestational age birth after the data were controlled for maternal characteristics and intake of total calories, protein, carbohydrate, fat, and 13 vitamin and mineral constituents that were obtained from a 24-hour recall at 13 to 21 weeks' gestation. Results: Black and non-Hispanic white women differed significantly in birth outcomes, with odds ratios of 2.06 (95% confidence interval, 1.48-2.86) for small for gestational age and 1.38 (95% confidence interval, 0.98-1.95) for preterm birth, after adjustment for maternal characteristics. These odds ratios were hardly changed by the further adjustment for all nutritional variables, even though there were substantial nutritional differences between black and white women. Differences in birth outcomes between Hispanic and non-Hispanic white women were small. Hispanic women who spoke only Spanish were better nourished than those Hispanic women who spoke English, but this had only a modest effect on birth outcomes. Conclusion: Nutritional variation among women in the United States does not appear to have a significant role in the explanation of ethnic differences in birth outcomes. (Am J Obstet Gynecol 2001;185:660-7.)

This study examined the incidence of and risk factors for recurrent and newly developed hypertensive disorders in the second pregnancy. We analysed data on 1641 women who had both the first and second pregnancies in the Collaborative Perinatal Project, a large prospective cohort study at 12 hospitals in the US. Nineteen per cent [95% CI 14%, 24%] of women who had gestational hypertension in the first pregnancy, 32% [95% CI 17%, 48%] of those with pre-eclampsia and 46% [95% CI 32%, 60%] of patients with gestational hypertension or pre-eclampsia superimposed on chronic hypertension, had recurrent hypertensive disorders in the second pregnancy. Risk factors for recurrence included history of chronic hypertension and thromboembolism, early onset of hypertension in the first pregnancy or persistent hypertension after 5 weeks postpartum and high baseline blood pressure in the second pregnancy. Women with a normotensive first pregnancy but a severe small-for-gestational-age birth had twice the risk of developing hypertension in the second pregnancy (RR = 2.1, 95% CI, 1.1, 4.0). In summary, hypertensive disorders have a 20--50% recurrence rate in the second pregnancy. The earlier the onset of hypertension in the first pregnancy, the higher the overall recurrence rate. Intrauterine growth restriction of the first birth is an independent risk factor for hypertension in the second pregnancy.

In large, prospective studies of pregnancy conducted in the 1960s, women reported very accurately whether or not they smoked. However, in the 1990s, pregnant women who smoke are often pressured to reduce or quit smoking, and the incentive to misreport may be greater than in the past. To assess the accuracy of reported smoking, the authors compared self-reported smoking with cotinine in the serum and/or urine of 105 women who participated in the Calcium for Pre-eclampsia Prevention pilot study in 1992. Cotinine confirmed the report of 84.6% of women who reported smoking and 94.5% of women who denied smoking. These fractions are virtually identical to those obtained in a pregnancy cohort from the 1960s. The authors conclude that in the setting of two obstetrical research studies not specifically focused on smoking, the accuracy of self-reported cigarette smoking did not change substantially from the 1960s to the 1990s.

Objective: The objective of this analysis was to prospectively determine the effects of nutrient intakes on the incidences of preeclampsia and pregnancy-associated hypertension among women enrolled in the Calcium for Preeclampsia Prevention study. Study Design: This was a prospective observational cohort study of women in a randomized clinical trial that included women seeking prenatal care at university medical centers and affiliated clinics and hospitals in 5 US communities. A total of 4589 nulliparous women were recruited between 13 and 21 weeks' gestation. Preeclampsia and pregnancy-associated hypertension were the main outcome measures. Results: Preeclampsia was noted in 326 (7.6%) of the 4314 women with known pregnancy outcomes followed up until ≥20 weeks' gestation, and pregnancy-associated hypertension was noted in 747 (17.3%). As previously reported, there was no significant difference in these outcomes between cohorts randomly assigned to supplementation with calcium or placebo. By means of logistic regression a baseline risk model was constructed for preeclampsia and pregnancy-associated hypertension. After adjustment for treatment and clinical site, body mass index >26 kg/m 2 and race were significantly associated with an increased risk of preeclampsia. Body mass index ≥35 kg/m 2 , race, and never smoking were significantly associated with an increased risk of pregnancy-associated hypertension. After adjustment for baseline risks, none of the 28 nutritional factors analyzed were significantly related to either preeclampsia or pregnancy-associated hypertension. Conclusion: We found no evidence in this study for a significant association of hypertensive disorders of pregnancy with any of the 23 nutrients measured. (Am J Obstet Gynecol 2001;184:643-51.)