Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials.

BACKGROUND: Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death. METHODS/DESIGN: We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups. DISCUSSION: Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.

Women with preterm premature rupture of the membranes do not benefit from weekly progesterone.

OBJECTIVE: We sought to determine if 17-alpha-hydroxyprogesterone (17P) extends gestation vs placebo in women with preterm premature rupture of the membranes (PPROM). STUDY DESIGN: Women with vertex presentations with PPROM, 20-30 weeks' gestation, were randomized to receive weekly 17P or placebo in an attempt to prolong the pregnancy. A total of 69 patients (17P, n = 33; placebo, n = 36) were randomized into this study. RESULTS: Initial cervical dilatation, gestational age at enrollment, and interval to delivery were not different between the 2 groups (P = .914, .424, and .146, respectively). Time of randomization to delivery (P = .250), mode of delivery (relative risk, 1.16; 95% confidence interval, 0.66-2.06), and the neonatal outcome statistics of morbidity (P = .820) and mortality (relative risk, 1.28; 95% confidence interval, 0.59-2.75) were similar between the 2 groups. CONCLUSION: In patients with PPROM, 17P did not extend gestation vs placebo and cannot be recommended for treatment in such women.

Treatment of bacterial vaginosis does not reduce preterm birth among high-risk asymptomatic women in fetal fibronectin positive patients.

OBJECTIVE: Bacterial vaginosis (BV) is associated with preterm labor and may be positive in 15% of asymptomatic high-risk women. Fetal fibronectin (fFN) has been shown in symptomatic women to predict infection-related preterm birth. The purpose of this study was to quantitate the relationship between BV/fFN and preterm delivery in high-risk asymptomatic women. METHODS: Women at high-risk for spontaneous preterm delivery were tested for BV/fFN between 20-28 weeks gestation. Women positive for BV were treated with metronidazole, and fFN results were not used by physicians in treatment. After delivery, test results and pregnancy outcomes were entered in a deidentified database and analyzed. RESULTS: Of 232 women tested for BV/fFN over a 24-month epoch, results divided participants into 4 groups: Group A (N = 12; +BV/+fFN); Group B (N = 22; -BV/+fFN); Group C (N = 68; +BV/-fFN); and Group D (N = 130; -BV/-fFN). Demographics were the same between the 4 groups (P = NS) as was the gestational age at delivery (36.41 +/- 3.96 to 37.18 +/- 3.03 weeks). The incidence ofpreterm labor (P = .075), spontaneous early delivery (P = .936) and infants < 2500 gm (P = .664) was also similar. CONCLUSIONS: In asymptomatic high-risk women, testing for fFN/BV during mid-pregnancy does not appear warranted.

Progesterone does not prevent preterm births in women with twins.

OBJECTIVE: To compare preterm birth rate and neonatal outcome in twin gestations randomized to either 17 alpha-hydroxyprogesterone caproate (17P) or placebo. MATERIALS AND METHODS: Women with twin gestations between 20-30 weeks were randomized to receive weekly injections of either 250 mg 17P injection (Group I), or placebo (Group II). Maternal and neonatal outcome data was recorded. RESULTS: Thirty twin intrauterine pregnancies were randomized; 16 received 17P and 14 received placebo. Demographic data as well as past history and gestational age at randomization were equivalent between groups (P = 0.286-0.847). All patients in both groups were Medicaid recipients. The incidence of preterm labor (P = 0.980), and premature rupture of the membranes (P = 0.525) were the same between groups. Gestational age at delivery was also similar between 17P (33.9 weeks) versus placebo (33.1 weeks, P = 0.190) as was the incidence of preterm birth <35 weeks (44% vs 79%, P = 0.117). Infant weight (P = 0.641), Apgar score at 5 minutes (P = 0.338) as well as neonatal morbidity such as respiratory distress syndrome (P = 0.838), patent ductus arteriosus (P = 0.704), intraventricular hemorrhage (P = 0.851) and necrotizing enterocolitis (P = 0.946) showed no difference. Days spent in the NICU among 17P (18.4) versus placebo (17.3, P = 0.155), neonatal death (P = 0.359) and those infants discharged with neurologic handicap (P = 0.594) were not different between groups. CONCLUSION: Amongst this group of twin gestations weekly 17HP injections did not reduce the incidence of preterm birth or the complications associated with prematurity.

Postpartum plasma exchange as adjunctive therapy for severe acute fatty liver of pregnancy.

Acute fatty liver of pregnancy (AFLP) is a rare disease of progressive hepatic insufficiency and secondary systemic compromise that poses significant fetal-maternal risk. Plasma exchange (PEX) is an effective bridge therapy to sustain liver function and enable hepatocellular regeneration to occur in nonpregnant patients following acute decompensation of a chronic liver disease or while awaiting liver transplantation. The application of PEX for patients with AFLP is a novel concept; since 1988 we have utilized postpartum PEX (PPEX) as adjunctive medical therapy for six patients with severe AFLP. Before PPEX initiation, four patients had signs and symptoms of encephalopathy, three required ventilatory support, five had advanced liver insufficiency, and all six were developing renal failure. PPEX was initiated 2-8 days following delivery and repeated (two to four times, mean = 3) at 24-48-h intervals thereafter. All patients responded with composite clinical (symptoms/signs) and laboratory improvement; the average length of hospitalization following final PPEX for five of six patients was 7 days. No significant PPEX-related complications occurred. PPEX utilization in patients with severe AFLP may enhance maternal recovery by preventing secondary sequelae from hepatic insufficiency until spontaneous healing can occur. Further study appears to be indicated to validate a role for PPEX as supportive therapy for puerperal patients with AFLP suffering multiorgan failure.

Obstetric characteristics for a prolonged third stage of labor and risk for postpartum hemorrhage.

AIM: To determine the obstetric characteristics associated with a prolonged third stage of labor and risk factors for a postpartum hemorrhage (PPH) in women undergoing vaginal delivery. METHOD: Secondary analysis of a prospective randomized investigation comparing placental removal at 20 versus 30 min to prevent PPH. RESULTS: Between 1 March 2004 and 1 March 2005, 1,607 women were recruited. Eighty-nine percent of the placentas had delivered by 10 min (n = 1,430) and 10.5% (n = 168) had delivered between 10 and 20 min, leaving 8 retained placentas (0.5%) >20 min. Simultaneous factors predictive of longer duration of third stage of labor included maternal age > or =35 years (hazard ratio HR = 0.990, 95% CI 0.981-0.999, p = 0.030) and duration of second stage of labor >2 h (HR = 0.745, 95% CI 0.628-0.883, p = 0.001) relative to second stage of labor <1 h. Significant risk factors for PPH included chorioamnionitis (odds ratio OR = 6.45, 95% CI 2.37-17.64, p < 0.001), nulliparity (OR = 2.38, 95% CI 1.19-4.77, p = 0.014), overdistended uterus (OR = 2.81, 95% CI 1.02-7.76, p = 0.047) and third stage of labor >10 min (OR = 6.45 95%, CI 2.73-22.84, p < 0.001 compared with third stage < or =5 min). CONCLUSIONS: Prolonged third stage of labor is correlated with an older maternal age and a prolonged second stage of labor. Significant risk factors for PPH include chorioamnionitis, an overdistended uterus and a third stage of labor >10 min.

Planned vs emergent cesarean hysterectomy.

OBJECTIVE: The aim of this study was to compare operative and postpartum outcomes between planned and emergent cesarean hysterectomy. STUDY DESIGN: In this multicenter retrospective review over a 5-year period, 65 cases of cesarean hysterectomy (30 planned vs 35 emergent) were identified. Demographic, operative, and postoperative data were extracted and stratified by group (planned vs emergent). RESULTS: Patients who underwent an emergent cesarean hysterectomy were more likely to have higher estimated blood loss (2597.1 +/- 1369.4 mL vs 1963.3 +/- 1180.2 mL; P = .05), have transfusion (66% vs 33%; P = .02), and require greater quantities of packed red blood cells (4.49 +/- 4.7 x10(12)/L vs 1.6 +/- 3.1 x10(12)/L; P = .006) compared with the planned cesarean hysterectomy group. Patients who underwent emergent cesarean hysterectomy had higher overall complication rates (37% vs 66%; P = .03) and more intensive care unit admissions (7% vs 29%; P = .03). CONCLUSION: After planned cesarean hysterectomy, patients had a significantly lower rate of blood loss, less need for blood transfusions, and fewer complications compared with patients who underwent an emergent cesarean hysterectomy.

Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison.

OBJECTIVE: To compare glycemic control and neonatal outcomes in women with gestational diabetes mellitus (GDM) treated with metformin vs. insulin. STUDY DESIGN: Women with GDM not controlled with diet and exercise were randomized to metformin (n = 32) or insulin (n = 31). The levels of glycemic control as well as maternal/neonatal complications were evaluated. RESULTS: The mean (+/- SD) fasting and 2-hour postprandial blood glucose did not differ statistically between the 2 treatment groups. No patient failed metformin and required insulin. The majority (27/32) were easily controlled on the initial dosage (500 mg twice a day). Gestational age at entry and delivery (p = 0.077, 0.412) were similar. The difference in the rate of cesarean delivery was not statistically significant between the 2 groups (p = 0.102). Neonatal statistics were also not different between the metformin and insulin groups: birth weight, Apgar score at 5 minutes, respiratory distress syndrome, hyperbilirubinemia, neonatal hypoglycemia and neonatal intensive care unit admission (p = 0.144-0.373). CONCLUSION: Based on these preliminary data, metformin appears to be an effective alternative to insulin in the treatment of GDM.

Tocolytic preference for treatment of preterm labor.

Preterm labor remains the most common complication of pregnancy. Although tocolytic treatment is the standard of care in such women, there is no FDA approved drug for therapy, and there is no unanimity of drug regimens among physicians. This survey details the patterns of twenty Maternal-Fetal Medicine specialists who manage over 6,000 cases of preterm labor with intact membranes annually. Approximately 90% of women were seen early enough to be effectively treated with tocolytics, and over 90% of these subjects received corticosteroids. First-line tocolytic use favored magnesium sulfate while antiprostaglandin drugs were the leading second-line drug whereas intravenous terbutaline and calcium channel antagonists were used less often. There were many different dosage patterns for each drug as well as combinations of various tocolytic drugs which were individually adjusted for patient circumstances. Women with preterm labor and intact membranes are usually treated with tocolytics and corticosteroids, but regimens are varied and all use is off label. This study demonstrates the need for an FDA approved tocolytic which could be used consistently for such women.

Lymphocytic myocarditis presenting as nausea, vomiting, and hepatic dysfunction in the first trimester of pregnancy.

BACKGROUND: Lymphocytic myocarditis, an immune disorder of left ventricular dysfunction with sometimes confounding clinical presentations, occurs rarely during pregnancy. CASE: At 12 weeks gestation, a multigravid patient presented with a 2-month history of nausea and vomiting. Other symptomatology included postprandial epigastric pain, loose stools, and a 10-lb (4.5-kg) weight loss. Laboratory evaluation revealed evidence of hepatic dysfunction with a coagulopathy and an absolute unconjugated hyperbilirubinemia. While undergoing evaluation, the patient deteriorated rapidly and suffered a cardiopulmonary arrest. Autopsy revealed a congested liver and spleen associated with a dilated cardiomyopathy and lymphocytic myocarditis. CONCLUSION: Medically virulent disease processes can mimic the common pregnancy complaint of nausea and vomiting. Intrinsic cardiac disease with secondary hepatic compromise is a rare cause of gastrointestinal symptomatology early in pregnancy.

Thrombotic thrombocytopenic purpura masquerading as hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome in late pregnancy.

BACKGROUND: Thrombotic thrombocytopenic purpura rarely presents during late pregnancy or immediately postpartum. This report describes the clinical course of a patient considered to have hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome but later determined to have thrombotic thrombocytopenic purpura. CASE: At 37 weeks of gestation, a multiparous woman was diagnosed with HELLP syndrome. She received high-dose dexamethasone, magnesium, antihypertensives, and platelets before delivery. Over the next 36 hours, renal function acutely worsened and death ensued. One week after death a plasma ADAMTS13 activity of 4% was reported. CONCLUSION: Thrombotic thrombocytopenic purpura can mimic HELLP syndrome late in gestation. Lack of response to dexamethasone within 12-24 hours and atypical relationships among laboratory values are two clues that thrombotic thrombocytopenic purpura may be the underlying pathology and that plasma exchange is emergently needed.

Understanding and managing HELLP syndrome: the integral role of aggressive glucocorticoids for mother and child.

Antepartum or postpartum HELLP syndrome constitutes an obstetric emergency that requires expert knowledge and management skills. The insidious and variable nature of disease presentation and progression challenges the clinician and complicates consensus on universally accepted diagnostic and classification criteria. A critical review of published research about this variant form of severe preeclampsia, focused primarily on what is known about the pathogenesis of this disorder as it relates to patient experience with corticosteroids for its management, leads to the conclusion that there is maternal-fetal benefit realized when potent glucocorticoids are aggressively used for its treatment. Although acknowledging the need for definitive multicenter trials to better define the limits of benefit and the presence of any maternal or fetal risk, and given an understanding of the nature of the disorder with its potential to cause considerable maternal morbidity and mortality, we recommend for the present that aggressively used potent glucocorticoids constitute the cornerstone of management for patients considered to have HELLP syndrome.

Tocolysis in women with advanced preterm labor: a secondary analysis of a randomized clinical trial.

OBJECTIVE: To compare the efficacy of tocolytic treatment with indomethacin (I), magnesium sulfate (M) and nifedipine (N) for acute tocolysis in women with advanced cervical dilation (4-6 cm). METHODS: A single center, randomized trial was carried out involving patients in preterm labor (cervix 1-6 cm). Secondary analysis of women with advanced cervical dilation (cervix 4-6 cm) at 24-32 weeks' gestation who received intravenous M, oral N or I suppositories comprised this study population. RESULTS: Over 38 months, 92 women with advanced cervical dilation were randomized to one tocoloytic type. Days gained in utero (11.7) and percent remaining undelivered at 48 h (60.8%), 72 h (53.1%) and >7 days (38.3%) were similar regardless of tocolytic employed (p = 0.923, 0.968, 0.791, 0.802, respectively). Likewise, gestational age at delivery (30.7 ± 3.2) was similar between groups (p = 0.771). Finally, neonatal statistics were not different when stratified by tocolytic treatment. CONCLUSION: There were no statistical differences between tocolytics in treating women with advanced cervical dilation. All offered significant days gained in utero after therapy, a high percentage remaining undelivered after 48 or 72 h and after 7 days. It would appear from data that there may be advantages to tocolytic treatment even in women with advanced cervical dilation.

Neonatal organ dysfunction among newborns at gestational age 34 weeks and umbilical arterial pH<7.00.

PURPOSE: Among newborns at 34 weeks or more with umbilical arterial pH<7.00, we endeavoured to determine the pH threshold and risk factors for neonatal organ injury within 72 hours of birth. STUDY DESIGN: Retrospectively, all non-anomalous newborns delivered over 6 years near term with a low pH were identified. Each case of a newborn with injury was compared with the next four neonates with a pH below 7.00 and no injury. A receiver-operating characteristic (ROC) curve and unconditional logistic regression was used. RESULTS: Of the 87 newborns with pathologic acidosis, 16% had neonatal organ system injury. Inspection of the ROC curve indicates that a pH of 6.92 is the threshold that identifies newborns who will have damage to organs. Unconditional logistic regression analysis indicates that the significant risk factors for morbidity were an Apgar score or=37 weeks, pH

The use of 17-hydroxy progesterone in women with arrested preterm labor: a randomized clinical trial.

BACKGROUND: The use of 17-alpha-hydroxyprogesterone caproate (17 P) has been shown to reduce preterm delivery in women who have had a prior preterm birth. The role of 17 P in women with arrested preterm labor is less certain. AIMS: To compare the preterm birth rate and neonatal outcome in women with arrested preterm labor randomized to receive 17 P or placebo. MATERIALS AND METHODS: Women with arrested preterm labor were randomized to weekly injections of either 17 P (250 mg) or placebo. Maternal and neonatal outcome were evaluated. RESULTS: Forty-five singleton pregnancies were randomized after successful tocolysis; 22 received 17 P while 23 got placebo. Gestational age at delivery (p = 0.067) and the interval from treatment to delivery (p = 0.233) were not affected by 17 P. Significantly less women in the 17 P group delivered at <34 weeks (14 versus 21, p = 0.035). There was also a significant reduction in the risk of neonatal sepsis (p = 0.047) and gr III/IV intraventricular hemorrhage (IVH) (p = 0.022) in the 17 P group. CONCLUSION: In this study, 17 P did not delay the interval to delivery after successful preterm labor, but births <34 weeks as well as neonatal sepsis and IVH were reduced by 17 P treatment.

A comparison of three tocolytics for preterm labor: a randomized clinical trial.

OBJECTIVE: To compare the efficacy and maternal side effects of nifedipine (N), magnesium sulfate (M), and indomethacin (I) for acute tocolysis. METHODS: In this single center randomized trial, women in preterm labor 24-32 weeks' gestation received intravenous M, oral N, or I suppositories. The primary outcomes of interest were arrest of preterm labor (>48 h, ≥7 days), gestational age at delivery, and maternal side effects. RESULTS: Over a 38-month period, 301 women were allocated to receive M (90), N (114), or I (90). Gestational age at delivery (p = 0.551) or arrest of labor >48 h, >7 days were similar between the three groups (p = 0.199, 0.654). Hypotension and tachycardia were more common in N patients compared to women receiving M or I (p = 0.003, 0.009). Patients receiving I had more fetal ductal constriction or oligohydramnios compared to M or N (p = 0.001, 0.020) but, I women were tested more often. There was one case of pulmonary edema in the M group and one with plural effusion in the N group. CONCLUSION: There were no differences in efficacy or in major maternal safety issues between the three tocolytic agents. Since there is no FDA approved tocolytic to treat preterm labor, clinicians should use the tocolytic that has afforded them the best results with the least maternal/neonatal side effects.

Effect of antenatal tocolysis on neonatal outcomes.

OBJECTIVE: Detail adverse neonatal effects in pregnancies treated with indomethacin (I), magnesium sulfate (M) or nifedipine (N). METHODS: Women in acute preterm labor with cervical dilatation 1-6 cm were randomized to receive one of three first-line tocolytic drugs. RESULTS: There were 317 neonates (I = 103, M = 95, N = 119) whose mothers were treated with tocolytic therapy. There was no difference in gestational age at randomization (average 28.6 weeks' gestation) or at delivery (31.6 weeks' gestation, p = 0.551), birth weight (p = 0.871) or ventilator days (p = 0.089) between the three groups. Neonatal morbidity was not different between the three groups; respiratory distress syndrome (p = 0.086), patent ductus arteriosus (p = 0.592), sepsis (p = 0.590), necrotizing enterocolitis (p = 0.770), intraventricular hemorrhage (p = 0.669) and periventricular leukomalacia (p = 0.124). CONCLUSIONS: There were no statistically significant differences between the three tocolytics as far as composite neonatal morbidity or mortality was concerned.

Timing of placental delivery to prevent post-partum haemorrhage: lessons learned from an abandoned randomised clinical trial.

It has been recognised that, if the length of the third stage of labour exceeds 30 min, then there is an increased risk of a post-partum haemorrhage. Recent information has suggested that 18 min is the optimal time for removal of the undelivered placenta to prevent a post-partum haemorrhage. A randomised trial comparing 20 vs. 30 min was stopped after an interim analysis because only eight of 1607 patients' placentas had not delivered by 20 min. A third stage of labour that exceeded 10 min was observed to be significantly correlated with an increased risk of post-partum haemorrhage.