Cervical funneling or intra-amniotic debris and preterm birth in nulliparous women with midtrimester cervical length less than 30 mm.

OBJECTIVE: To evaluate whether the presence of cervical funneling or intra-amniotic debris identified in the second trimester is associated with a higher rate of preterm birth (PTB) in asymptomatic nulliparous pregnant women with a midtrimester cervical length (CL) less than 30 mm (i.e. below the 10th percentile). METHODS: This was a secondary cohort analysis of data from a multicenter trial in nulliparous women between 16 and 22 weeks' gestation with a singleton gestation and CL less than 30 mm on transvaginal ultrasound, randomized to treatment with either 17-alpha-hydroxyprogesterone caproate or placebo. Sonographers were centrally certified in CL measurement, as well as in identification of intra-amniotic debris and cervical funneling. Univariable and multivariable analysis was performed to assess the associations of cervical funneling and intra-amniotic debris with PTB. RESULTS: Of the 657 women randomized, 112 (17%) had cervical funneling only, 33 (5%) had intra-amniotic debris only and 45 (7%) had both on second-trimester ultrasound. Women with either of these findings had a shorter median CL than those without (21.0 mm vs 26.4 mm; P < 0.001). PTB prior to 37 weeks was more likely in women with cervical funneling (37% vs 21%; odds ratio (OR), 2.2 (95% CI, 1.5-3.3)) or intra-amniotic debris (35% vs 23%; OR, 1.7 (95% CI, 1.1-2.9)). Results were similar for PTB before 34 and before 32 weeks' gestation. After multivariable adjustment that included CL, PTB < 34 and < 32 weeks continued to be associated with the presence of intra-amniotic debris (adjusted OR (aOR), 1.85 (95% CI, 1.00-3.44) and aOR, 2.78 (95% CI, 1.42-5.45), respectively), but not cervical funneling (aOR, 1.17 (95% CI, 0.63-2.17) and aOR, 1.45 (95% CI, 0.71-2.96), respectively). CONCLUSIONS: Among asymptomatic nulliparous women with midtrimester CL less than 30 mm, the presence of intra-amniotic debris, but not cervical funneling, is associated with an increased risk for PTB before 34 and 32 weeks' gestation, independently of CL. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Vitamin D, pre-eclampsia, and preterm birth among pregnancies at high risk for pre-eclampsia: an analysis of data from a low-dose aspirin trial.

OBJECTIVE: To examine the relation between maternal vitamin D status and risk of pre-eclampsia and preterm birth in women at high risk for pre-eclampsia. DESIGN: Analysis of prospectively collected data and blood samples from a trial of prenatal low-dose aspirin. SETTING: Thirteen sites across the USA. POPULATION: Women at high risk for pre-eclampsia. METHODS: We measured 25-hydroxyvitamin D [25(OH)D] concentrations in stored maternal serum samples drawn at 12-26 weeks' gestation (n = 822). We used mixed effects models to examine the association between 25(OH)D and risk of pre-eclampsia and preterm birth, controlling for confounders including prepregnancy BMI and race. MAIN OUTCOME MEASURES: Pre-eclampsia and preterm birth. RESULTS: Twelve percent of women were vitamin D deficient [25(OH)D <30 nmol/l]. Women with 25(OH)D <30 versus ≥75 nmol/l had a 2.4-fold (95% CI 1.0-5.6) higher risk of early-onset pre-eclampsia (<35 weeks' gestation) after confounder adjustment. Women with 25(OH)D <50 nmol/l had a 1.8-fold (95% CI 1.0-3.2) increased risk of preterm birth at <35 weeks compared with women who had 25(OH)D ≥75 nmol/l, which was driven by indicated preterm births at <35 weeks' gestation [25(OH)D <50 versus ≥75 nmol/l adjusted RR 2.5 (95% CI 1.1-5.8)]. There was no association between vitamin D status and pre-eclampsia or preterm birth at <37 weeks. CONCLUSION: Maternal vitamin D status in the second trimester was inversely associated with risk of early-onset pre-eclampsia and preterm birth at <35 weeks in women at high risk for pre-eclampsia. TWEETABLE ABSTRACT: Vitamin D is inversely related to risk of pre-eclampsia and preterm birth at <35 weeks in high-risk pregnancies.

17-Hydroxyprogesterone caproate in triplet pregnancy: an individual patient data meta-analysis.

BACKGROUND: Preterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective. OBJECTIVE: To determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-hydroxyprogesterone caproate (17OHPc). SEARCH STRATEGY: We searched literature databases, trial registries and references in published articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies. DATA COLLECTION AND ANALYSIS: Investigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32 weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at <24, <28 and <34 weeks of gestation. MAIN RESULTS: Three RCTs of 17OHPc versus placebo included 232 mothers with triplet pregnancies and their 696 offspring. Risk-of-bias scores and between-study heterogeneity were low. Baseline characteristics were comparable between 17OHPc and placebo groups. The rate of the composite adverse perinatal outcome was similar among those treated with 17OHPc and those treated with placebo (34 and 35%, respectively; risk ratio [RR] 0.98, 95% confidence interval [95% CI] 0.79-1.2). The rate of birth at <32 weeks was also similar in the two groups (35 and 38%, respectively; RR 0.92, 95% CI 0.55-1.56). There were no significant between-group differences in perinatal mortality rate, randomisation-to-delivery interval, or other specified outcomes. CONCLUSION: Prophylactic 17OHPc given to mothers with triplet pregnancies had no significant impact on perinatal outcome or pregnancy duration. TWEETABLE ABSTRACT: 17-Hydroxyprogesterone caproate had no significant impact on the outcome or duration of triplet pregnancy.

The association of beta-2 adrenoceptor genotype with short-cervix mediated preterm birth: a case-control study.

OBJECTIVE: To determine whether ß2 -adrenoceptor (ß2 AR) genotype is associated with shortening of the cervix or with preterm birth (PTB) risk among women with a short cervix in the second trimester. DESIGN: A case-control ancillary study to a multicentre randomised controlled trial. SETTING: Fourteen participating centres of the Maternal-Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. POPULATION: Four hundred thirty-nine women, including 315 with short cervix and 124 with normal cervical length. METHODS: Nulliparous women with cervical length <30 mm upon a 16-22-week transvaginal sonogram and controls frequency-matched for race/ethnicity with cervical lengths ≥40 mm were studied. ß2 AR genotype was determined at positions encoding for amino acid residues 16 and 27. MAIN OUTCOME MEASURES: Genotype distributions were compared between case and control groups. Within the short cervix group, pregnancy outcomes were compared by genotype, with a primary outcome of PTB <37 weeks. RESULTS: Genotype data were available at position 16 for 433 women and at position 27 for 437. Using a recessive model testing for association between short cervix and genotype, and adjusted for ethnicity, there was no statistical difference between cases and controls for Arg16 homozygosity (OR 0.7, 95% CI 0.4-1.3) or Gln27 homozygosity (OR 0.9, 95% CI 0.3-2.7). Among cases, Arg16 homozygosity was not associated with protection from PTB or spontaneous PTB. Gln27 homozygosity was not associated with PTB risk, although sample size was limited. CONCLUSIONS: ß2 AR genotype does not seem to be associated with short cervical length or with PTB following the second-trimester identification of a short cervix. Influences on PTB associated with ß2 AR genotype do not appear to involve a short cervix pathway.

Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.

BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB). OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA). SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles. SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB. MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75). AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

Neonatal Genetic Variation in Steroid Metabolism and Key Respiratory Function Genes and Perinatal Outcomes in Single and Multiple Courses of Corticosteroids.

OBJECTIVE: The aim of the study is to evaluate the association of steroid metabolism and respiratory gene polymorphisms in neonates exposed to antenatal corticosteroids (ACS) with respiratory outcomes, small for gestational age (SGA), and response to repeat ACS. STUDY DESIGN: This candidate gene study is a secondary analysis of women enrolled in a randomized controlled trial of single versus weekly courses of ACS. Nineteen single nucleotide polymorphisms (SNPs) in 13 steroid metabolism and respiratory function genes were evaluated. DNA was extracted from placenta or fetal cord serum and analyzed with TaqMan genotyping. Each SNP was evaluated for association via logistic regression with respiratory distress syndrome (RDS), continuous positive airway pressure (CPAP)/ventilator use (CPV), and SGA. RESULTS: CRHBP, CRH, and CRHR1 minor alleles were associated with an increased risk of SGA. HSD11B1 and SCNN1B minor alleles were associated with an increased likelihood of RDS. Carriage of minor alleles in SerpinA6 was associated with an increased risk of CPV. CRH and CRHR1 minor alleles were associated with a decreased likelihood of CPV. CONCLUSION: Steroid metabolism and respiratory gene SNPs are associated with respiratory outcomes and SGA in patients exposed to ACS. Risks for respiratory outcomes are affected by minor allele carriage as well as by treatment with multiple ACS.

Characteristics of women with nausea and vomiting of pregnancy who chose to continue compassionate use of placebo after a randomised trial.

The placebo effect has not been characterised in pregnant women suffering from nausea and vomiting of pregnancy (NVP). Our aim was to characterise determinants of the placebo effect in women treated with placebo for NVP. We analysed data from a multicentre, double blind randomised controlled trial of Diclectin (delayed release doxylamine and pyridoxine) vs placebo for the treatment of NVP. A total of 127 women in the placebo arm and 130 in the active arm provided evaluable data for this analysis. Women who chose to continue placebo on a compassionate basis (n = 41) had significantly better improvement in symptoms of NVP and higher Wellbeing scores than those who did not ask to continue compassionate use. Results were similar in the active drug arm. The request to continue compassionate use of either placebo or active drug could be predicted by greater improvement in symptoms of NVP during the trial period.

Vitamin D status and recurrent preterm birth: a nested case-control study in high-risk women.

OBJECTIVE: To determine whether vitamin D status is associated with recurrent preterm birth, and any interactions between vitamin D levels and fish consumption. DESIGN: A nested case-control study, using data from a randomised trial of omega-3 fatty acid supplementation to prevent recurrent preterm birth. SETTING: Fourteen academic health centres in the USA. POPULATION: Women with prior spontaneous preterm birth. METHODS: In 131 cases (preterm delivery at <35 weeks of gestation) and 134 term controls, we measured serum 25-hydroxyvitamin D [25(OH)D] concentrations by liquid chromatography-tandem mass spectrometry (LC-MS) from samples collected at baseline (16-22 weeks of gestation). Logistic regression models controlled for study centre, maternal age, race/ethnicity, number of prior preterm deliveries, smoking status, body mass index, and treatment. MAIN OUTCOME MEASURES: Recurrent preterm birth at <37 and <32 weeks of gestation. RESULTS: The median mid-gestation serum 25(OH)D concentration was 67 nmol/l, and 27% had concentrations of <50 nmol/l. Serum 25(OH)D concentration was not significantly associated with preterm birth (OR 1.33; 95% CI 0.48-3.70 for lowest versus highest quartiles). Likewise, comparing women with 25(OH)D concentrations of 50 nmol/l, or higher, with those with <50 nmol/l generated an odds ratio of 0.80 (95% CI 0.38-1.69). Contrary to our expectation, a negative correlation was observed between fish consumption and serum 25(OH)D concentration (-0.18, P < 0.01). CONCLUSIONS: In a cohort of women with a prior preterm birth, vitamin D status at mid-pregnancy was not associated with recurrent preterm birth.

Preterm prediction study: comparison of the cervical score and Bishop score for prediction of spontaneous preterm delivery.

OBJECTIVE: To prospectively compare digital cervical score with Bishop score as a predictor of spontaneous preterm delivery before 35 weeks of gestation. METHODS: Data from a cohort of 2,916 singleton pregnancies enrolled in a multicenter preterm prediction study were available. Patients underwent digital cervical examinations at 22-24 and 26-29 weeks of gestation for calculation of Bishop score and cervical score. Relationships between Bishop score, cervical score, and spontaneous preterm delivery were assessed with multivariable logistic regression analysis, McNemar test, and receiver operating characteristic (ROC) curves to identify appropriate diagnostic thresholds and predictive capability. RESULTS: One hundred twenty-seven of 2,916 patients (4.4%) undergoing cervical examination at 22-24 weeks had a spontaneous preterm delivery before 35 weeks. Eighty-four of the 2,538 (3.3%) reexamined at 26-29 weeks also had spontaneous preterm delivery. Receiver operating characteristic curves indicated that optimal diagnostic thresholds for Bishop score were at least 4 at 22-24 weeks, at least 5 at 26-29 weeks, and less than 1.5 at both examinations for cervical score. At 22-24 weeks, areas under the ROC curve favored Bishop score. At 26-29 weeks, there was no significant difference in areas under the ROC curve; however, a cervical score less than 1.5 (sensitivity 35.7%, false positive rate 4.8%) was superior to a Bishop score of 5 or more (P<.001). CONCLUSION: Both cervical evaluations are associated with spontaneous preterm delivery in a singleton population; however, predictive capabilities for spontaneous preterm delivery were modest among women with low event prevalence. Although Bishop score performed better in the mid trimester, by 26-29 weeks a cervical score less than 1.5 was a better predictor of spontaneous preterm delivery before 35 weeks than a Bishop score of at least 5.

Oseltamivir for the treatment of H1N1 influenza during pregnancy.

Pregnancy heightens the risk of adverse outcomes from influenza infections. This is true for both seasonal epidemics as well as occasional pandemics. Seasonal influenza vaccines are the focus of disease prevention and are recommended for all pregnant women in any trimester of pregnancy and postpartum. Oseltamivir (Tamiflu) is currently the recommended and most commonly used pharmaceutical agent for influenza prophylaxis and treatment. Oseltamivir has been demonstrated to prevent disease after exposure, treat infected individuals, as well as lessen the likelihood of complications. The physiologic adaptations of pregnancy alter the pharmacokinetics of this important drug. Evidence of these alterations, knowledge gaps, and future investigative directions to fill these knowledge gaps are highlighted.

Adrenergic stimulation of placental progesterone production.

Cells from term human placentas were maintained in culture, and progesterone production was monitored over 24 h. The beta 1-adrenergic receptor agonist dobutamine (10(-5) M) and the beta 2-adrenergic receptor agonist terbutaline (10(-5) M) increased progesterone production by 36 +/- 19% and 49 +/- 8% (+/- SE), respectively, compared with that in controls (P less than 0.001). Propranolol (10(-5) M) completely blocked the stimulatory effects of both drugs. The cAMP analog 8-bromo-cAMP (0.5 mM) also significantly altered (increased) progesterone production compared with controls (P less than 0.001), but this effect was not blocked to a significant degree by propranolol. The alpha-adrenergic receptor agonist methoxamine (10(-4) - 10(-6) M) did not significantly alter placental progesterone production compared with controls, and the stimulatory effect of terbutaline on progesterone production was not significantly affected by blockade of the alpha-adrenergic receptor with phentolamine. These data indicate that placental progesterone production can be significantly modulated by stimulation of beta-adrenergic, but not by alpha-adrenergic, receptors. This response may be mediated by increased intracellular cAMP. These findings may be important in considering other metabolic functions of the placenta as well as the treatment of preterm labor.

Treatment of preterm labour. A review of the therapeutic options.

Preterm delivery accounts for a major proportion of perinatal deaths. The cause of preterm labour is usually not known, but in most instances, maintaining the fetus in utero appears to be preferred to allowing preterm delivery. Numerous pharmacological agents have been utilised to inhibit preterm labour, but none has proven to be ideal. Currently, the beta-adrenoceptor stimulants such as ritodrine, terbutaline, isoxsuprine, salbutamol and fenoterol provide the best combination of safety and efficacy. However, because of their potential adverse effects, adequate maternal and fetal surveillance needs to be maintained throughout their administration. Magnesium sulphate, although probably not as effective as other labour-inhibiting drugs, is an appropriate choice when the beta-adrenoceptor stimulants are either contraindicated or poorly tolerated. Other drugs such as the prostaglandin inhibitors, diazoxide or the calcium antagonists are also potent labour-inhibitors, but further controlled studies are required to evaluate the risks associated with their use. Ethanol has been supplanted by the beta-adrenoceptor stimulants and is unlikely to be used in the future.

Changes in uterine venous prostaglandin F metabolites following intravenous infusion of ritodrine in sheep.

The effectiveness of the beta-adrenergic receptor agonist ritodrine as a tocolytic agent is limited by the tachyphylaxis that occurs with its sustained usage. In order to understand the nature of this tachyphylaxis, we investigated the effect of ritodrine on uteroplacental prostaglandin (PG)F2 alpha production in pregnant sheep. Using general anesthesia in five pregnant sheep, we placed catheters in the aorta and vena cava and in the uterine vein from the uterine horn. In random order on different days, we infused ritodrine (4 micrograms/kg/minute) or physiologic saline into the maternal vena cava at a rate of 0.184 mL/minute. Uterine venous and maternal arterial blood was sampled 60 minutes before and immediately before the infusion and then at 60, 120, 180, and 240 minutes during the infusion. After centrifugation, the serum was frozen and then assayed for the metabolite of PGF2 alpha (PGFM). Uterine venous PGFM increased significantly after 60 minutes of ritodrine infusion (mean increase 1.164 ng/mL; P less than .05), and this increase was sustained during the 4-hour infusion. The PGFM gradient across the uteroplacental bed (uterine vein - aorta) was also significantly elevated during the infusion, suggesting a uteroplacental or fetal membrane source of the PG. Saline had no effect on uterine venous PGFM or the PGFM gradient. These results suggest that ritodrine stimulates PGF2 alpha production, and this may contribute to the tachyphylaxis that occurs with ritodrine and limits its long-term effectiveness as a tocolytic agent.

Fetal acid-base state following spinal or epidural anesthesia for cesarean section.

The authors compared fetal acid-base state and maternal blood pressure response in 111 women undergoing repeat cesarean section with either epidural or spinal anesthesia. Fetal umbilical acidemia (umbilical venous pH less than 7.25 or umbilical arterial pH less than 7.20) was more commonly observed following spinal anesthesia with a preanesthetic fluid load of 500 to 999 ml (20% of cases) than with epidural anesthesia (4% of cases. P > .05, chi 2). The incidence of fetal acidemia following spinal anesthesia was similar to that following epidural anesthesia when 1000 to 1500 ml of fluid was infused prior to spinal anesthesia. The maximum reduction in systolic blood pressure following spinal anesthesia was not related to preanesthetic fluid load; however, in cases of severe hypotension the hypotensive episode was shorter and easier to treat when the preanesthetic fluid load was 1000 to 1500 ml rather than 500 to 999 ml. These data suggest that women receiving spinal anesthesia for repeat cesarean section should be given an intravenous fluid load of 1 liter or more.

Sinusoidal fetal heart rate pattern following intrauterine fetal transfusion.

Two patients with severe rhesus isoimmunization had sinusoidal fetal heart rate patterns following intrauterine fetal transfusion. A consistent temporal relationship between fetal transfusion and sinusoidal fetal heart rate pattern was observed. Survival of a fetus who had a sinusoidal fetal heart rate pattern after each of three transfusions suggests that this pattern may not be ominous when observed transiently after fetal transfusion.

Placental abruption in the preterm gestation: an association with chorioamnionitis.

Thirty-seven women with acute severe preterm placental abruption were compared with a control group of 51 women requiring preterm delivery for a medical complication of pregnancy. Histologic chorioamnionitis and funisitis were present significantly more often in patients with abruption than in control patients (41 versus 4%; P less than .0001). No patient in either group had clinical evidence of chorioamnionitis. We conclude that a significant association exists between preterm placental abruption and histologic chorioamnionitis.

Effects of terbutaline on the pregnant baboon and fetus.

The effects of terbutaline on the mother and fetus were evaluated in 8 near-term pregnant baboons. Significant suppression of postoperative spontaneous and oxytocin-augmented uterine activity was achieved with infusion rates of 0.36 and 0.56 microgram/kg/min, respectively. Maternal and fetal blood pressure and acid-base states as well as fetal heart rate were unaffected by the administration of terbutaline to the mother, but a mild maternal tachycardia was observed. Both maternal and fetal blood glucose increased during terbutaline infusion. Direct administration of terbutaline to the fetus did not alter the fetal cardiovascular or acid-base state. It is concluded that in the baboon, terbutaline is an effective tocolytic agent with minimal untoward effects on either mother or fetus.

Nonsurgical management of placenta percreta: a case report.

BACKGROUND: Although placenta percreta is rare, its sequelae include potentially lethal hemorrhage and loss of reproductive function. Therapy directed toward control of life-threatening hemorrhage frequently includes emergency hysterectomy. CASE: A woman with placenta percreta, suspected clinically and documented radiographically, was treated nonsurgically. Following delivery, the placenta was left in situ and methotrexate chemotherapy was initiated to aid destruction of the trophoblastic tissue. Eight months later, hysteroscopy showed a normal uterine cavity with only a small area of calcification at the presumed implantation site. Two years later, the patient had a normal pregnancy and vaginal delivery. CONCLUSION: Placenta percreta can be managed with preservation of the uterus, but careful follow-up may be required until the entire placenta has resorbed.