Materials and Methods
Patient selection and data collection
A retrospective study was conducted with data from January 2005 until August 2012 in 1 academic and 2 affiliated teaching hospitals in the Utrecht region, the Netherlands. All cases of ICP were identified through the laboratory computer systems. ICP was diagnosed when BA levels were ≥10 μmol/L and signs of pruritus during pregnancy where found in the hospital records. All pregnancies that were complicated by severe congenital malformations, which consisted of chromosomal abnormalities and/or multiple congenital anomalies, and all twin pregnancies were excluded from the study. Enzymatic colorimetric determination of total bile acids in serum was performed with Sentinel reagents using an AU5811 analyzer (Beckman Coulter, Brea, CA). BA levels were measured at diagnosis and on average 2-3 times per patient; there is no current standardized protocol for this in the Netherlands. In this study, the highest measured value throughout the pregnancy and the value before delivery were used for analysis.
Data on maternal demographics (ie, maternal age, parity, ethnicity), obstetric and medical history, biochemical parameters (ie, aspartate transaminase, alanine transaminase, bilirubin), treatment, and pregnancy outcomes (ie, birthweight, mode of delivery, Apgar score) were retrieved from the hospital records of all ICP cases.
This study was reviewed and approved by the local Institutional Ethical Review Board of the University Medical Center Utrecht, reference number: WAG/om/14/0005544.
Definitions
A history of ICP was positive if the disease had been present in any previous pregnancy in that particular woman. History of hepatobiliary disease was defined as cholecystectomy for cholelithiasis, hepatitis A, B, C, or a history of elevated liver transaminases with a different cause.
Three ICP severity groups (mild, BA 10-39 μmol/L; moderate, BA 40-99 μmol/L; severe, BA ≥100μmol/L) were constructed based on the highest measured BA throughout the pregnancy, according to international literature to perform subgroup analyses.
Analysis of adverse pregnancy outcome included mode of delivery, meconium staining of the amniotic fluid, spontaneous and induced preterm birth (defined as <37 weeks of gestation), postpartum hemorrhage (defined as >1000 mL), small for gestational age (defined as birthweight <10th percentile), asphyxia (defined as a pHa <7.05 and base deficit of >12 mmol/L or pHa <7.00), low Apgar score (<7 after 5 minutes), admissions to medium care unit and neonatal intensive care unit, and perinatal death (24 weeks of gestation to 7 days after delivery). Late preterm birth was defined as birth between 34 and 36-6/7 weeks of pregnancy. Outcome measures were based on previous large studies on ICP and national guidelines.
Statistical analysis
For baseline comparison between the ICP groups (mild, moderate, severe) medians and interquartile range were calculated for continuous variables; numbers and percentages were calculated for categoric variables. Differences between groups were analyzed with the nonparametric Kruskal-Wallis test and the Fisher exact test for continuous and categoric variables, respectively. Pairwise comparisons were performed with the Mann-Whitney U tests or by pairwise chi-square tests if variables were categoric. Correlations between BA levels in maternal and neonatal blood were calculated with Spearman’s correlation coefficient.
Univariate logistic regression analyses were performed to calculate crude odds ratios (ORs) with 95% confidence intervals (95% CIs) with the use of the highest measured BA levels as a continuous predictor for several dichotomous adverse pregnancy outcomes. In a multivariate logistic regression analysis, ORs were adjusted for maternal age, gestational age, and birthweight.
Statistical analyses were performed with SPSS software (release 20.0; SPSS Inc, Chicago, IL). Probability values of < .05 were considered statistically significant.
Results
During the study period, 215 cases of ICP were diagnosed in women with singleton pregnancies. Of these 215 women, 108 had mild ICP; 86 had moderate ICP, and 21 had severe ICP. Eleven women had >1 ICP-affected pregnancy in the study period and were included as separate cases in this study.
Baseline characteristics of the study population are shown in Table 1 . A large number of women (70.2%) received oral medication (ursodeoxycholic acid or in 2 cases cholestyramine) to treat ICP. In the severe ICP group, 90.5% of patients were treated with ursodeoxycholic acid; 2 patients were not treated with any medication because they were induced for labor immediately after diagnosis. In this population, 82.8% of the women were white. There was a relatively large proportion of patients with a history of ICP in a previous pregnancy (14.9%); only 6 patients (2.8%) had a history of hepatobiliary disease.
| Baseline demographic | Population (n = 215) | Intrahepatic cholestasis of pregnancy | P value | ||
|---|---|---|---|---|---|
| Mild (n = 108) | Moderate (n = 86) | Severe (n = 21) | |||
| Maternal age, y a | 31 (29-34) | 32 (29-36) | 31 (29-33) | 33 (30-36) | .072 |
| Gravidity, n a | 2 (1-3) | 2 (1-3) | 1 (1-2) | 2 (1-3) | .218 |
| Parity, n a | 0 (0-1) | 1 (0-1) | 0 (0-1) | 1 (0-1) | .287 |
| White, n (%) | 178 (82.8) | 89 (82.4) | 75 (87.2) | 14 (66.7) | .142 |
| Smoking, n (%) | 8 (3.7) | 6 (5.6) | 1 (1.2) | 1 (4.8) | .206 |
| History of intrahepatic cholestasis of pregnancy, n (%) | 32 (14.9) | 19 (17.6) | 8 (9.3) | 5 (23.8) | .127 |
| History of hepatobiliary disease, n (%) | 6 (2.8) | 2 (1.9) | 2 (2.3) | 3 (14.3) | .179 |
| Gestational age at diagnosis, d a | 252 (238-265) | 259 (244-266) | 248 (239-263) | 234 (207-248) | .001 b,c,d |
| Use of medication, n (%) e | 151 (70.2) | 69 (63.9) | 63 (73.3) | 19 (90.5) | .042 d |
| Laboratory measurements a f | |||||
| Bile acid, μmol/L | 39 (21–66) | 21 (15–29) | 60 (51–73) | 149 (109–200) | < .001 b,c,d |
| Aspartate transaminase, IU/L | 55 (34–86) | 41 (27–71) | 68 (40–133) | 71 (38–183) | < .001 b,d |
| Alanine transaminase, IU/L | 90 (37–162) | 66 (26–123) | 130 (46–222) | 100 (66–208) | < .001 b,d |
| Gama-glutamyl transpeptidase, IU/L | 24(16–43) | 23 (15–34) | 28 (17–54) | 20 (16–41) | .113 |
| Alkaline phosphatase, IU/L | 220 (165–268) | 190 (135–249) | 237 (195–279) | 226 (164–287) | .002 b |
| Lactate dehydrogenase, IU/L | 247 (196–379) | 240 (187–374) | 253 (214–439) | 216 (180–298) | .055 |
| Bilirubin, μmol/L | 11 (8–14) | 10 (8–12) | 11 (8–15) | 16 (11–22) | .002 c,d |
a Values are presented as median (interquartile range)
b Significant difference between mild and moderate levels
c Significant difference between moderate and severe levels
d Significant difference between mild and severe levels
e Mainly ursodeoxycholic acid (in 2 cases cholestyramine)
f Highest measured laboratory data throughout the pregnancy were used.
Maternal age, parity, and ethnicity had no effect on the severity of ICP. Gestational age at diagnosis of ICP was significantly lower in the moderate and severe ICP groups ( P = .001). Almost all laboratory data could be retrieved; however, in approximately 15% of cases, liver function parameters were not determined. Aspartate transaminase, alanine transaminase, bilirubin, and alkaline phosphatase levels all were elevated significantly, related to the severity of ICP ( Table 1 ).
Perinatal pregnancy outcomes are shown in Table 2 . Patients in the moderate and severe groups had a lower average gestational age at delivery ( P < .001). Preterm birth occurred in 28 cases (13.0%), of which 8 cases (38.1%) were in the severe ICP group ( P =.003). Labor was induced in 159 cases (74.0%), and 14 patients (6.5%) had an elective cesarean delivery.
| Obstetric outcome | Population (n = 215) | Intrahepatic cholestasis of pregnancy | P value | ||
|---|---|---|---|---|---|
| Mild (n = 8) | Moderate (n = 86) | Severe (n = 21) | |||
| Gestational age at delivery, d a | 267 (260–275) | 272 (264–279) | 265 (260–270) | 259 (252–267) | < .001 b,c,d |
| Bile acid levels at time of delivery, μmol/L a | |||||
| Maternal | 27 (15–56) | 17 (12–23) | 50 (24–68) | 100 (22–141) | < .001 b,d |
| Umbilical e | 8 (5–14) | 6 (4–8) | 9 (5–15) | 14 (10–24) | .076 |
| Fetal sex (male) | 115 (53.5) | 54 (50.0) | 48 (55.8) | 13 (61.9) | .544 |
| Apgar scores a | |||||
| 1-Minute | 9 (8–9) | 9 (8–9) | 9 (9–9) | 9 (8–9) | .263 |
| 5-Minute | 10 (10–10) | 10 (10–10) | 10 (10–10) | 10 (9–10) | .45 |
| pH a | 7.26 (7.21–7.32) | 7.27 (7.20–7.32) | 7.26 (7.21–7.32) | 7.27 (7.20–7.30) | .923 |
| Birthweight, g a | 3210 (2900–3550) | 3290 (2950–3680) | 3180 (2980–3480) | 2930 (2710–3360) | .009 c,d |
| Small for gestational age, n (%) f | 13 (6.0) | 8 (7.3) | 4 (4.7) | 1 (4.8) | .831 |
| Preterm birth, n (%) g | 28 (13.0) | 9 (8.3) | 11 (12.8) | 8 (38.1) | .003 c,d |
| Start of labor, n (%) | 0.081 | ||||
| Spontaneous | 42 (19.5) | 28 (25.9) | 10 (11.6) | 4 (19.0) | |
| Induced | 159 (74.0) | 74 (68.5) | 68 (79.1) | 17 (81.0) | |
| Elective caesarean delivery | 14 (6.5) | 6 (5.6) | 8 (9.3) | – | |
| Mode of delivery, n (%) | 0.409 | ||||
| Vaginal delivery | 185 (86.0) | 94 (87.0) | 72 (83.7) | 20 (95.2) | |
| Cesarean delivery | 30 (14.0) | 14 (13.0) | 14 (16.3) | 1 (4.8) | |
| Adverse neonatal outcome, n (%) | |||||
| Spontaneous preterm birth | 10 (4.7) | 3 (2.8) | 3 (3.5) | 4 (19.0) | .023 c d |
| Meconium-stained fluid | 44 (20.5) | 15 (13.8) | 19 (22.1) | 10 (47.6) | .003 c d |
| Postpartum hemorrhage h | 16 (7.4) | 3 (2.8) | 11 (12.8) | 2 (9.5) | .019 b |
| Asphyxia i | 2 (0.9) | — | 2 (2.3) | — | .345 |
| Perinatal death j | 2 (0.9) | — | — | 2 (9.5) | .009 c d |
| Admission medium care | 49 (22.8) | 21 (19.4) | 21 (24.4) | 7 (33.3) | .374 |
| Admission neonatal intensive care unit | 5 (2.4) | 1 (0.9) | 2 (2.3) | 2 (9.5) | .062 |
a Values are presented as median (interquartile range)
b Significant difference between mild and moderate
c Significant difference between moderate and severe
d Significant difference between mild and severe
e Umbilical levels of bile acid at time of delivery (micromoles per liter) that was determined for only 35 neonates
f Defined as birthweight <10th percentile
g Defined as <37 weeks of gestation
i Defined as pHa <7.05 and base deficit of >12 μmol/L or pHa <7.00
j Defined as 24 weeks of gestation to 7 days after delivery.
Birthweight was significantly lower in the more severe cases of ICP ( P = .009), but no difference was seen in the percentage of small-for-gestational-age children ( P = .831). Apgar scores were comparable between groups ( P = .263 and 0.45 after 1 minute and 5 minutes, respectively). Spontaneous preterm birth was more common with increasing severity of ICP ( P = .023). In addition, meconium-stained amniotic fluid was found more often in the more severe cases ( P = .003). Postpartum hemorrhage was present in 7.4% of all cases, with the highest percentage seen in the moderate group ( P = .019). Asphyxia was seen in 2 cases throughout the study period; both cases were in the moderate ICP group. In this study population, perinatal death occurred in 2 cases (0.9%). Both intrauterine deaths were found in the severe ICP group ( P = .009), which amounts to 9.5% of the severe ICP cases. In 1 of these patients, placental histopathologic examination showed a small placenta (<p10) with villitis. In the other patient, no placental abnormalities were found. Both women declined autopsy.
Higher maternal levels of BA were also seen at time of delivery in the more severe group compared with the mild and moderate groups ( P < .001). However, in all groups, the average level of BAs at delivery was lower than the highest measured level during the entire pregnancy.
In 35 cases, the umbilical cord BA levels were tested. Umbilical BA levels were elevated in patients with severe ICP; however, this was not statistically significant ( P = .076). As shown in Table 3 and the Figure , there was a significant positive correlation between the highest measured maternal BA and umbilical BA (r = 0.453; P = .006) and between maternal BA at delivery and umbilical BA (r = 0.425; P =.012).
| Variable | n | Spearman correlation coefficient | P value |
|---|---|---|---|
| Highest measured maternal a vs umbilical bile acid, b μmol/L | 35 | 0.453 | .006 |
| Maternal bile acid at time of delivery c vs umbilical bile acid, μmol/L | 34 | 0.425 | .012 |
a Highest value found throughout the pregnancy
b In a sample of umbilical blood directly after delivery
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