Postpartum Blood Loss in Women Treated for Intrahepatic Cholestasis of Pregnancy

OBJECTIVE To evaluate postpartum blood loss in women with treated intrahepatic cholestasis of pregnancy. METHODS In a retrospective case-control study, 15,083 deliveries including 348 women with intrahepatic cholestasis of pregnancy (2.3%) were analyzed from 2004 to 2014. To adjust for differences in baseline characteristics, a propensity analysis was performed and women in the control group were matched to the women in the intrahepatic cholestasis of pregnancy group in a 5:1 ratio. Blood loss was analyzed by estimated blood loss and Δ hemoglobin (Hb, difference between prepartum and postpartum Hb). A subgroup analysis regarding severity of intrahepatic cholestasis of pregnancy based on maximum bile acid level (mild [less than 40 micromoles/L], moderate [40-99 micromoles/L], and severe intrahepatic cholestasis of pregnancy [100 micromoles/L or greater]) was performed. Differences in estimated blood loss, ΔHb, and meconium staining between subgroups were analyzed. A Spearman rank correlation was performed to evaluate the association of bile acid levels and blood loss within subgroups. RESULTS Estimated blood loss (median 400 [300-600] mL compared with 400 [300-600] mL, P=.22), ΔHb (14.0 [5.0-22.0] compared with 12.0 [4.0-21.0] g/L, P=.09), meconium staining (14.5% compared with 11.4%, P=.12), and number of stillbirths after 26 weeks of gestation (0.6% compared with 1.8%, P=.10) were not significantly different in the study compared with the control group. In moderate and severe intrahepatic cholestasis of pregnancy, meconium staining was observed significantly more often compared with that in a control group (23.0% and 32.3% compared with 11.4%, P<.01). There was no correlation between estimated blood loss or ΔHb and severity of intrahepatic cholestasis of pregnancy. CONCLUSIONS In our cohort of women with intrahepatic cholestasis of pregnancy who are treated with ursodeoxycholic acid and have planned delivery (induction of labor or planned cesarean delivery) at 38 weeks of gestation, no differences in postpartum blood loss were seen

Maternal and fetal outcomes after uterine fundal pressure in spontaneous and assisted vaginal deliveries

AbstractAim: This study aimed to evaluate maternal and fetal outcomes after uterine fundal pressure (UFP) in spontaneous and assisted vaginal deliveries. Methods: In a retrospective cohort study, 9743 singleton term deliveries with cephalic presentation were analyzed from 2004 to 2013. Spontaneous and assisted vaginal deliveries were analyzed separately with and without the application of UFP. Odds ratios were adjusted in a multivariate logistic regression analysis. Results: Prevalence of UFP was 8.9% in spontaneous and 12.1% in assisted vaginal deliveries. UFP was associated with a higher incidence of shoulder dystocia in both spontaneous (adjusted odds ratio [adj. OR] 2.44, confidence interval [CI] 95% 1.23-4.84) and assisted vaginal deliveries (adj. OR 6.88 CI 95% 3.50-13.53). Fetal acidosis (arterial umbilical pH<7.2) was seen more often after the application of UFP in spontaneous vaginal deliveries (adj. OR 3.18, CI 95% 2.64-3.82) and assisted vaginal deliveries (adj. OR 1.59 CI 95% 1.17-2.16). The incidence of 5′-Apgar<7 (adj. OR 2.19 CI 95% 1.04-4.6) and 10′-Apgar<7 (adj. OR 3.04 CI 95% 1.17-7.88) was also increased after the application of UFP in spontaneous deliveries. A higher incidence of anal sphincter tears (AST) (adj. OR 46.25 CI 95% 11.78-181.6) in the UFP group of spontaneous deliveries was observed. Conclusions: UFP is associated with increased occurrence of shoulder dystocia and fetal acidosis. In spontaneous deliveries, the risk for lower Apgar scores after 5 and 10 min is increased, as well as the risk for AST

Maternal and fetal outcomes after uterine fundal pressure in spontaneous and assisted vaginal deliveries

AIM: This study aimed to evaluate maternal and fetal outcomes after uterine fundal pressure (UFP) in spontaneous and assisted vaginal deliveries. METHODS: In a retrospective cohort study, 9743 singleton term deliveries with cephalic presentation were analyzed from 2004 to 2013. Spontaneous and assisted vaginal deliveries were analyzed separately with and without the application of UFP. Odds ratios were adjusted in a multivariate logistic regression analysis. RESULTS: Prevalence of UFP was 8.9% in spontaneous and 12.1% in assisted vaginal deliveries. UFP was associated with a higher incidence of shoulder dystocia in both spontaneous (adjusted odds ratio [adj. OR] 2.44, confidence interval [CI] 95% 1.23-4.84) and assisted vaginal deliveries (adj. OR 6.88 CI 95% 3.50-13.53). Fetal acidosis (arterial umbilical pH<7.2) was seen more often after the application of UFP in spontaneous vaginal deliveries (adj. OR 3.18, CI 95% 2.64-3.82) and assisted vaginal deliveries (adj. OR 1.59 CI 95% 1.17-2.16). The incidence of 5'-Apgar<7 (adj. OR 2.19 CI 95% 1.04-4.6) and 10'-Apgar<7 (adj. OR 3.04 CI 95% 1.17-7.88) was also increased after the application of UFP in spontaneous deliveries. A higher incidence of anal sphincter tears (AST) (adj. OR 46.25 CI 95% 11.78-181.6) in the UFP group of spontaneous deliveries was observed. CONCLUSIONS: UFP is associated with increased occurrence of shoulder dystocia and fetal acidosis. In spontaneous deliveries, the risk for lower Apgar scores after 5 and 10 min is increased, as well as the risk for AST

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses

Background Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. Methods We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. Findings We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·91%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73–2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74–0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35–0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02–0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08–0·72) of 1412 cases with total bile acids of 40–99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52–10·50]; p=0·26), and versus 18 (3·44%; 2·05–5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83–105·30]; p<0·0001). Interpretation The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 μmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. Funding Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses

Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001). The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 μmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust

Maternal and fetal outcomes after uterine fundal pressure in spontaneous and assisted vaginal deliveries

AIM: This study aimed to evaluate maternal and fetal outcomes after uterine fundal pressure (UFP) in spontaneous and assisted vaginal deliveries. METHODS: In a retrospective cohort study, 9743 singleton term deliveries with cephalic presentation were analyzed from 2004 to 2013. Spontaneous and assisted vaginal deliveries were analyzed separately with and without the application of UFP. Odds ratios were adjusted in a multivariate logistic regression analysis. RESULTS: Prevalence of UFP was 8.9% in spontaneous and 12.1% in assisted vaginal deliveries. UFP was associated with a higher incidence of shoulder dystocia in both spontaneous (adjusted odds ratio [adj. OR] 2.44, confidence interval [CI] 95% 1.23-4.84) and assisted vaginal deliveries (adj. OR 6.88 CI 95% 3.50-13.53). Fetal acidosis (arterial umbilical pH<7.2) was seen more often after the application of UFP in spontaneous vaginal deliveries (adj. OR 3.18, CI 95% 2.64-3.82) and assisted vaginal deliveries (adj. OR 1.59 CI 95% 1.17-2.16). The incidence of 5'-Apgar<7 (adj. OR 2.19 CI 95% 1.04-4.6) and 10'-Apgar<7 (adj. OR 3.04 CI 95% 1.17-7.88) was also increased after the application of UFP in spontaneous deliveries. A higher incidence of anal sphincter tears (AST) (adj. OR 46.25 CI 95% 11.78-181.6) in the UFP group of spontaneous deliveries was observed. CONCLUSIONS: UFP is associated with increased occurrence of shoulder dystocia and fetal acidosis. In spontaneous deliveries, the risk for lower Apgar scores after 5 and 10 min is increased, as well as the risk for AST

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis

Background Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35–3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04–2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86–1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39–0·91; p=0·016). Interpretation Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Funding Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Researc

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis

Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35–3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04–2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86–1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39–0·91; p=0·016). Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.Fil: Ovadia, Caroline. King's College London; Reino UnidoFil: Sajous, Jenna. King's College London; Reino UnidoFil: Seed, Paul T.. King's College London; Reino UnidoFil: Patel, Kajol. King's College London; Reino UnidoFil: Williamson, Nicholas J.. King's College London; Reino UnidoFil: Attilakos, George. University College London; Estados UnidosFil: Azzaroli, Francesco. Universidad de Bologna; ItaliaFil: Bacq, Yannick. Universite de Tours; FranciaFil: Batsry, Linoy. Universitat Tel Aviv; IsraelFil: Broom, Kelsey. Healthcare Group; AustraliaFil: Brun Furrer, Romana. University Hospital Zurich; SuizaFil: Bull, Laura. University of California; Estados UnidosFil: Chambers, Jenny. Imperial College London; Reino UnidoFil: Cui, Yue. Chongqing Medical University; ChinaFil: Ding, Min. Chongqing Medical University; ChinaFil: Dixon, Peter H.. King's College London; Reino UnidoFil: Estiú, Maria C.. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital Materno Infantil Ramon Sarda; ArgentinaFil: Gardiner, Fergus W.. Royal Flying Doctor Service; AustraliaFil: Geenes, Victoria. King's College London; Reino UnidoFil: Grymowicz, Monika. Medical University of Warsaw; PoloniaFil: Günaydin, Berrin. Gazi University School of Medicine; TurquíaFil: Hague, William M. University of Adelaide; AustraliaFil: Haslinger, Christian. University Hospital Zurich; SuizaFil: Hu, Yayi. Sichuan University; ChinaFil: Indraccolo, Ugo. Alto Tevere Hospital of Città di Castello; ItaliaFil: Juusela, Alexander. Newark Beth Israel Medical Center; Estados UnidosFil: Kane, Stefan C. Royal Women's Hospital; Australia. University of Melbourne; AustraliaFil: Kebapcilar, Ayse. Selcuk University; TurquíaFil: Kebapcilar, Levent. Selcuk University; TurquíaFil: Tripodi, Valeria Paula. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin