Gail Harger

Prospective evaluation of 618 pregnant women exposed to parvovirus B19: Risks and symptoms

Objective To assess the risk of maternal parvovirus B19 infection from exposure to various sources and the fetal morbidity of those infections. Methods We obtained demographic and occupational information about pregnant women exposed to sources of B19 and about the nature and duration of the exposures. We performed serologic testing 10–14 days after exposure using an indirect capture enzyme-linked immunosorbent assay. Women with immunoglobulin (Ig) M were examined with weekly ultrasound until 12 weeks after exposure, and the outcome of the pregnancy was ascertained from interviews with patients and their obstetricians. Logistic regression analysis was used to determine risk factors for maternal immunity and infection by B19. Results Of 618 pregnant women exposed, 307 (49.7%) were immune to B19, 259 remained susceptible after exposure, and 52 (16.7% of all susceptibles) contracted B19 infection. None of the 52 fetuses of infected women developed nonimmune hydrops, and there were no fetal deaths attributable to B19 in this group. The relative risk of maternal B19 infection was 2.8 if the source was a related child living in the household (95% confidence interval 1.7, 4.6; P < .001). No significant differences were found for maternal B19 infection in eight categories of maternal occupation. Maternal symptoms of polyarthralgia (46%), fever (19%), and nonspecific rash (38%) were significantly more common (P < .001) in IgM-positive patients than in noninfected women (4.1%, 2.8%, and 5.7%, respectively). Only 17 (33%) of the IgM-positive women were entirely asymptomatic. Conclusion The risk of maternal B19 infection in pregnancy could not be predicted by a gravidas occupation, but it was significantly higher when the source of exposure was her own child. The fetal risk of nonimmune hydrops after maternal B19 infection must be very low. As a consequence, exclusion of pregnant women from the workplace during endemic periods with seasonal clusters of cases is not justified. Weekly fetal ultrasound evaluation in these cases carried a low Yield.

Cigarette Smoke Exposure and Angiogenic Factors in Pregnancy and Preeclampsia

BACKGROUND Cigarette smoking during pregnancy is paradoxically associated with a reduced risk of developing preeclampsia. Both smoking and preeclampsia are associated with alterations in circulating angiogenic factors. The objective of this study was to investigate the relationship between cigarette smoking and the angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in pregnant women with and without preeclampsia. METHODS Plasma sFlt-1, PlGF, and cotinine were measured using enzyme-linked immunosorbent assay in 125 women with uncomplicated pregnancies (controls) and 58 women with preeclampsia. RESULTS In uncomplicated pregnancies, maternal sFlt-1 concentrations were lower in smokers compared to nonsmokers (779.6 (487.5-1,140.8) vs. 1,116.5 (793.6-1,905.2) pg/ml, P < 0.005). Preeclamptic women who smoked also demonstrated a trend toward lower concentrations of sFlt-1 compared to nonsmokers (3,423.0 (2,183.4-5,689.0) vs. 5,504.9 (3,418.0-6,361.3) pg/ml, P = 0.07). Maternal PlGF concentrations were higher in smokers with uncomplicated pregnancies (398.4 (165.2-621.7) vs. 191.4 (104.6-446.8) pg/ml); however, this was not a statistically significant difference (P = 0.07). PlGF concentrations were not different in preeclamptic smokers compared to nonsmokers. The sFlt/PlGF ratio was significantly lower in smokers with uncomplicated pregnancies, but not in smokers with preeclampsia compared to nonsmokers. CONCLUSIONS Cigarette smoking is associated with lower maternal sFlt-1 concentrations during pregnancy and preeclampsia. On the basis of these data, cigarette smoke exposure may decrease the risk of preeclampsia in part by moderating the anti-angiogenic phenotype observed in the syndrome.

S-Nitrosoalbumin–Mediated Relaxation Is Enhanced by Ascorbate and Copper: Effects in Pregnancy and Preeclampsia Plasma

S-nitrosoalbumin (SNO-Alb) is a major reservoir of releasable nitric oxide (NO) in plasma. In preeclampsia, a pregnancy-specific disorder associated with endothelial dysfunction, we previously found significant elevations in plasma SNO-Alb concentrations and decreased plasma ascorbate (Asc) levels. This increased SNO-Alb may result from low-plasma Asc if Asc, along with transition metals (eg, copper [Cu]) are necessary for release of NO from S-nitrosothiols. We propose that vasodilator effects of SNO-Alb, mediated by release of NO, are fully realized only when Asc/Cu availability is sufficient. Relaxation responses to SNO-Alb or the control reduced human serum albumin (SH-Alb), and responses to pooled plasma from normal or preeclamptic pregnancies were examined in isolated mouse arteries. Arteries preconstricted with phenylephrine were exposed to SNO-Alb or SH-Alb at physiologically relevant concentrations. When free Cu was added in excess (10 &mgr;mol/L), NO release was not dependent on Asc. However, when Cu was added at lower (physiological) levels, NO release was dependent on Asc. The addition of Asc and Cu to SNO-Alb stimulated vasodilatory responses in isolated arteries >90%, whereas no change in the SH-Alb (5%) response was observed. Preeclampsia plasma with higher levels of SNO-Alb caused arteries to relax 44.1±4.7%, whereas normal pregnancy plasma caused 11.9±4.2% relaxation (P=0.007). These data indicate that SNO-Alb alone or in plasma can act as a potent vasodilator, and that sufficient Asc/Cu promotes this action. We suggest that the higher circulating levels of SNO-Alb, in women with preeclampsia, reflect a deficiency in Asc/Cu-mediated release of NO from SNO-Alb.

Elevated asymmetric dimethylarginine concentrations precede clinical preeclampsia, but not pregnancies with small-for-gestational-age infants.

OBJECTIVE The purpose of this study was to investigate maternal plasma concentrations of asymmetric dimethylarginine (ADMA) in mid pregnancy and at the time of disease in women who experience preeclampsia, compared with women with uncomplicated pregnancies and women with small-for-gestational-age infants. STUDY DESIGN Plasma samples were collected at mid-pregnancy and at the time of delivery from 31 women with uncomplicated pregnancies, from 12 women with small-for-gestational-age infants, and from 15 women with preeclampsia. ADMA and L-arginine concentrations were measured using high-pressure liquid chromatography. RESULTS Maternal ADMA concentrations were elevated at mid pregnancy and remained elevated at delivery in women who later experienced preeclampsia (0.45 +/- 0.09 micromol/L) compared with women with uncomplicated pregnancies (0.34 +/- 0.08 micromol/L; P < .01) and with women with small-for-gestational-age infants (0.33 +/- 0.06 micromol/L; P < .01). CONCLUSION Maternal ADMA concentrations are higher in mid pregnancy in women who experience preeclampsia, compared with women with uncomplicated pregnancies and small-for-gestational-age infants. Elevated ADMA concentration before clinical onset of preeclampsia suggests a role of this nitric oxide synthase inhibitor in the pathophysiologic condition of preeclampsia.

Increased Myeloperoxidase in the Placenta and Circulation of Women With Preeclampsia

Myeloperoxidase (MPO) is a hemoprotein normally released from activated monocytes and neutrophils. Traditionally viewed as a microbicidal enzyme, MPO also induces low-density lipoprotein oxidation, activates metalloproteinases, and oxidatively consumes endothelium-derived NO. The elevated plasma MPO level is a risk factor for myocardial events in patients with coronary artery disease. Patients with preeclampsia display evidence of the inflammation and endothelial dysfunction associated with oxidative stress in the circulation, vasculature, and placenta. We hypothesized that MPO levels in the circulation and placental extracts from women with preeclampsia would be greater than levels in women with normal pregnancies. Placental extracts were prepared from placental villous biopsies from preeclamptic (n=27) and control (n=43) placentas. EDTA plasma samples were obtained from gestationally age-matched preeclamptic and control normal pregnancies. MPO concentrations were measured by ELISA. Immunohistochemistry was used to determine MPO localization in the placenta. MPO levels in placental extracts from women with preeclampsia were significantly higher than the levels in normal control subjects (546±62 versus 347±32 ng/mL; P=0.025). MPO was found in the floating villi and basal plate of placentas with a greater staining in the basal plates from preeclampsia placentas compared with normal pregnancies. Plasma MPO levels were 3-fold higher in patients with preeclampsia compared with normal control subjects (36.6±7.6 versus 11.0±3.1 ng/mL; P=0.003). In conclusion, MPO levels are significantly increased in the circulation and placenta of women with preeclampsia. We speculate that MPO may contribute to the oxidative damage reported in the endothelium and placenta of women with preeclampsia.

A Comparison of Circulating TNF Alpha in Obese and Lean Women With and Without Preeclampsia

Objectives: We hypothesized that TNF-α would be higher in obese versus lean women with preeclampsia. Methods: Total plasma TNF-α was measured in a nested case-control study of 123 nulliparous lean and obese control women and women with preeclampsia. Results: Adjusted mean TNF-α concentrations were 0.97 ± 0.11 (pg/mL ± SEM) in lean controls, 1.01 ± 0.10 in obese controls, 1.43 ± 0.11 in lean women with preeclampsia and 1.16 ± 0.11 in obese women with preeclampsia. Pregnancy outcome was the single predictor of TNF-α concentration in the general linear regression model (p = 0.04). Conclusion: TNF-α concentration was higher in preeclampsia compared with control subjects. Obesity was not associated with higher TNF-α concentrations in either preeclampsia or control subjects.

Barrier methods, length of preconception intercourse, and preeclampsia.

Background: The immune maladaptation theory suggests that tolerance to paternal antigens, resulting from prolonged exposure to sperm, protects against the development of preeclampsia. We tested whether barrier contraception and shorter sexual experience with the father of the pregnancy would increase the risk of preeclampsia. Methods: Of 2211 women delivering singleton births after enrollment in a pregnancy cohort study, 85 (3.8%) developed preeclampsia as defined by antepartum systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 plus proteinuria. At a mean of 10.2 weeks of gestation, all women in the cohort were asked about preconception contraception and timing of first sexual intercourse with the father of the pregnancy. Odds ratios (OR) comparing cases with preeclampsia to the rest of the cohort were adjusted for age, smoking, parity, and body mass index (BMI). Results: Women using barrier contraception prior to conception were no more likely than women not using barrier contraception to develop preeclampsia (adjusted OR 1.0, 95% CI 0.6–1.6). In unadjusted analyses, a prolonged time to conception was associated with preeclampsia (OR 1.9), however, after adjustment, the association was less prominent (OR 1.6) and after stratification by contraception method, the link between time to conception and preeclampsia was eliminated. Conclusion: These data do not support the immune maladaptation theory of preeclampsia.

Cigarette smoking during pregnancy: Chromosome translocations and phenotypic susceptibility in mothers and newborns

The effects of maternal cigarette smoking during pregnancy on structural chromosome aberrations were evaluated in peripheral lymphocytes from 239 mothers and their 241 newborns to determine whether smoking during pregnancy, genetic susceptibility, and race are associated with chromosome aberrations including translocations. Demographic information and cigarette smoking data were obtained via questionnaire. There were 119 Caucasian Americans, 118 African Americans, and 2 Asian Americans. The average maternal age was 24.9+/-5.8 (mean+/-S.D.) years. Thirty-nine percent of the Caucasian Americans and 45.4% of the African Americans self-reported that they were active smokers during the index pregnancy. The average number of cigarettes smoked per day was 2.65+/-5.75 and 1.37+/-3.17 for Caucasian and African American mothers, respectively. Peripheral blood lymphocytes from the mother and from the fetal side of the placenta were evaluated for chromosome aberrations by whole chromosome painting. Aliquots from the same blood samples were also used to assess genetic susceptibility with an in vitro bleomycin challenge assay. Spontaneous translocation frequencies in both maternal and newborn lymphocytes were not associated with cigarette smoking, socioeconomic status, or education. The absence of a smoking effect may be attributable to the low level of cigarette usage in these subjects. The average bleomycin-induced damage in the maternal and newborn populations was 0.37+/-0.27 and 0.15+/-0.14 breaks per cell, respectively, a difference that was highly significant (p<0.0001). In newborns there was a positive association between bleomycin sensitivity and the frequencies of aberrations as measured by chromosome painting: p</=0.0007 for dicentrics and fragments, and p</=0.002 for translocations. Caucasian American newborns demonstrated a significant association between dicentrics and fragments as measured by painting, and bleomycin sensitivity (p</=0.0002), but no such association was observed for African American newborns. The results of this study indicate that while differences were observed between African Americans and Caucasian Americans, race does not appear to be a major contributor to chromosome damage in newborns or their mothers. However, peripheral lymphocytes in pregnant women are more susceptible to genetic damage than peripheral lymphocytes in newborns.

Is There Evidence of Separate Inflammatory or Metabolic Forms of Preeclampsia

Objectives. To examine whether high insulin resistance versus high inflammation identifies subtypes of preeclampsia. Methods. A cytokine panel, glucose and insulin were measured in 37 preeclampsia plasma samples. Wilcoxon rank sum assessed median concentration of HOMAIR by pro-inflammatory:anti-inflammatory ratio. Regression stratifying by BMI and preterm birth was conducted. Results. There was no difference in median HOMAIR by the pro-inflammatory:anti-inflammatory ratio (p = 0.16). No subsets scatterplot clusters emerged. A positive correlation between HOMAlog and the ratio was significant (p = 0.04). Conclusions. No dichotomous subsets of preeclampsia by inflammation versus insulin resistance were detected. Contrary to our hypothesis, insulin resistance was higher as inflammation increased in preeclampsia.

Maternal plasma homocysteine concentrations are not increased in twin pregnancies.

Objective(s). We tested the hypothesis that twin pregnancies would lead to increased maternal plasma homocysteine. We further hypothesized that twin pregnancies complicated by preeclampsia would have increased plasma homocysteine compared to twin pregnancies without preeclampsia and normal singleton pregnancies. Methods. Plasma was collected at delivery from 127 nulliparous subjects: 57 women with normal singleton pregnancies, 39 women with singleton and preeclampsia, 17 women with uncomplicated twin pregnancies, and 14 women with twins and preeclampsia. Subjects were group matched for prepregnancy body mass index (BMI) and race. Plasma homocysteine was analyzed by high pressure liquid chromatography (HPLC) with fluorescence detection, and plasma folic acid was measured by radio immunoassay (RIA). Results. The mean plasma concentration of homocysteine was significantly increased in all women with preeclampsia (7.4 ± 2.9 µM) compared to all normal pregnant women (5.9 ± 2.1 µM, p = 0.002). However, homocysteine was not significantly increased in all women with twins (6.7 ± 2.1 µM) compared to all women with singleton pregnancies (6.5 ± 2.7 µM, p = 0.61). In addition, women with twins and preeclampsia did not have increased homocysteine (6.8 ± 2.1 µM) compared to women with twins and normal pregnancy (6.7 ± 2.1 µM, p = 0.72). As expected, because ofextra supplementation, plasma folic acid was significantly increased in women with twins (27.9 ± 11.6 ng/mL) compared to women with singleton pregnancies (20.8 ± 8.5 ng/mL, p = 0.0003). However, folic acid was not different between preeclamptics and controls (23.5 ± 10.8 vs. 21.9 ± 9.2 ng/mL respectively, p = 0.36). Lastly, there was a significant inverse correlation between homocysteine and folic acid among all the subjects (r2 = − 0.053, p< 0.01), and this correlation persisted in the women with singleton pregnancies (r2 = − 0.078, p< 0.01), but was lost in the twins (r2 = − 0.073, p = 0.14). Conclusions. With contemporary management including increased folic acid supplementation, plasma homocysteine is not increased in twin pregnancies with or without preeclampsia.