Digoxin antibody fragment, antigen binding (Fab), treatment of preeclampsia in women with endogenous digitalis-like factor: a secondary analysis of the DEEP Trial.

OBJECTIVE: Endogenous digitalis-like factors (EDLFs) are elevated in women with preeclampsia, and the use of an anti-digoxin antibody Fab (DIF) in women with preeclampsia who were remote from term reduced maternal blood pressure and preserved renal function. The objective was to determine whether DIF treatment in women with severe preeclampsia in association with positive EDLFs in maternal serum improves maternal-perinatal outcomes. STUDY DESIGN: This was a planned secondary analysis from a randomized, placebo-controlled, double-blind study of DIF in women with severe preeclampsia with positive EDLF status that was managed expectantly between 23 weeks 5 days and 34 weeks' gestation (19 women received placebo, and 17 women received DIF). Primary outcome variables were a change in creatinine clearance and the use of antihypertensives. Secondary outcomes were maternal and perinatal complications. RESULTS: Women with positive EDLFs who received DIF had an attenuated decline in creatinine clearance from baseline compared with placebo (-4.5 ± 12.9 vs -53.2 ± 12.6 mL/min; P = .005). In this same group, the use of antihypertensives (the other primary outcome) was lower but not significantly so (41% vs 63%; P = .12). However, women who were treated with DIF had a lower rate of pulmonary edema (1/17 vs 6/19 women; P = .035) and lower rates of neonatal intraventricular hemorrhage (DIF: 0/17 women vs placebo: 5/19 women; P = .015). CONCLUSION: In women with severe preeclampsia who were remote from term who were EDLF positive, the use of DIF was associated with improved maternal and neonatal outcome. These findings suggest the need for a large multicenter trial that would evaluate the benefits of DIF in the treatment of women with severe preeclampsia who are remote from term and with positive EDLF status.

Association of maternal vitamin D and placenta growth factor with the diagnosis of early onset severe preeclampsia.

OBJECTIVE: Decreased maternal 25-hydroxyvitamin D (25-OH-D) and placenta growth factor (PlGF) have both been associated with the diagnosis of early onset severe preeclampsia (EOSPE). This investigation aimed to define the association of these biomarkers with EOSPE. STUDY DESIGN: Patients with EOSPE (n = 40) and healthy controls (n = 40) were recruited and information on demographics, outcomes, and plasma was collected at diagnosis of EOSPE or gestational age-matched controls. 25-OH-D was assessed by radioimmunoassay and reported in nanogram per milliliter. PlGF was assessed by enzyme-linked immunosorbent assay and reported in picogram per milliliter. Kruskal-Wallis test was used to compare biomarkers between groups. Multivariable logistic regression was used to determine associations between 25-OH-D or PlGF and the diagnosis of EOSPE. RESULTS: In EOSPE, both 25-OH-D and PlGF were decreased significantly compared with controls. After controlling for age, race, body mass index, and gestational age at sample collection, both 25-OH-D (adjusted odds ratio 0.14 [0.05, 0.36]) and PlGF (adjusted odds ratio 0.03 [0.01, 0.24] were significantly associated with diagnosis of ESOPE (p < 0.001 for both markers). CONCLUSION: PlGF and 25-OH-D are both associated with the diagnosis of EOSPE. These biomarkers may be helpful in development of novel rapid diagnostic tests for preeclampsia.

Maternal vitamin D and fetal growth in early-onset severe preeclampsia.

OBJECTIVE: Recently, vitamin D deficiency has been associated with increased risks for preeclampsia and diagnosis of early-onset, severe preeclampsia (EOSPE). The purpose of this investigation was to examine the association between vitamin D levels and small-for-gestational age (SGA) in patients with EOSPE. STUDY DESIGN: Patients with EOSPE were recruited, and demographics, outcomes, and plasma were collected. We assessed 25-hydroxyvitamin D (25[OH]D) by radioimmunoassay and reported our findings in nanograms per milliliter. Results were analyzed by Mann-Whitney U test and Spearman correlation and were reported as median (Q1-Q3). RESULTS: In patients with EOSPE (n = 56), 25(OH)D was lower in patients with SGA (16.8 ng/mL; range, 8.9-23 ng/mL) vs normal fetal growth (25.3 ng/mL; range, 16-33 ng/mL; P = .02). 25(OH)D was correlated significantly with percentile growth at delivery (ρ = 0.31; P = .02). CONCLUSION: Vitamin D is lower among patients with SGA in EOSPE than those without growth retardation. We suspect that vitamin D may impact fetal growth through placental mechanisms.

Vitamin D deficiency and insufficiency is common during pregnancy.

The objective was to determine the incidence of vitamin D deficiency, insufficiency, and sufficiency in African-American, Hispanic, and Caucasian pregnant women. Blood samples were taken from 154 African-American, 194 Hispanic, and 146 Caucasian women at <14 weeks of gestation; 25 hydroxyvitamin D levels (25(OH)D) levels were measured by radioimmunoassay. The mean 25(OH)D levels in African-American, Hispanic, and Caucasian pregnant women were 15.5 ± 7.2 (standard deviation), 24.1 ± 8.7, 29.0 ± 8.5 ng/mL, respectively. Ninety-seven percent of African-Americans, 81% of Hispanics, and 67% of Caucasians were deficient (25(OH)D levels <20 ng/mL or <50 nmol/L) or insufficient (25(OH)D levels ≥ 20 ng/mL or <32 ng/mL or ≥ 50 nmol/L or <80 nmol/L). Of these pregnant women, 82% had vitamin D levels <32 ng/mL (<80 ng/mL). In logistic regression models, race was the most important risk factor for vitamin D deficiency or insufficiency. African-American women and Hispanic women were more likely to have vitamin D insufficiency and deficiency than Caucasian women. Furthermore, primigravid women were more at risk for vitamin D insufficiency. This study demonstrates widespread vitamin D deficiency and insufficiency in pregnant females living at a southern latitude. African-Americans are at greatest risk.

Timing of elective repeat cesarean delivery at term and neonatal outcomes: a cost analysis.

OBJECTIVE: The purpose of this investigation was to examine the economic impact of performing elective repeat cesarean during 37 or 38 weeks of gestation relative to the American College of Obstetricians and Gynecologists recommendation of a 39-week delivery. STUDY DESIGN: Decision analysis modeling was used to estimate economic outcomes for a hypothetical cohort of neonates using data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network study of "Timing of Elective Repeat Cesarean Delivery at Term and Neonatal Outcomes." Costs and charges were estimated using the Florida Healthcare Cost and Utilization Project. RESULTS: A total of 82,541 deliveries occurring between 37-39 completed weeks of gestation were analyzed for the incidence of adverse outcomes and their hospital costs and charges. The model demonstrated increased costs through increasing adverse outcomes among elective repeat cesarean deliveries performed <39 weeks of gestation. CONCLUSION: Our findings suggest that there are benefits to waiting until 39 weeks of gestation to perform an elective repeat cesarean delivery.

Plasma 25-hydroxyvitamin D levels in early-onset severe preeclampsia.

OBJECTIVE: Vitamin D deficiency has been linked to adverse pregnancy outcomes. The purpose of this investigation was to assess total 25-hydroxyvitamin D (25-OH-D) levels at diagnosis of early-onset severe preeclampsia (EOSPE). STUDY DESIGN: After institutional review board approval, we enrolled subjects with EOSPE (<34 weeks' gestation with severe preeclampsia) in this case-control investigation in a 1:2 ratio with gestation-matched, contemporaneous control subjects. Demographic and outcome information was collected for each subject. Plasma total 25-OH-D levels were determined by radioimmunoassay and reported in nanograms per milliliter. Results were analyzed by Mann-Whitney U and multivariable regression. RESULTS: Subjects with EOSPE (n = 50) were noted to have decreased total 25-OH-D levels relative to healthy control subjects (n = 100; P < .001). This difference in total 25-OH-D remained significant after control for potential confounders. CONCLUSION: Total 25-OH-D is decreased at diagnosis of EOSPE. Further study is needed to understand the impact of vitamin D deficiency on pregnancy outcomes.

Maternal super-obesity (body mass index > or = 50) and adverse pregnancy outcomes.

OBJECTIVE: To determine if pregnancy complications are increased in super-obese (a body mass index (BMI) of 50 or more) compared to other, less obese parturients. DESIGN: Cross-sectional study. SETTING AND POPULATION: All 19,700 eligible women, including 425 (2.2%) super-obese women with singleton births between 1996 and 2007 delivering at a tertiary referral center, identified using a perinatal research database. METHODS: Bivariate and trend analyses were used to assess the relation between super-obesity and various pregnancy complications compared to other well-established BMI categories. Adjusted odds ratios (ORs) were calculated using multivariable logistic regression techniques. MAIN OUTCOME MEASURES: Outcomes for adjusted and unadjusted analyses were small-for-gestational age (SGA) birth, large-for-gestational age (LGA) birth, preeclampsia, gestational diabetes mellitus (GDM), fetal death, preterm birth, placental abruption, cesarean delivery, and Apgar scores < 7. RESULTS: Compared to all other obese and non-obese women, super-obese women had the highest rates of preeclampsia, GDM, LGA, and cesarean delivery (all p < 0.05 for trend test). Super-obesity was also associated with a 44% reduction in SGA compared to all other women (OR 0.55, 95% confidence interval (CI) 0.40-0.76) and a 25% reduction compared to other, less obese women (OR 0.75, 95% CI 0.54-1.03). Super-obesity was positively associated with LGA, GDM, preeclampsia, cesarean delivery, and a 5-minute Apgar score < 7 compared to all other women after controlling for important confounders. CONCLUSION: Super-obesity is associated with higher rates of pregnancy complications compared to women of all other BMI classes, including other obese women.

Digoxin immune fab treatment for severe preeclampsia.

We evaluated the efficacy, safety, and biological mechanisms of digoxin immune Fab (DIF) treatment of severe preeclampsia. Fifty-one severe preeclamptic patients were randomized in double-blind fashion to DIF ( N = 24) or placebo ( N = 27) for 48 hours. Primary outcomes were change in creatinine clearance (CrCl) at 24 to 48 hours and antihypertensive drug use. Serum sodium pump inhibition, a sequela of endogenous digitalis-like factors (EDLF), was also assessed. CrCl in DIF subjects was essentially unchanged from baseline versus a decrease with placebo (-3 +/- 10 and -34 +/- 10 mL/min, respectively, P = 0.02). Antihypertensive use was similar between treatments (46 and 52%, respectively, P = 0.7). Serum sodium pump inhibition was decreased with DIF compared with placebo at 24 hours after treatment initiation (least squares mean difference, 19 percentage points, P = 0.03). DIF appeared to be well tolerated. These results suggest DIF prevents a decline in renal function in severe preeclampsia by neutralizing EDLF. Sodium pump inhibition was significantly improved. Further research is warranted.

Prediction of pelvic organ prolapse using an artificial neural network.

OBJECTIVE: The objective of this investigation was to test the ability of a feedforward artificial neural network (ANN) to differentiate patients who have pelvic organ prolapse (POP) from those who retain good pelvic organ support. STUDY DESIGN: Following institutional review board approval, patients with POP (n = 87) and controls with good pelvic organ support (n = 368) were identified from the urogynecology research database. Historical and clinical information was extracted from the database. Data analysis included the training of a feedforward ANN, variable selection, and external validation of the model with an independent data set. RESULTS: Twenty variables were used. The median-performing ANN model used a median of 3 (quartile 1:3 to quartile 3:5) variables and achieved an area under the receiver operator curve of 0.90 (external, independent validation set). Ninety percent sensitivity and 83% specificity were obtained in the external validation by ANN classification. CONCLUSION: Feedforward ANN modeling is applicable to the identification and prediction of POP.

Early-onset severe preeclampsia: induction of labor vs elective cesarean delivery and neonatal outcomes.

OBJECTIVE: The purpose of this study was to describe the success rate of and analyze differences in neonatal outcomes with labor induction, compared with elective cesarean delivery in women with early-onset severe preeclampsia. STUDY DESIGN: We conducted a cross-sectional study of women with severe preeclampsia who required delivery between 24 and 34 weeks of gestation. Bivariate and multivariable regression analyses were used to determine factors that were associated with assignment to, success of, and odds of neonatal outcomes after induction of labor. RESULTS: Fifty-seven and four-tenths percent of 491 women underwent induction of labor. Vaginal delivery occurred in 6.7%, 47.5%, and 68.8% of women who underwent labor induction between 24 and 28, 28 and 32, and 32 and 34 weeks of gestation, respectively. Induction of labor was not associated with an increase in neonatal morbidity or mortality rate after we controlled for gestational age and other confounders. CONCLUSION: Neonatal outcomes are not worsened by induction of labor in women with early-onset severe preeclampsia, although it is rarely successful at <28 weeks of gestation.

Soluble endoglin as a second-trimester marker for preeclampsia.

OBJECTIVE: The objective of this investigation was to characterize soluble endoglin (sEng) concentrations in second-trimester serum of women who either develop preeclampsia or have a normal pregnancy. STUDY DESIGN: Single second-trimester serum samples obtained from healthy, nonsmoking women who subsequently developed severe preeclampsia (n = 48) or from healthy nonsmoking women who experienced a normal pregnancy (n = 56) were measured by enzyme-linked immunosorbent assay. Data were reported as mean +/- standard deviation. RESULTS: Maternal age or gestational age at time of sample was not different between the 2 groups. Patients who later developed preeclampsia delivered earlier, had smaller infants, and had a higher mean arterial pressure than controls. Patients who later developed severe preeclampsia had elevated sEng, compared with those with normal pregnancy (6.19 +/- 2.1 vs 5.00 +/- 1.0 ng/mL, P = .02). CONCLUSION: Soluble endoglin is elevated in second-trimester maternal serum in patients destined to develop severe preeclampsia.

Second-trimester angiogenic factors as biomarkers for future-onset preeclampsia.

OBJECTIVE: The purpose of this study was to determine whether second-trimester soluble fms-like tyrosine kinase-1 and placenta growth factor (PlGF) are altered in patients who have preeclampsia develop compared with controls. Furthermore, soluble fms-like tyrosine kinase-1 and placenta growth factor levels in patients with chronic hypertension are described. STUDY DESIGN: With the use of a research database, 21 patients who had severe preeclampsia develop, 34 controls, and 9 patients with chronic hypertension were enrolled. Placenta growth factor and soluble fms-like tyrosine kinase-1 serum levels were determined by enzyme-linked immunosorbent assay. Appropriate statistical tests were used and results were reported as median (quartile 1-quartile 3) in picograms per milliliter. RESULTS: Placenta growth factor was significantly lower in patients in the second trimester who later had severe preeclampsia develop but soluble fms-like tyrosine kinase-1 was unchanged compared with healthy pregnancies. In patients with chronic hypertension, placenta growth factor and soluble fms-like tyrosine kinase-1 levels were not different compared with controls. CONCLUSION: Second-trimester placenta growth factor levels are altered in patients who had severe preeclampsia develop.

Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe preeclampsia.

OBJECTIVE: The purpose of this study was to determine if maternal serum concentrations of placenta growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 receptor (s-Flt1) are more abnormal in patients with severe preeclampsia compared with mild preeclampsia. STUDY DESIGN: Serum samples were collected from 32 control patients and 80 patients with mild or severe preeclampsia. PlGF and s-Flt1 concentrations were quantitated by enzyme-linked immunosorbent assay (ELISA). Results are expressed as median (Q1-Q3) unless stated otherwise. After normalization, serum markers were compared using one-way analysis of covariance (ANCOVA). RESULTS: Patients with preeclampsia had decreased levels of PlGF (75.1 +/- 14 vs 391 +/- 54 pg/mL, P < .0001) and elevated s-Flt1 concentration (1081 +/- 108 vs 100.1 +/- 26.9 pg/mL, P < .0001) compared with the respective controls (mean +/- SEM). PlGF concentration was lower in patients with mild preeclampsia compared with severe, respectively (67 pg/mL [39-158] vs 24 pg/mL [4-57], P < .02). s-Flt1 was not different between mild and severe preeclampsia (674 pg/mL [211-1297] vs 1015 pg/mL [731-1948], P = .08). CONCLUSION: PlGF and s-Flt1 serum levels are abnormal in patients with preeclampsia compared with controls, but only PlGF is more abnormal in severe preeclampsia compared with mild preeclampsia.

Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis.

OBJECTIVE: To assess the safety and health effects of vitamin D supplementation during pregnancy. METHODS AND DESIGN: Datasets from two randomized clinical trials were first analyzed separately then combined for this analysis using a common data dictionary. In the NICHD trial, women were randomized to 400, 2000, or 4000IU vitamin D3/day, stratified by race. In the Thrasher Research Fund trial, participants were randomized to 2000 or 4000IU vitamin D3/day. Study drugs were from the same manufacturing lot for both trials. Identical questionnaires were given for comparable sociodemographics & clinical characteristics. Outcome measures were: [1] maternal and neonatal 25(OH)D achieved, and [2] maternal comorbidities of pregnancy (COP). SAS 9.3 was used for all analyses. RESULTS: In the combined cohort, there were 110 controls, 201 in the 2000IU group, and 193 in the 4000IU group. No differences between groups in baseline 25(OH)D were found; however, delivery and cord blood values were greater in the 4000IU group (p<0.0001), an effect that persisted even after controlling for race and study. A greater percent were vitamin D replete in the 4000IU group (p<0.0001). There was a trend where the 4000IU group had decreased rates of comorbidities of pregnancy. There was a strong association between COP and final maternal 25(OH)D; an effect that persisted even after controlling for race and study (p=0.006). CONCLUSIONS: Supplementation with 4000IU/day was associated with lower risk of hypovitaminosis D than Control and 2000IU groups. While not statistically significant, there was a trend toward lower rates of COP as supplementation dose increased. Maternal delivery 25(OH)D was inversely associated with any comorbidity of pregnancy, with fewer events as 25(OH)D increased. Future studies are needed to confirm these findings and determine the mechanisms of action of such effects. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Vitamin D and its role during pregnancy in attaining optimal health of mother and fetus.

Despite its discovery a hundred years ago, vitamin D has emerged as one of the most controversial nutrients and prohormones of the 21st century. Its role in calcium metabolism and bone health is undisputed but its role in immune function and long-term health is debated. There are clear indicators from in vitro and animal in vivo studies that point to vitamin D's indisputable role in both innate and adaptive immunity; however, the translation of these findings to clinical practice, including the care of the pregnant woman, has not occurred. Until recently, there has been a paucity of data from randomized controlled trials to establish clear cut beneficial effects of vitamin D supplementation during pregnancy. An overview of vitamin metabolism, states of deficiency, and the results of recent clinical trials conducted in the U.S. are presented with an emphasis on what is known and what questions remain to be answered.

The role of vitamin D in pregnancy and lactation: emerging concepts.

Pregnancy is a critical time in the lifecycle of a woman where she is responsible not only for her own well-being, but also that of her developing fetus, a process that continues during lactation. Until recently, the impact of vitamin D status during this period had not been fully appreciated. Data regarding the importance of vitamin D in health have emerged to challenge traditional dogma, and suggest that vitamin D - through its effect on immune function and surveillance - plays a role beyond calcium and bone metabolism on the health status of both the mother and her fetus. Following birth, this process persists; the lactating mother continues to be the main source of vitamin D for her infant. Thus, during both pregnancy and lactation, maternal deficiency predicts fetal and infant deficiency; the significance of this is just beginning to be understood and will be highlighted in this review.

Examining the effect of maternal obesity on outcome of labor induction in patients with preeclampsia.

OBJECTIVE: The objective of this investigation was to evaluate the effect of maternal obesity, as measured by prepregnancy body mass index (BMI), on the mode of delivery in women undergoing indicated induction of labor for preeclampsia. STUDY DESIGN: Following Institutional Review Board (IRB) approval, patients with preeclampsia who underwent an induction of labor from 1997 to 2007 were identified from a perinatal information database, which included historical and clinical information. Data analysis included bivariable and multivariable analyses of predictor variables by mode of delivery. An artificial neural network was trained and externally validated to independently examine predictors of mode of delivery among women with preeclampsia. RESULTS: Six hundred and eight women met eligibility criteria and were included in this investigation. Based on multivariable logistic regression (MLR) modeling, a 5-unit increase in BMI yields a 16% increase in the odds of cesarean delivery. An artificial neural network trained and externally validated confirmed the importance of obesity in the prediction of mode of delivery among women undergoing labor induction for preeclampsia. CONCLUSION: Among patients who are affected by preeclampsia, obesity complicates labor induction. The risk of cesarean delivery is enhanced by obesity, even with small increases in BMI. Prediction of mode of delivery by an artificial neural network performs similar to MLR among patients undergoing labor induction for preeclampsia.