Retained placenta: will medical treatment ever be possible?

The standard treatment for retained placenta is manual removal whatever its subtype (adherens, trapped or partial accreta). Although medical treatment should reduce the risk of anesthetic and surgical complications, they have not been found to be effective. This may be due to the contrasting uterotonic needs of the different underlying pathologies. In placenta adherens, oxytocics have been used to contract the retro‐placental myometrium. However, if injected locally through the umbilical vein, they bypass the myometrium and perfuse directly into the venous system. Intravenous injection is an alternative but exacerbates a trapped placenta. Conversely, for trapped placentas, a relaxant could help by resolving cervical constriction, but would worsen the situation for placenta adherens. This confusion over medical treatment will continue unless we can find a way to diagnose the underlying pathology. This will allow us to stop treating the retained placenta as a single entity and to deliver targeted treatments

Nitroglycerin for Management of Retained Placenta: A Multicenter Study

The primary aim was to determine if sequential administration of oxytocin and nitroglycerin is effective for management of retained placenta when performed by obstetricians with no experience of the method. Secondary aims were to examine possible adverse effects of nitroglycerin. One hundred and five women with retained placenta were randomly selected to receive either 1 mg nitroglycerin or placebo tablets sublingually if intravenous oxytocin had failed to expel the placenta. At two of the hospitals some of the midwives were familiar with the use of nitroglycerin. The other midwives and all the participating obstetricians had no clinical experience of the method. In the treatment group, detachment of placenta following nitroglycerin occurred in 37.3% of the women compared to 20.4% in the placebo group (P = 0.056). In the two hospitals with some experience of the method, placenta was removed in 9 of 19 (47.4%) women in the nitroglycerin group compared to 3 of 17 (15.0%) women in the placebo group. No adverse effects of clinical importance were registered. Although the difference between the two groups did not reach statistical significance, the higher success rate in the two hospitals with some experience could indicate that clinical experience is of importance in order to achieve placental detachment

Vitamin D Status during Pregnancy in a Multi-Ethnic Population-Representative Swedish Cohort

There is currently little information on changes in vitamin D status during pregnancy and its predictors. The aim was to study the determinants of change in vitamin D status during pregnancy and of vitamin D deficiency (<30 nmol/L) in early pregnancy. Blood was drawn in the first (T1) and third trimester (T3). Serum 25-hydroxyvitamin D (25(OH)D) (N = 1985) was analysed by liquid chromatography tandem-mass spectrometry. Season-corrected 25(OH)D was calculated by fitting cosine functions to the data. Mean (standard deviation) 25(OH)D was 64.5(24.5) nmol/L at T1 and 74.6(34.4) at T3. Mean age was 31.3(4.9) years, mean body mass index (BMI) was 24.5(4.2) kg/m2 and 74% of the women were born in Sweden. Vitamin D deficiency was common among women born in Africa (51%) and Asia (46%) and prevalent in 10% of the whole cohort. Determinants of vitamin D deficiency at T1 were of non-North European origin, and had less sun exposure, lower vitamin D intake and lower age. Season-corrected 25(OH)D increased by 11(23) nmol/L from T1 to T3. The determinants of season-corrected change in 25(OH)D were origin, sun-seeking behaviour, clothing style, dietary vitamin D intake, vitamin D supplementation and recent travel <35° N. In conclusion, season-corrected 25(OH)D concentration increased during pregnancy and depended partly on lifestyle factors. The overall prevalence of vitamin D deficiency was low but common among women born in Africa and Asia. Among them, the determinants of both vitamin D deficiency and change in season-corrected vitamin D status were fewer, indicating a smaller effect of sun exposure

The association between selected mid-trimester amniotic fluid candidate proteins and spontaneous preterm delivery

Objective: The aim of this study was to explore inflammatory response and identify early potential biomarkers in mid-trimester amniotic fluid associated with subsequent spontaneous preterm delivery (PTD). Methods: A cohort study was performed at Sahlgrenska University Hospital/ 6stra, Gothenburg, Sweden, between 2008 and 2010. Amniotic fluid was collected from consecutive women undergoing mid-trimester transabdominal genetic amniocentesis at 14–19 gestational weeks. Clinical data and delivery outcome variables were obtained from medical records. The analysis included 19 women with spontaneous PTD and 118 women who delivered at term. A panel of 26 candidate proteins was analyzed using Luminex xMAP technology. Candidate protein concentrations were analyzed with ANCOVA and adjusted for plate effects. Results: The median gestational age at delivery was 35 + 3 weeks in women with spontaneous PTD and 40 + 0 weeks in women who delivered at term. Nominally significantly lower amniotic fluid levels of adiponectin (PTD: median 130,695 pg/mL (IQR 71,852–199,414) vs term: median 185,329 pg/mL (IQR (135,815–290,532)), granulocyte-macrophage colony stimulating factor (PTD: median 137 pg/mL (IQR 74–156) vs term: median 176 pg/mL (IQR 111–262)), and macrophage migration inhibitory factor (PTD: median 3025 pg/mL (IQR 1885–3891) vs term: median 3400 pg/mL (IQR 2181–5231)) were observed in the spontaneous PTD group, compared with the term delivery group, after adjusting for plate effects. No significant differences remained after Bonferroni correction for multiple comparisons. Conclusions: Our results are important in the process of determining the etiology behind spontaneous PTD but due to the non-significance after Bonferroni correction, the results should be interpreted with caution. Further analyses of larger sample size will be required to determine whether these results are cogent and to examine whether microbial invasion of the amniotic cavity or intra-amniotic inflammation occurs in asymptomatic women in the mid-trimester with subsequent spontaneous PTD

Late pregnancy vitamin D deficiency is associated with doubled odds of birth asphyxia and emergency caesarean section: A prospective cohort study

Objectives: The aim of this prospective cohort study was to investigate the associations between maternal vitamin D status in late pregnancy and emergency caesarean section (EMCS) and birth asphyxia, in a population based sample of women in Sweden. Methods: Pregnant women were recruited at the antenatal care in Sweden and 1832 women were included after exclusion of miscarriages, terminated pregnancies and missing data on vitamin D status. Mode of delivery was retrieved from medical records. EMCS was defined as caesarean section after onset of labour. Birth asphyxia was defined as either 5 min Apgar score < 7 or arterial umbilical cord pH < 7.1. Serum was sampled in the third trimester of pregnancy (T3) and 25-hydroxyvitamin D (25OHD) was analysed by liquid chromatography tandem mass spectrometry. Vitamin D deficiency was defined as 25OHD < 30 nmol/L, and associations were studied using logistic regression analysis and expressed as adjusted odds ratios (AOR). Results: In total, 141 (7.7%) women had an EMCS and 58 (3.2%) children were born with birth asphyxia. Vitamin D deficiency was only associated with higher odds of EMCS in women without epidural anaesthesia (AOR = 2.01, p = 0.044). Vitamin D deficiency was also associated with higher odds of birth asphyxia (AOR = 2.22, p = 0.044). Conclusions for Practice: In this Swedish prospective population-based cohort study, vitamin D deficiency in late pregnancy was associated with doubled odds of birth asphyxia and with EMCS in deliveries not aided by epidural anaesthesia. Prevention of vitamin D deficiency among pregnant women may reduce the incidence of EMCS and birth asphyxia. The mechanism behind the findings require further investigation

Trajectory of vitamin D status during pregnancy in relation to neonatal birth size and fetal survival: a prospective cohort study

Background: We investigated the associations between vitamin D status in early and late pregnancy with neonatal small for gestational age (SGA), low birth weight (LBW) and preterm delivery. Furthermore, associations between vitamin D status and pregnancy loss were studied. Methods: Serum 25-hydroxyvitamin D (25OHD) was sampled in gestational week ≤ 16 (trimester 1 (T1), N = 2046) and > 31 (trimester 3 (T3), N = 1816) and analysed using liquid chromatography tandem mass spectrometry. Pregnant women were recruited at antenatal clinics in south-west Sweden at latitude 57–58°N. Gestational and neonatal data were retrieved from medical records. Multiple gestations and terminated pregnancies were excluded from the analyses. SGA was defined as weight and/or length at birth < 2 SD of the population mean and LBW as < 2500 g. Preterm delivery was defined as delivery < 37 + 0 gestational weeks and pregnancy loss as spontaneous abortion or intrauterine fetal death. Associations between neonatal outcomes and 25OHD at T1, T3 and change in 25OHD (T3-T1) were studied using logistic regression. Results: T1 25OHD was negatively associated with pregnancy loss and 1 nmol/L increase in 25OHD was associated with 1% lower odds of pregnancy loss (OR 0.99, p = 0.046). T3 25OHD ≥ 100 nmol/L (equal to 40 ng/ml) was associated with lower odds of SGA (OR 0.3, p = 0.031) and LBW (OR 0.2, p = 0.046), compared to vitamin D deficiency (25OHD < 30 nmol/L, or 12 ng/ml). Women with a ≥ 30 nmol/L increment in 25OHD from T1 to T3 had the lowest odds of SGA, LBW and preterm delivery. Conclusions: Vitamin D deficiency in late pregnancy was associated with higher odds of SGA and LBW. Lower 25OHD in early pregnancy was only associated with pregnancy loss. Vitamin D status trajectory from early to late pregnancy was inversely associated with SGA, LBW and preterm delivery with the lowest odds among women with the highest increment in 25OHD. Thus, both higher vitamin D status in late pregnancy and gestational vitamin D status trajectory can be suspected to play a role in healthy pregnancy

Preeclampsia and Blood Pressure Trajectory during Pregnancy in Relation to Vitamin D Status

Every tenth pregnancy is affected by hypertension, one of the most common complications and leading causes of maternal death worldwide. Hypertensive disorders in pregnancy include pregnancy-induced hypertension and preeclampsia. The pathophysiology of the development of hypertension in pregnancy is unknown, but studies suggest an association with vitamin D status, measured as 25-hydroxyvitamin D (25(OH)D). The aim of this study was to investigate the association between gestational 25(OH)D concentration and preeclampsia, pregnancy-induced hypertension and blood pressure trajectory. This cohort study included 2000 women. Blood was collected at the first (T1) and third (T3) trimester (mean gestational weeks 10.8 and 33.4). Blood pressure at gestational weeks 10, 25, 32 and 37 as well as symptoms of preeclampsia and pregnancy-induced hypertension were retrieved from medical records. Serum 25(OH)D concentrations (LC-MS/MS) in T1 was not significantly associated with preeclampsia. However, both 25(OH)D in T3 and change in 25(OH)D from T1 to T3 were significantly and negatively associated with preeclampsia. Women with a change in 25(OH)D concentration of ≥30 nmol/L had an odds ratio of 0.22 (p = 0.002) for preeclampsia. T1 25(OH)D was positively related to T1 systolic (β = 0.03, p = 0.022) and T1 diastolic blood pressure (β = 0.02, p = 0.016), and to systolic (β = 0.02, p = 0.02) blood pressure trajectory during pregnancy, in adjusted analyses. There was no association between 25(OH)D and pregnancy-induced hypertension in adjusted analysis. In conclusion, an increase in 25(OH)D concentration during pregnancy of at least 30 nmol/L, regardless of vitamin D status in T1, was associated with a lower odds ratio for preeclampsia. Vitamin D status was significantly and positively associated with T1 blood pressure and gestational systolic blood pressure trajectory but not with pregnancy-induced hypertension

Which method is best for the induction of labour?: A systematic review, network meta-analysis and cost-effectiveness analysis

Background: More than 150,000 pregnant women in England and Wales have their labour induced each year. Multiple pharmacological, mechanical and complementary methods are available to induce labour. Objective: To assess the relative effectiveness, safety and cost-effectiveness of labour induction methods and, data permitting, effects in different clinical subgroups. Methods: We carried out a systematic review using Cochrane methods. The Cochrane Pregnancy and Childbirth Group’s Trials Register was searched (March 2014). This contains over 22,000 reports of controlled trials (published from 1923 onwards) retrieved from weekly searches of OVID MEDLINE (1966 to current); Cochrane Central Register of Controlled Trials (The Cochrane Library); EMBASE (1982 to current); Cumulative Index to Nursing and Allied Health Literature (1984 to current); ClinicalTrials.gov; the World Health Organization International Clinical Trials Registry Portal; and hand-searching of relevant conference proceedings and journals. We included randomised controlled trials examining interventions to induce labour compared with placebo, no treatment or other interventions in women eligible for third-trimester induction. We included outcomes relating to efficacy, safety and acceptability to women. In addition, for the economic analysis we searched the Database of Abstracts of Reviews of Effects, and Economic Evaluations Databases, NHS Economic Evaluation Database and the Health Technology Assessment database. We carried out a network meta-analysis (NMA) using all of the available evidence, both direct and indirect, to produce estimates of the relative effects of each treatment compared with others in a network. We developed a de novo decision tree model to estimate the cost-effectiveness of various methods. The costs included were the intervention and other hospital costs incurred (price year 2012–13). We reviewed the literature to identify preference-based utilities for the health-related outcomes in the model. We calculated incremental cost-effectiveness ratios, expected costs, utilities and net benefit. We represent uncertainty in the optimal intervention using cost-effectiveness acceptability curves. Results: We identified 1190 studies; 611 were eligible for inclusion. The interventions most likely to achieve vaginal delivery (VD) within 24 hours were intravenous oxytocin with amniotomy [posterior rank 2; 95% credible intervals (CrIs) 1 to 9] and higher-dose (≥ 50 μg) vaginal misoprostol (rank 3; 95% CrI 1 to 6). Compared with placebo, several treatments reduced the odds of caesarean section, but we observed considerable uncertainty in treatment rankings. For uterine hyperstimulation, double-balloon catheter had the highest probability of being among the best three treatments, whereas vaginal misoprostol (≥ 50 μg) was most likely to increase the odds of excessive uterine activity. For other safety outcomes there were insufficient data or there was too much uncertainty to identify which treatments performed ‘best’. Few studies collected information on women’s views. Owing to incomplete reporting of the VD within 24 hours outcome, the cost-effectiveness analysis could compare only 20 interventions. The analysis suggested that most interventions have similar utility and differ mainly in cost. With a caveat of considerable uncertainty, titrated (low-dose) misoprostol solution and buccal/sublingual misoprostol had the highest likelihood of being cost-effective. Limitations: There was considerable uncertainty in findings and there were insufficient data for some planned subgroup analyses. Conclusions: Overall, misoprostol and oxytocin with amniotomy (for women with favourable cervix) is more successful than other agents in achieving VD within 24 hours. The ranking according to safety of different methods was less clear. The cost-effectiveness analysis suggested that titrated (low-dose) oral misoprostol solution resulted in the highest utility, whereas buccal/sublingual misoprostol had the lowest cost. There was a high degree of uncertainty as to the most cost-effective intervention

Nitric oxide donors in labor management

ABSTRACT Nitric oxide donors in labor management Maria Bullarbo Department of Obstetrics and Gynecology Institute of Clinical Sciences Background: Nitric oxide (NO), a free radical with ultra-short half-life synthesized from L- arginine by the enzyme nitric oxide synthase (NOS), is in the human involved in many physiological and pathophysiological processes, including different reproductive processes. During pregnancy NO is produced endogenously in the human uterine cervix and placenta. Different effects of NO can be studied by administering NO donors. Aims and methods: The aims of the thesis were to perform experimental and clinical studies on late pregnant women to examine the effects of NO donors on cervical ripening and labor induction and to evaluate possible effects of NO on the management of retained placenta. In Paper I the effects of the NO donor isosorbide mononitrate (IMN) administered vaginally were examined by measuring cervical distensibility using a cervical tonometer. In addition, maternal and fetal side effects of the medication were evaluated. In Paper II the efficiency of vaginally adminstered IMN to induce cervical ripening and labor induction in an outpatient setting was examined. The safety and side effects of this treatment were also evaluated. In Paper III cervical biopsies were obtained prior to elective caesarean section following vaginal administration of IMN. Western blotting was used for semiquantitative measurements of cyclooxygenase-1 and -2 (COX-1 and COX-2), enzymes involved in prostaglandin synthesis as well as cervical ripening. Immunohistochemistry was used for localizing these enzymes within the cervical tissue. Paper IV describes the efficiency of sequential treatment with oxytocin and nitroglycerin for management of retained placenta. Results: Treatment with IMN resulted in a significantly increased cervical distensibility. Headache and palpitations of little to moderate intensity were common maternal side effects. A significant decrease in maternal blood pressure and increase in pulse rate were registered. However, the effects were modest and not of clinical importance. No fetal side effects were observed according to CTG, Doppler ultrasound, Apgar score and umbilical pH. Vaginally administered IMN seemed to be effective in promoting labor induction within 24 hours (22 patients compared to 8 in the placebo group). There were no differences in fetal side effects and the rate of caesarean section between women treated with IMN and women in the placebo group. Semiquantitative measurements by immunoblotting revealed increased expression of COX-2, but not of COX-1 in the NO donor group compared to placebo group. Immunohistchemistry showed similar localizations of COX-1 and COX-2 in the two groups. Sublingually administered nitroglycerin in combination with oxytocin resulted in successfully delivered placenta among all 12 women compared to only 1 woman in the control group. Maternal hemodynamic effects were mild to moderate. Blood loss was increased in women who needed manual removal of placenta. Conclusion: The data suggest that IMN administered vaginally at term and postterm for cervical ripening and labor induction seems to be effective and safe. Combined treatment with oxytocin and nitroglycerin seems to promote detachment of retained placenta. Key Words: cervical ripening, labor induction, nitric oxide donor, retained placenta