Background
Intrahepatic cholestasis of pregnancy is associated with adverse pregnancy outcomes, including sudden fetal cardiac arrhythmias, resulting in stillbirth. This association has been correlated with the total bile acid levels, which are a marker for disease severity. Studies are yet to determine if intrahepatic cholestasis of pregnancy severity is also associated with increased rates of other adverse neonatal outcomes.
Objective
This study aimed to determine whether pregnancies complicated by intrahepatic cholestasis of pregnancy show a bile acid severity-based relationship with other adverse obstetrical outcomes beyond stillbirth alone.
Study Design
This was a retrospective cohort study of singleton, nonanomalous gestations complicated by intrahepatic cholestasis of pregnancy at the Elmhurst Hospital Center from 2005 to 2019. Severity was defined by the peak total bile acid levels (μmol/L): mild (10–19), low moderate (20–39), high moderate (40–99), and severe (>100). We examined the rates of spontaneous preterm labor, fetal growth restriction, preterm prelabor rupture of membranes, iatrogenic preterm birth, meconium-stained amniotic fluid, cesarean delivery for nonreassuring fetal heart tracing, umbilical artery pH, neonatal intensive care unit admission, and neonatal birthweight. The chi-square, Fisher exact, Student t , Mann–Whitney, and multivariate regression tests were used to determine the association of intrahepatic cholestasis of pregnancy severity and adverse neonatal outcomes. In all analyses, mild severity was used as the base comparator. A P value of <.05 and 95% confidence interval not crossing 1.00 indicated statistical significance.
Results
Of the 1202 pregnancies complicated by intrahepatic cholestasis of pregnancy, 306 (25.5%) were mild, 449 were low moderate (37.4%), 327 were high moderate (27.2%), and 120 were severe (10.0%). After adjusting for confounders, progressive intrahepatic cholestasis of pregnancy severity was associated with an increased risk of spontaneous preterm labor (low moderate adjusted odds ratio, 1.60; 95% confidence interval, 0.76–3.38; high moderate adjusted odds ratio, 3.49; 95% confidence interval, 1.69–7.22; severe adjusted odds ratio, 6.58; 95% confidence interval, 2.97–14.55), iatrogenic preterm birth (low moderate adjusted odds ratio, 1.54; 95% confidence interval, 0.95–2.52; high moderate adjusted odds ratio, 3.11; 95% confidence interval, 1.91–5.06; severe adjusted odds ratio, 4.94; 95% confidence interval, 2.81–8.71), and meconium-stained amniotic fluid (low moderate adjusted odds ratio, 1.33; 95% confidence interval, 0.75–2.36; high moderate adjusted odds ratio, 2.63; 95% confidence interval, 1.48–4.65; severe adjusted odds ratio, 3.91; 95% confidence interval, 1.98–7.69). There was no significant association between intrahepatic cholestasis of pregnancy severity and other adverse outcomes.
Conclusion
The findings suggest that intrahepatic cholestasis of pregnancy disease severity is associated with an increased risk of spontaneous preterm labor, iatrogenic preterm birth, and meconium-stained amniotic fluid. These findings provide valuable insight toward patient anticipatory counseling.
Introduction
The typical onset of intrahepatic cholestasis of pregnancy (IHCP) is in the second and third trimesters, and it is characterized by generalized pruritis—predominantly on the palm and soles, often worsening at night, with associated elevated serum total bile acid (TBA) concentrations and lack of primary skin lesions. Beside the maternal symptoms of pruritis, elevated bile acids confer significant fetal risks. These include stillbirth, spontaneous preterm labor, iatrogenic preterm birth, meconium-stained amniotic fluid, and respiratory distress syndrome. Although the incidence of IHCP in most areas is relatively low at 0.3% to 0.5%, certain regions of the world have incidences of IHCP upward of 15%. , The risk factors for IHCP include previous history of IHCP, advanced maternal age, chronic hepatitis C, multifetal gestation, Hispanic ethnicity and underlying liver or biliary pathology, including nonalcoholic liver cirrhosis, gallstones, cholecystitis, and hepatitis. Despite IHCP being the most common hepatobiliary complication of pregnancy, its etiology and pathophysiology are largely unknown. However, it is suspected to be secondary to a combination of genetic, hormonal, and environmental factors. ,
Why was this study conducted?
This study aimed to determine the association of intrahepatic cholestasis of pregnancy (IHCP) disease severity and adverse outcomes other than stillbirth.
Key findings
Worsening severity of IHCP is associated with increased rates of spontaneous preterm labor, iatrogenic preterm birth, and meconium-stained amniotic fluid.
Worsening severity of IHCP was not associated with umbilical arterial pH, preterm prelabor rupture of membranes, cesarean delivery for nonreassuring fetal heart tracing, suspected fetal growth restriction, neonatal birthweight, or neonatal intensive care unit admission.
What does this add to what is known?
This study highlights adverse outcomes other than stillbirth that are associated with IHCP severity, which will allow for physiological understanding of the association by the provider and will allow patient anticipatory counseling.
Definitive diagnosis is made if the serum TBA concentrations are elevated (>10 μmol/L), and the TBA levels are commonly utilized to categorize the severity of disease. The clinical progression of IHCP complicates diagnosis, as pruritis often precedes the rise of TBA by as much as several weeks. Therefore, even in the setting of normal TBA, a close follow-up is warranted in patients. Once elevated TBA levels are observed to be present, studies have shown that maternal bile acids readily cross the placental barrier and accumulate in the fetal circulation and amniotic fluid, which is thought to infer the risks to the fetus noted above. Specifically, stillbirth is thought to be secondary to TBA cardiac toxicity, resulting in fetal arrythmia and subsequent demise. Unfortunately, antepartum testing has not been shown to improve outcomes, and multiple studies and case reports have noted stillbirth occurring shortly after reassuring fetal testing.
In a recent systematic review, IHCP was associated with increased rates of stillbirth, spontaneous preterm labor, iatrogenic preterm birth, meconium-stained fluid, and neonatal intensive care unit (NICU) admission. A severity-based analysis (delineated by TBA levels) was only performed on the rates of stillbirth and revealed a positive association, which has been reported in multiple other studies. , , , However, studies to determine the relationship between IHCP severity and other adverse outcomes are limited. , We aimed to determine whether pregnancies complicated by IHCP show a bile acid severity-based relationship with adverse pregnancy outcomes beyond stillbirth.
Materials and Methods
We conducted a retrospective cohort study of singleton, nonanomalous live births complicated by IHCP and receiving prenatal care and delivering between 2005 and 2019 at Elmhurst Hospital Center (EHC) in Queens, New York. EHC is a safety net city hospital that is neither a referral nor a transfer center for any pathology, including cholestasis. At EHC, the prevalence of IHCP at any given point ranges from 6% to 8%, likely because of the primarily Hispanic and South Asian population getting admitted to the hospital. We excluded patients under the age of 18, multifetal pregnancies, and pregnancies complicated by fetal anomalies. Data for this study were obtained from maternal and neonatal charts within the electronic health record. On the basis of literature definitions, we classified IHCP severity by pregnancy peak TBA levels (μmol/L) into the following categories: mild (TBA, 10–19), low moderate (TBA, 20–39), high moderate (TBA, 40–99), and severe (TBA >100). Although no set protocol within our institution exists, the TBA levels are often repeated every 3 to 4 weeks per provider preference. As bile acids are often trended to guide clinical management, we utilized the peak bile acid levels for analysis. ,
The primary outcome was the rate of spontaneous preterm labor defined as onset and delivery before 37 weeks. The secondary outcomes included rates of fetal growth restriction (FGR), preterm prelabor rupture of membranes (PPROM), iatrogenic preterm birth defined as induction of labor or planned cesarean delivery before 37 weeks, meconium-stained amniotic fluid, cesarean delivery for nonreassuring fetal heart tracing (NRFHT), umbilical artery pH, NICU admission, and neonatal birthweight. The stillbirth rates were not analyzed in our study, as only live births were included.
The chi-square, Fisher exact, student t , and Mann–Whitney U tests were used for univariate analysis on the basis of results distribution and sample sizes as statistically appropriate. Multivariate regression tests were used to determine the association between IHCP severity and adverse neonatal outcomes. Multivariate analysis was adjusted for baseline demographic differences and clinical confounders previously determined by the literature. In all analyses, mild IHCP was used as the base comparator. A P value of <.05 and 95% confidence interval (CI) not crossing 1.00 indicated statistical significance. All statistical analyses were performed using STATA IC version 15 (StataCorp LLC, College Station, TX). As deidentified data were utilized for our study with minimal risk to patients, waiver of informed consent was obtained via Icahn School of Medicine at Mount Sinai Institutional Review Board.
Results
During our study period, there were 1202 pregnancies complicated by IHCP, of which 306 (25.5%) were mild, 449 were low moderate (37.4%), 327 were high moderate (27.2%), and 120 were severe (10.0%). IHCP was more often diagnosed in people identifying as Hispanic; they were also more likely to have increased severity of IHCP ( Table 1 ). Increasing bile acid severity was associated with diagnosis at an earlier gestational age, delivery at earlier gestational age, and more frequent ursodiol (ursodeoxycholic acid) therapy ( Table 1 ). Among the groups, there was a statistically significant association with hypertensive disorders of pregnancy (gestational hypertension, chronic hypertension, preeclampsia, and superimposed preeclampsia) that did not follow a severity-associated relationship. There was no statistically significant difference between IHCP severity and age, parity, previous cesarean delivery, history of preterm birth, pregestational diabetes mellitus, gestational diabetes mellitus, or delivery mode ( Table 1 ).
| Characteristics | Mild (n=306) | Low moderate (n=449) | High moderate (n=327) | Severe (n=120) | P value |
|---|---|---|---|---|---|
| Age, mean±SD | 28.91±5.79 | 28.76±6.04 | 28.34±5.81 | 28.19±5.35 | .50 |
| Ethnicity, n (%) | <.01 | ||||
| Hispanic | 225 (73.77) | 361 (80.76) | 286 (88.00) | 112 (93.33) | |
| Bengali | 32 (10.49) | 37 (8.28) | 18 (5.54) | 3 (2.50) | |
| European | 3 (0.98) | 3 (0.67) | 0 (0.00) | 0 (0.00) | |
| African | 3 (0.98) | 1 (0.22) | 1 (0.31) | 0 (0.00) | |
| Other/unknown | 15 (4.92) | 10 (2.24) | 10 (3.08) | 1 (0.83) | |
| Southeast Asian | 27 (8.85) | 35 (7.83) | 10 (3.08) | 4 (3.33) | |
| Parity, quartiles | 1 (0–2) | 1 (0–2) | 1 (0–2) | 1 (0–2) | .71 |
| History of preterm birth, n (%) | 24 (7.84) | 26 (5.79) | 25 (7.65) | 16 (13.33) | .06 |
| Previous cesarean delivery, n (%) | 43 (14.24) | 54 (12.62) | 41 (12.93) | 16 (14.41) | .91 |
| Pregestational diabetes mellitus, n (%) | 9 (2.91) | 9 (2.01) | 5 (1.53) | 2 (1.67) | .65 |
| Gestational diabetes mellitus, n (%) | 50 (16.18) | 85 (18.93) | 43 (13.11) | 23 (19.17) | .16 |
| Hypertensive disorder of pregnancy, n (%) | 17 (5.56) | 34 (7.57) | 39 (11.93) | 8 (6.67) | .02 |
| Gestational age at diagnosis, mean±SD | 34.27±5.26 | 34.73±4.31 | 34.27±4.65 | 33.04±4.76 | <.01 |
| Gestational age at delivery, mean±SD | 37.83±1.20 | 37.50±1.52 | 37.16±1.32 | 36.28±1.94 | <.01 |
| Ursodiol therapy, n (%) | 120 (39.34) | 208 (46.53) | 155 (47.40) | 77 (64.17) | <.01 |
| Delivery mode, n (%) | .41 | ||||
| Vaginal | 206 (69.13) | 299 (67.65) | 235 (73.21) | 84 (71.19) | |
| Cesarean delivery | 92 (30.87) | 143 (32.35) | 86 (26.79) | 34 (28.81) |
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