Materials and Methods
We performed a multicenter retrospective cohort study of all women diagnosed with ICP across 5 regional hospitals including MedStar Washington Hospital Center (Washington, DC), MedStar Georgetown University Hospital (Washington, DC), Medstar Franklin Square Medical Center (Baltimore, MD), Medstar Harbor Hospital (Baltimore, MD), and Virginia Hospital Center (Arlington, VA) from January 2009 through December 2014. All participating institutions obtained institutional review board approval. Women with the diagnosis of ICP were identified through the electronic perinatal database in each hospital. Subsequent chart abstraction was undertaken to collect relevant outcome data. ICP was diagnosed by presence of pruritus without a rash and documented maximum serum TBA level of ≥10 μmol/L. Women with TBA level <10 μmol/L and pregnancies complicated by multiple gestations or infants with congenital and chromosomal abnormalities were excluded. Ursodeoxycholic acid was considered first-line therapy for the treatment of ICP in the study cohort at the discretion of the managing physician. Fetal monitoring was performed at each institution for patients with cholestasis of pregnancy. While there is some variation depending on gestational age of diagnosis, each patient received weekly or twice weekly biophysical profile following diagnosis with delivery planned for 36 1/7 to 37 6/7 weeks of gestation. Women with ICP were categorized based on their TBA level into 3 groups (10-39.9, 40-99.9, and ≥100 μmol/L). Information on maternal demographics, medical comorbidities, and serum biochemical parameters were collected for evaluation.
Pregnancy outcomes including delivery gestational age, spontaneous preterm delivery, iatrogenic preterm delivery, birthweight, mode of delivery, oligohydramnios, intrauterine growth restriction, placental abruption, preterm premature rupture of membrane (PPROM), concerning fetal heart tracing, chorioamnionitis, endometritis, postpartum hemorrhage, transfusion, stillbirth, neonatal intensive care unit (NICU) admission, hyperbilirubinemia, meconium-stained amniotic fluid, RDS or transient tachypnea of the newborn (TTN), and composite neonatal outcome were ascertained. A composite adverse neonatal outcome was created and defined as any of the following: NICU admission, hypoglycemia, hyperbilirubinemia, RDS, TTN, mechanical ventilation use, oxygen by nasal cannula, pneumonia, and stillbirth. PPROM was defined by rupture of membrane <37 weeks’ gestation. Concerning fetal heart tracing was defined as recurrent variable or late decelerations with moderate variability, prolonged decelerations, or category 3 tracing. Providers who were caring for the women reviewed and independently characterized fetal heart tracings. Since fetal heart tracings were not accessible to authors, authors accepted the providers’ interpretation. For analysis of concerning fetal heart tracing, women with nonlabor cesarean delivery were excluded. Hyperbilirubinemia was defined by neonatal hyperbilirubinemia that required phototherapy. Hypoglycemia was defined by neonatal hypoglycemia that required intravenous infusion. Diagnosis of RDS and TTN were made by the managing neonatologist and based on standard clinical guidelines.
Predictors for composite neonatal outcome including TBA level, gestational age at diagnosis of ICP, ursodeoxycholic acid use, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and preexisting liver disease were evaluated by multivariable logistic regression model.
Categories of TBA level were evaluated as a predictor for composite neonatal outcome, NICU admission, meconium-stained amniotic fluid, hyperbilirubinemia, RDS or TTN, and mechanical ventilation. Also, subgroup analysis was conducted after excluding women with iatrogenic preterm delivery.
A univariate receiver operating characteristic curve was also used to predict composite neonatal complications in association to TBA level. Sensitivity and specificity were calculated.
A previous study using a similar composite adverse neonatal outcome (fetal distress, major congenital anomalies, hyperbilirubinemia, meconium staining of amniotic fluid at delivery, meconium aspiration, pneumonia, respiratory distress and sepsis) reported that infants from women with TBA level ≥100 μmol/L had a 60% chance of adverse neonatal outcome, whereas infants from women with TBA level 40-99.9 μmol/L and 10-39.9 μmol/L had a 19% and 29% chance of adverse neonatal outcome, respectively. We hypothesized that infants from women with TBA level 10-39.9 μmol/L had a 20% chance, infants from women with TBA level 40-99.9 μmol/L had a 40% chance, and infants from women with TBA level ≥100 μmol/L had a 60% of chance of composite neonatal outcome. A sample size of 206 (123 women with TBA level 10-39.9, 62 women with TBA level 40-99.9, and 21 women with TBA level ≥100 μmol/L) could achieve 80% power to detect a 20% difference in composite adverse neonatal outcome between TBA level 10-39.9 and 40-99.9 μmol/L and 95% power to detect a difference of 40% between TBA level 10-39.9 and ≥100 μmol/L (alpha < .05). We assumed 10% of data may be incomplete and sample size of 227 was calculated.
Statistical analysis was performed using SAS 9.3 (SAS Institute Inc, Cary, NC). The maximum documented TBA level for a patient was categorized into 3 groups: 10-39.9, 40-99.9, and ≥100 μmol/L. Student t test or Mann-Whitney U was used to assess continuous variables according to their distribution. The χ 2 analysis and Fisher exact test were used for the analysis of categorical variables. Multivariable logistic regression analysis was used to assess effects on composite neonatal outcomes, controlling for maternal age, race, site, any hypertensive disease, any diabetes, body mass index (BMI), and gestational age at delivery. For all tests, a P value < .05 was considered statistically significant.
Results
There were 72,970 women from all 5 centers who delivered from January 2009 through December 2014. ICP was a presumed diagnosis in 421 women (0.58%). Of these 421 women, 131 women were excluded due to lack of bile acid data in the inpatient record and 57 women were excluded because their documented TBA level was <10 μmol/L. Of the remaining 233 women, 152 women had a TBA level 10-39.9 μmol/L, 55 had a TBA level 40-99.9 μmol/L, and 26 had a TBA level ≥100 μmol/L. The overall incidence of confirmed ICP in women with a singleton gestation was 0.3% in our cohort.
Demographic and clinical data are shown in Table 1 . There were no significant differences in maternal age, race, parity, prepregnancy BMI, any hypertensive disease, any diabetes, induction of labor, history of liver or biliary disease, maternal hepatitis B and C infection, and improvement of pruritus among the 3 groups of TBA level. The rate of induction of labor was high (89-91%) regardless of the level of bile acid. Increased TBA level was associated with higher AST, ALT, and total bilirubin level ( P < .05). Women with TBA level 40-99.9 and ≥100 μmol/L were more likely to be on ursodeoxycholic acid and have early gestational age at diagnosis than women with TBA level <40 μmol/L ( P = .02 and < .01, respectively).
| Variable | TBA 10–39.9 μmol/L n = 152 | TBA 40–99.9 μmol/L n = 55 | TBA ≥100 μmol/L n = 26 | P value |
|---|---|---|---|---|
| Mean maternal age, y, ± SD | 29.7 ± 6.0 | 30.4 ± 5.6 | 30.2 ± 7.4 | .73 |
| Nulliparous | 66 (43.4) | 28 (50.9) | 12 (46.2) | .63 |
| Race/ethnicity | .22 | |||
| White | 52 (34.2) | 23 (41.8) | 11 (42.3) | |
| African American | 37 (24.3) | 5 (9.1) | 7 (26.9) | |
| Hispanic | 39 (25.7) | 14 (25.5) | 3 (11.5) | |
| Asian | 16 (10.5) | 7 (12.7) | 2 (7.7) | |
| Other | 8 (5.3) | 6 (10.9) | 3 (11.5) | |
| Induction of labor | 116 (88.6) | 40 (88.9) | 21 (91.3) | 1 |
| Prepregnancy BMI, a kg/m 2 | .41 | |||
| Underweight/normal weight | 83 (54.6) | 37 (67.3) | 14 (53.9) | |
| Overweight | 36 (23.7) | 12 (21.8) | 7 (26.9) | |
| Obese | 33 (21.7) | 6 (10.9) | 5 (19.2) | |
| Any diabetes | 13 (8.6) | 10 (18.2) | 1(3.9) | .09 |
| Preexisting | 2 (1.3) | 1 (1.8) | 0 (0) | 1 |
| Gestational | 11 (7.2) | 9 (16.4) | 1 (3.9) | .11 |
| Any hypertensive disease | 16 (10.5) | 5 (9.1) | 0 (0) | .23 |
| Chronic hypertension | 5 (3.3) | 0 (0) | 0 (0) | .48 |
| Preeclampsia | 11 (7.2) | 4 (7.3) | 0 (0) | .47 |
| Gestational hypertension | 4 (2.6) | 2 (3.6) | 0 (0) | .83 |
| ICP in prior pregnancy | 22 (25.9) | 10 (37.0) | 4 (26.7) | .54 |
| History of liver or biliary disease b | 16 (10.5) | 4 (7.3) | 5 (19.2) | .24 |
| Maternal hepatitic B infection | 1 (0.7) | 0 (0) | 0 (0) | 1 |
| Maternal hepatitic C infection | 7 (4.6) | 2 (3.6) | 2 (7.7) | .79 |
| Smoking | 9 (6.0) | 0 (0) | 0 (0) | .14 |
| Ursodiol use | 67 (44.1) | 35 (63.6) | 16 (61.54) | .02 |
| Improvement of pruritus | 49 (43.0) | 14 (32.6) | 8 (34.78) | .44 |
| Gestational age at diagnosis, mean ± SD | 34.2 ± 3.9 | 33.6 ± 4.3 | 30.6 ± 5.8 | < .01 |
| Highest AST, IU/L, mean ± SD | 97.7 ±114.3 | 172.04 ± 161.33 | 215.77 ± 271.88 | < .01 |
| Highest ALT, IU/L, mean ± SD | 64.3 ± 68.7 | 120.71 ± 112.95 | 120.77 ± 120.77 | < .01 |
| Highest ALP, IU/L, mean ± SD | 228.9 ± 101.4 | 267.73 ± 99.2 | 270.56 ± 107.31 | .06 |
| Total bilirubin, mg/dL, mean ± SD | 0.496 ± 0.320 | 0.626 ± 0.490 | 0.856 ± 1.005 | .02 |
a Underweight <18.5, normal weight 18.5–24.9, overweight 25.0–29.9, obese 30.0–34.9, and morbidly obese ≥35.0
b Includes cholecystitis, cholelithiasis, and liver sarcoidosis.
Pregnancy outcomes are shown in Table 2 . Women with TBA level 40-99.9 and ≥100 μmol/L were more likely to have preterm delivery <37 weeks’ gestation ( P = .01). There was no difference in spontaneous preterm delivery among the 3 groups. Women with TBA level 40-99.9 and ≥100 μmol/L were more likely to have iatrogenic preterm delivery ( P < .01), meconium-stained amniotic fluid ( P < .01), and composite neonatal outcome ( P < .01). All 4 stillbirths were found in the TBA ≥100 μmol/L group ( P < .01). There was no significant difference in oligohydramnios, intrauterine growth restriction, mode of delivery, PPROM, placental abruption, chorioamnionitis, endometritis, postpartum hemorrhage, transfusion, NICU admission, hyperbilirubinemia, RDS or TTN, and mechanical ventilation use among the 3 groups of TBA level. Concerning fetal heart tracing was higher in women with bile acid level 40-99.9 and ≥100 μmol/L, but the difference was not statistically significant ( P = .08).
| Variable | TBA 10–39.9 μmol/L n = 152 | TBA 40–99.9 μmol/L n = 55 | TBA ≥100 μmol/L n = 26 | P value |
|---|---|---|---|---|
| Gestational age at delivery, wk | .01 | |||
| 22–<34 | 2 (1.3) | 1 (1.8) | 2 (7.7) | |
| 34–<37 | 27 (17.8) | 16 (29.1) | 11 (42.3) | |
| ≥37 | 123 (80.9) | 38 (69.1) | 13 (50.0) | |
| Spontaneous preterm delivery | 7 (4.6) | 4 (7.3) | 1 (3.85) | .71 |
| Iatrogenic preterm delivery | 22 (14.5) | 13 (23.6) | 12 (46.2) | < .01 |
| Birthweight group, g | .18 | |||
| <2500 | 12 (7.9) | 9 (16.4) | 5 (19.2) | |
| 2500–4000 | 137 (90.1) | 46 (83.6) | 21 (80.8) | |
| >4000 | 3 (2.0) | 0 (0) | 0 (0) | |
| Mode of delivery | .64 | |||
| Vaginal | 89 (58.6) | 33 (60.0) | 15 (57.7) | |
| Operative vaginal | 5 (3.3) | 0 (0) | 2 (7.7) | |
| Cesarean | 58 (38.2) | 22 (40.0) | 9 (34.6) | |
| Oligohydramnios | 4 (2.6) | 1 (1.8) | 2 (7.7) | .28 |
| IUGR a | 7 (4.6) | 5 (9.1) | 1 (4.0) | .46 |
| PPROM b | 6 (4.0) | 3 (5.5) | 1 (3.9) | .88 |
| Concerning fetal heart tracing c | 50 (39.1) | 26 (57.8) | 9 (50.0) | .08 |
| Placental abruption | 3 (2.0) | 0 (0) | 0 (0) | .70 |
| Chorioamnionitis | 4 (2.6) | 4 (7.3) | 0 (0) | .22 |
| Endometritis | 2 (1.3) | 2 (3.7) | 0 (0) | .56 |
| Postpartum hemorrhage | 15 (9.9) | 7 (12.7) | 0 (0) | .17 |
| Transfusion | 2 (1.3) | 2 (3.6) | 1 (3.9) | .26 |
| Stillbirth | 0 (0) | 0 (0) | 4 (15.4) | < .01 |
| NICU admission | 31 (20.4) | 15 (27.3) | 4 (18.2) | .52 |
| Hyperbilirubinemia d | 17 (11.3) | 13 (23.6) | 5 (22.7) | .06 |
| Meconium-stained amniotic fluid | 15 (10) | 14 (25.9) | 9 (36.0) | < .01 |
| RDS or TTN | 16 (10.6) | 8 (14.6) | 3 (13.6) | .71 |
| Mechanical ventilation use | 9 (6.0) | 6 (11.0) | 3 (13.6) | .21 |
| Composite neonatal outcome e | 48 (32.0) | 26 (49.1) | 16 (61.5) | < .01 |
c Recurrent variable or late deceleration with moderate variability, prolonged deceleration, or category 3 tracing
e Includes any of: NICU admission, hypoglycemia requiring intravenous fluid, hyperbilirubinemia requiring phototherapy, meconium-stained amniotic fluid, RDS/TTN, mechanical ventilation use oxygen by nasal cannula, pneumonia, and stillbirth.
As shown in Table 3 , after adjusting for confounders, there were no predictors associated with increased risk of composite neonatal outcome. Also, we conducted a subgroup analysis by excluding any women who had iatrogenic preterm delivery (data not shown). There were no predictors associated with increased risk of composite neonatal outcome.
| Variable | CNO, adjusted OR a (95% CI) b |
|---|---|
| TBA, μmol/L c | |
| 40–99.9 | 1.22 (0.41–3.63) |
| ≥100 | 2.90 (0.67–12.61) |
| GA at diagnosis, wk d | |
| 0–<34 | 0.23 (0.05–1.12) |
| 34–<37 | 0.26 (0.06–1.12) |
| Ursodeoxycholic acid use | 2.44 (0.77–7.73) |
| AST, IU/L e | |
| 40–79.9 | 2.09 (0.37–11.96) |
| ≥80 | 0.80 (0.10–6.166) |
| ALT, IU/L f | |
| 40–79.9 | 0.37 (0.06–2.41) |
| ≥80 | 0.67 (0.10–4.80) |
| Preexisting liver disease g | 0.264 (0.05–1.56) |
a Adjusted for maternal age, race, site, any hypertensive disorder, any diabetes, body mass index, GA at delivery, TBA level, GA at diagnosis of intrahepatic cholestasis of pregnancy, ursodeoxycholic acid use, AST and ALT, and preexisting liver disease
b Includes any of: neonatal intensive care unit admission, hypoglycemia requiring intravenous fluid, hyperbilirubinemia requiring phototherapy, meconium-stained amniotic fluid, respiratory distress syndrome/transient tachypnea of newborn, mechanical ventilation use oxygen by nasal cannula, pneumonia, and stillbirth
c Reference category is 0–39.9 μmol/L
d Reference category is ≥37 wk of gestation
e Reference category is 0–< 40 IU/L
f Reference category is 0–<40 IU/L
g Includes hepatitis B and C virus infection, cholecystitis, cholelithiasis, and liver sarcoidosis.
Table 4 shows the multivariable logistic regression analysis in which bile acid levels were used as a categorical predictor for composite neonatal outcome and individual neonatal outcomes. TBA level 40-99.9 and ≥100 μmol/L were associated with increased risk of meconium-stained amniotic fluid after adjusting for maternal age, prepregnancy BMI, any hypertensive disorder, any diabetes, and gestational age at delivery. After excluding any women who had iatrogenic preterm delivery, TBA level 40-99.9 μmol/L was associated with increased risk of meconium-stained amniotic fluid.
| Variable | CNO, adjusted OR (95% CI) a , b | NICU, adjusted OR (95% CI) a | Meconium-stained amniotic fluid, adjusted OR (95% CI) a | Hyperbilirubinemia, adjusted OR (95% CI) a , c | RDS or TTN, adjusted OR (95% CI) a | Mechanical ventilation, adjusted OR (95% CI) a , d |
|---|---|---|---|---|---|---|
| TBA, e 40–99.9 μmol/L | 1.221 (0.411–3.626) | 1.13 (0.46–2.75) | 3.55 (1.45–8.68) | 2.31 (0.804–6.65) | 1.49 (0.51–4.31) | 2.37 (0.65–8.67) |
| TBA, e ≥100 μmol/L | 2.904 (0.669–12.608) | 0.42 (0.09–1.92) | 4.55 (1.47–14.08) | 2.13 (0.50–9.16) | 0.82 (0.15–4.44) | 1.55 (0.25–9.49) |
| After excluding iatrogenic preterm deliveries f | ||||||
| TBA, e 40–99.9 μmol/L | 1.30 (0.32–5.28) | 0.83 (0.31–2.27) | 3.55 (1.41–9.60) | 2.92 (0.73–11.63) | 0.83 (0.22–3.14) | 2.37 (0.65–8.67) |
| TBA, e ≥100 μmol/L | 4.28 (0.71–25.83) | N/A | 3.56 (0.90–14.20) | 1.71 (0.83–36.67) | N/A | N/A |
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