Abnormal placentation: evidence-based diagnosis and management of placenta previa, placenta accreta, and vasa previa.

Placenta previa, placenta accreta, and vasa previa cause significant maternal and perinatal morbidity and mortality. With the increasing incidence of both cesarean delivery and pregnancies using assisted reproductive technology, these 3 conditions are becoming more common. Advances in grayscale and Doppler ultrasound have facilitated prenatal diagnosis of abnormal placentation to allow the development of multidisciplinary management plans to achieve the best outcomes for mother and baby. We present a comprehensive review of the literature on abnormal placentation including an evidence-based approach to diagnosis and management.

The impact of prior preeclampsia on the risk of superimposed preeclampsia and other adverse pregnancy outcomes in patients with chronic hypertension.

OBJECTIVE: We sought to compare the rates of superimposed preeclampsia and adverse outcomes in women with chronic hypertension with or without prior preeclampsia. STUDY DESIGN: We conducted secondary analysis of 369 women with chronic hypertension (104 with prior preeclampsia) enrolled at 12-19 weeks as part of a multisite trial of antioxidants to prevent preeclampsia (no reduction was found). Outcome measures were rates of superimposed preeclampsia and other adverse perinatal outcomes. RESULTS: Prepregnancy body mass index, blood pressure, and smoking status at enrollment were similar between groups. The rates of superimposed preeclampsia (17.3% vs 17.7%), abruptio placentae (1.0% vs 3.1%), perinatal death (6.7% vs 8.7%), and small for gestational age (18.4% vs 14.3%) were similar between groups, but preterm delivery <37 weeks was higher in the prior preeclampsia group (36.9% vs 27.1%; adjusted risk ratio, 1.46; 95% confidence interval, 1.05-2.03; P = .032). CONCLUSION: In women with chronic hypertension, a history of preeclampsia does not increase the rate of superimposed preeclampsia, but is associated with an increased rate of delivery at <37 weeks.

Antioxidant supplementation and premature rupture of the membranes: a planned secondary analysis.

OBJECTIVE: The purpose of this study was to determine if antioxidant supplementation during pregnancy reduces the incidence of premature rupture of the membranes (PROM). STUDY DESIGN: A placebo-controlled, double-blind trial was conducted. PROM and preterm PROM (PPROM) were planned secondary outcomes of the trial. Women between 12(0/7) and 19(6/7) weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomized to daily treatment with both vitamin C (1000 mg) and E (400 IU) or placebo. RESULTS: Outcome data for PROM were available for 697 of 739 patients. The rates of PROM (37/349 [10.6%] vs 19/348 [5.5%]; adjusted risk ratio [RR] 1.89 [95.42% CI, 1.11-3.23]; P = .015), and PPROM (16/349 [4.6%] vs 6/348 [1.7%]; RR 2.68 [1.07-6.71]; P = .025) were increased in the antioxidant group. CONCLUSION: Contrary to expectations, vitamins C and E supplementation in this dose combination may be associated with an increased risk of PROM and PPROM.

Serum inhibin A and angiogenic factor levels in pregnancies with previous preeclampsia and/or chronic hypertension: are they useful markers for prediction of subsequent preeclampsia?

OBJECTIVE: Our objective was to determine whether measurement of placenta growth factor (PLGF), inhibin A, or soluble fms-like tyrosine kinase-1 (sFlt-1) at 2 times during pregnancy would usefully predict subsequent preeclampsia (PE) in women at high risk. STUDY DESIGN: We analyzed serum obtained at enrollment (12(0/7) to 19(6/7) weeks) and follow-up (24-28 weeks) from 704 patients with previous PE and/or chronic hypertension (CHTN) enrolled in a randomized trial for the prevention of PE. Logistic regression analysis assessed the association of log-transformed markers with subsequent PE; receiver operating characteristic analysis assessed predictive value. RESULTS: One hundred four developed preeclampsia: 27 at 37 weeks or longer and 77 at less than 37 weeks (9 at less than 27 weeks). None of the markers was associated with PE at 37 weeks or longer. Significant associations were observed between PE at less than 37 weeks and reduced PLGF levels at baseline (P = .022) and follow-up (P < .0001) and elevated inhibin A (P < .0001) and sFlt-1 (P = .0002) levels at follow-up; at 75% specificity, sensitivities ranged from 38% to 52%. Using changes in markers from baseline to follow-up, sensitivities were 52-55%. Associations were observed between baseline markers and PE less than 27 weeks (P < or = .0004 for all); sensitivities were 67-89%, but positive predictive values (PPVs) were only 3.4-4.5%. CONCLUSION: Inhibin A and circulating angiogenic factors levels obtained at 12(0/7) to 19(6/7) weeks have significant associations with onset of PE at less than 27 weeks, as do levels obtained at 24-28 weeks with onset of PE at less than 37 weeks. However, because the corresponding sensitivities and/or PPVs were low, these markers might not be clinically useful to predict PE in women with previous PE and/or CHTN.

Antioxidant therapy to prevent preeclampsia: a randomized controlled trial.

OBJECTIVE: To study whether antioxidant supplementation will reduce the incidence of preeclampsia among patients at increased risk. METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted at four Brazilian sites. Women between 12 0/7 weeks and 19 6/7 weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomly assigned to daily treatment with both vitamin C (1,000 mg) and vitamin E (400 International Units) or placebo. Analyses were adjusted for clinical site and risk group (prior preeclampsia, chronic hypertension, or both). A sample size of 734 would provide 80% power to detect a 40% reduction in the risk of preeclampsia, assuming a placebo group rate of 21% and alpha=.05. The alpha level for the final analysis, adjusted for interim looks, was 0.0458. RESULTS: Outcome data for 707 of 739 randomly assigned patients revealed no significant reduction in the rate of preeclampsia (study drug, 13.8% [49 of 355] compared with placebo, 15.6% [55 of 352], adjusted risk ratio 0.87 [95.42% confidence interval 0.61-1.25]). There were no differences in mean gestational age at delivery or rates of perinatal mortality, abruptio placentae, preterm delivery, and small for gestational age or low birth weight infants. Among patients without chronic hypertension, there was a slightly higher rate of severe preeclampsia in the study group (study drug, 6.5% [11 of 170] compared with placebo, 2.4% [4 of 168], exact P=.11, odds ratio 2.78, 95% confidence interval 0.79-12.62). CONCLUSION: This trial failed to demonstrate a benefit of antioxidant supplementation in reducing the rate of preeclampsia among patients with chronic hypertension and/or prior preeclampsia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.ClinicalTrials.gov, NCT00097110 LEVEL OF EVIDENCE: I.

Tissue distribution and elimination of N-methyl-N-2,4,6-tetranitroaniline (tetryl) in rats.

The elimination of tetryl was studied using ring-labeled 14C-tetryl. Tetryl was given subcutaneously to male Sprague-Dawley rats at doses of 25, 100, and 300 mg kg(-1), and urine and feces were collected 24 h post-injection. Percent urinary elimination was observed to be 10.02 +/- 2.48, 11.2 +/- 1.66, and 13.24 +/- 5.79 (mean +/- SEM) respectively. Percent fecal elimination was 15.68 +/- 6.13, 9.41 +/- 1.52, and 8.45 +/- 1.81 respectively. At 24 h post-injection, tissues from male Sprague-Dawley rats were collected from animals that received 100 mg kg(-1) 14C-tetryl. Tetryl was found to be poorly absorbed with approximately 65% of the administered dose remaining at the site of subcutaneous injection. Blood was found to be the principal depot of radioactivity, followed by muscle, liver, and kidney. Analysis of the tissue to blood radioactivity ratio revealed that the liver had the highest ratio (1.2), followed by brain (0.45), kidney (0.38), and testes (0.35). All other tissues analyzed had ratios less than 0.30. Urine of animals receiving 14C-tetryl (100 mg kg(-1)) was analyzed using HPLC coupled with UV detection (200-600 nm; 1.2 nm resolution). During HPLC analysis, 1 min fractions were collected and radioactivity measured. Two major peaks of radioactivity were identified at approximately 5 and 14 min retention times, respectively. The 14 min peak had the same retention time and UV spectrum as picric acid and 5 min peak had the same retention time and UV profile as picramic acid. The data presented demonstrates that that there is little retention of tetryl in specific tissue depots and that tetryl is eliminated in roughly equal amounts in both urine and feces. The major urinary metabolites identified picric acid and picramic acid (a known urinary metabolite observed in rabbits). From microsomal fraction studies, a major metabolite, NMPA, was identified. The formation of this metabolite was found to be dependent on at least two enzymes. One enzyme is dependent on NAD+ for NMPA formation and is likely to be NADP(H):quinone oxidoreductase. The second metabolite is NADP+ dependent and is probably related to NADPH:cytochrome-P450 reductase.

Metabolism, tissue distribution, and pharmacokinetics of N-methyl-N-2,4,6-tetranitroaniline (tetryl).

Tetryl (N-methyl-N,2,4,6-tetranitroaniline) is a booster explosive that was used in the production of detonators and blasting caps. It is an environmental contaminant that is found in detectable levels in areas associated with its production, use, storage, and disposal. Preliminary microsomal assays showed that one major metabolite was formed under anaerobic and aerobic conditions with both NADH and NADPH as cofactors. Metabolite formation was not inhibited by carbon monoxide but did not form in the absence of cofactor or with heat-killed microsomes. The major metabolite was identified as N-methyl-2,4,6-trinitroaniline (NMPA) by IR spectroscopy, (1)H and (14)C NMR, and chemical ionization/MS. Kinetic parameters of NMPA formation in the microsomal fraction were determined using Lineweaver-Burke plots. A V(max) of 448nmoles/(minmg) of protein and K(m) of 1.25mM was determined when NAD+ was the cofactor. When NADP+ was the cofactor, a V(max) of 139nmoles/(minmg) of protein and a K(m) of 1.4mM was determined. In the microsomal fraction, inhibition studies revealed that NMPA formation was slightly inhibited (10%) by 2'-AMP (2mM) when NADP+, but not NAD+, was used as a cofactor. This suggests that NMPA formation is partially dependent on cytochrome-P450 reductase. NMPA formation was also inhibited by dicumarol (2mM) when NADP+ (14%) and NAD+ (84%) (14%) were cofactors, suggesting that NAD(P)H: quinone oxidoreductase catalyzes NMPA formation in the microsomes. A nonspecific flavoprotein inhibitor, DPI, inhibited NMPA formation (91%) using NADP+ as a cofactor, but not NAD+. Other inhibitors, miconazole (cytochrome-P450), methimazole (flavin monooxygenase), and propylthiouracil (NADH: b5 reductase), did not prevent NMPA formation in the microsomal fraction.

New therapies in the prevention of preeclampsia.

PURPOSE OF REVIEW: The review summarizes the results of recent randomized clinical trials whose primary purpose was to prevent preeclampsia and explores safety concerns that have been raised by these trials. Preeclampsia remains one the most common causes of perinatal and maternal mortality, particularly in resource-poor developing countries where its impact on morbidity and mortality is 20 to 100-fold greater than that in developed countries. The potential benefit of antioxidant vitamins and calcium continue to be explored, and are the subject of this review. RECENT FINDINGS: Two large, prospective, randomized trials involving more than 4000 low and high-risk subjects, respectively, compared vitamin C/E to placebo. There were no differences noted in the frequency of preeclampsia between groups. Additionally, potential adverse influences of supplementation on low birthweight, late stillbirth, and severity and timing of preeclampsia and neonatal acidosis were noted. A large, multicenter calcium vs. placebo trial sponsored by the World Health Organization in locations known to have dietary calcium deficiency failed to reduce preeclampsia or low birthweight rates. SUMMARY: These negative trials have reduced the likelihood that antioxidant or calcium supplementation will significantly impact the incidence of this disease. The safety concerns regarding antioxidants must be carefully explored.

Tocolysis in women with preterm labor between 32 0/7 and 34 6/7 weeks of gestation: a randomized controlled pilot study.

OBJECTIVE: The purpose of this study was to determine whether intravenous magnesium sulfate (MgSO4) followed by oral nifidepine tocolysis in women with preterm labor between 32 0/7 and 34 6/7 weeks' gestation reduces neonatal hospital stay. STUDY DESIGN: Fifty-four women between 32 0/7 and 34 6/7 weeks with preterm labor were randomized to receive either MgSO4 and oral nifidepine (n = 24) or no tocolysis (n = 30). All women received betamethasone and prophylactic antibiotics. The primary outcome was total neonatal hospital stay. Data were analyzed using Chi-square and Mann Whitney U test. RESULTS: The 2 groups had similar mean cervical dilation and gestational age at enrollment. There were no statistically significant differences in total neonatal hospital stay (5.8 +/- 7.2 days; median of 3 days in the no tocolysis vs. 7.5 +/- 8.6 days; median of 3 days in the tocolysis group), rate of preterm delivery (57% vs. 75%) or need for oxygen supplementation (7% vs. 21%, p < 0.23). The neonatal complications were similar in each group. CONCLUSION: Tocolysis after 32 weeks gestation does not reduce neonatal hospital stay.

Prevention and management of RhD isoimmunization.

An Rh-negative woman is at risk for developing Rh isoimmunization upon exposure to RhD antigens from her Rh-positive baby through fetal-maternal hemorrhage. The incidence of Rh isoimmunization and fetal hemolytic disease has decreased substantially since Rh immune globulin was introduced in 1968. When RhD sensitization does occur, careful follow-up of these mothers and judicious intervention can result in good outcomes for most pregnancies. Both Doppler assessment of middle cerebral artery peak systolic velocity and spectral analysis of amniotic fluid at 450 nm (DeltaOD 450) are useful in the diagnosis and management of fetal anemia.

The pattern of change in the lecithin/sphingomyelin ratio in patients with preterm premature rupture of membranes between 24 and 34 weeks' gestation.

OBJECTIVE: To report the pattern of change in the lecithin/sphingomyelin (L/S) ratio in patients with preterm premature rupture of membranes (PPROM) between 24 and 34 weeks' gestation. STUDY DESIGN: L/S was determined prospectively using transvaginally and transabdominally collected amniotic fluid from patients with PPROM between 24 and 34 weeks' gestation. Samples were collected prospectively on admission and every 48 to 96 hours until L/S was > or =2.0. All patients received intramuscular betamethasone weekly. RESULTS: Fifty-five patients were included in the study. One hundred twenty-seven samples were collected transvaginally and nine were collected transabdominally. Cox regression analysis showed that a higher initial L/S value and more advanced gestational age were associated with accelerated lung maturation. Among patients at > or =29 weeks' gestation with an initial L/S of > or =1.5 and <2.0 (n=17), 15 of 17 (88%) reached L/S > or = 2 at a mean of 3.1 +/- 1.7 days (range 1.0 to 7.0 days). With an initial L/S of > or =1.0 and <1.5 (n=16), 14 of 16 (88%) patients reached L/S > or =2 at a mean of 4.1 +/- 1.9 days (range 1.7 to 7.0 days). With an initial L/S of <1.0 (n=11), 6 of 11 (54%) patients reached L/S > or =2 at a mean of 5.0 +/- 1.6 days (range 4.7 to 6.8 days). CONCLUSION: Our data document a dramatic acceleration of fetal lung maturation among patients with PPROM at > or = 29 weeks.

Pain and discomfort thresholds in late pregnancy.

Gintzler found an abrupt increase in pain thresholds in rats during the last days of gestation. While some data suggest a similar increase in pain thresholds for pregnant women, Goolkasian and Rimer have found, using signal detection procedures, that women are increasingly likely to report stimuli as painful during the last 2 weeks of pregnancy. The present studies were carried out to assess pain and discomfort thresholds in the last weeks of women's pregnancies. In the first study, daily measures of the pressure-induced pain thresholds of 6 women who had spontaneous, vaginal births increased during the last 16 days of pregnancy and exceeded the 300 mm Hg maximum stimulus pressure for the last 9 days of pregnancy. In the second study, the discomfort thresholds of 6 women were measured each day during the last 11 days of pregnancy before spontaneous vaginal births. The discomfort thresholds of the pregnant women were higher than those of 6 non-pregnant women whose discomfort thresholds were also measured each day. Pregnant women's thresholds increased before the onset of labor, while the discomfort thresholds of the non-pregnant women were unchanged during the course of the study. These results extend Gintzler's findings of reduced sensitivity to pain shortly before parturition.