Should women with intrahepatic cholestasis of pregnancy be delivered early?
No. Routine use of active management of ICP is not supported by data.
Intrahepatic cholestasis of pregnancy (ICP), or obstetric cholestasis, is a hepatic disorder of pregnancy characterized by elevated bile acids accompanied by intense pruritus. Prevalence of ICP in the United States varies from 0.32% in Connecticut to 5.5% in southern California’s primarily Latina population.1,2
Although authors of a 1968 case series of stillbirths that occurred in ICP-affected pregnancies attributed the fetal deaths to comorbid conditions, this early report continues to be cited as evidence that ICP is a risk factor for unexplained term stillbirth.3 To decrease this suspected perinatal risk, empiric use of active management to achieve delivery between 36 and 38 weeks’ gestation has become accepted practice throughout the world. However, reports endorsing routine use of active management for this hepatic condition provide no valid evidence that ICP is a risk factor for fetal demise and fail to present or describe the short- and long-term risk borne by the off spring of this obstetric intervention.
Here I review the flawed evidence that stillbirth rates in ICP-affected pregnancies are higher than in pregnancies not affected by ICP and also present evidence that offspring iatrogenically delivered before 39 weeks’ gestation are subjected to increased morbidity during the neonatal, pediatric, and adolescent periods when compared to those delivered after 39 weeks’ gestation.
Since 2006, in the United States, the fetal mortality rate has remained relatively constant at 2.87.4 Efforts to reduce it have focused on eliminating preventable causes of stillbirth.5 Modifiable maternal factors associated with higher rates of fetal mortality include pre-gestational diabetes or hypertension, body mass index ³ 30, and tobacco or alcohol use.6 Cesarean delivery may be a risk factor for subsequent stillbirth. Although it was reported by Gray et al. to increase the stillbirth rate for the subsequent pregnancy from 3.5/1000 to 4.5/1000, other investigators using a large national database found cesarean delivery was not associated with an increased risk of stillbirth.7,8 Current best practice does not routinely support early term (ET) or late preterm delivery (LPT) to avoid stillbirth in pregnancies affected by these conditions associated with higher fetal mortality rates. In contrast, despite only anecdotal support for ICP as an independent risk for fetal demise, without regard to neonatal and pediatric implications, active management before 38 weeks’ gestation is an accepted standard of care for ICP-affected pregnancies.
No clear causal association between ICP and stillbirth
The association between ICP and stillbirths began with observational case reports.9,10 Initial reports of adverse perinatal outcomes associated with ICP focused on increased perinatal mortality due primarily to prematurity sequel. Subsequent case reports and uncontrolled case series narrowed perinatal concern to avoiding unexplained term stillbirth.11 Active management with delivery by induction of labor or cesarean between 36 and 38 weeks’ gestation has been internationally accepted and included in obstetric guidelines.12
Initiation of this practice often begins after confirmation of fetal lung maturity.13 Notably, adoption of these guidelines predates data showing that consequences of prematurity are not limited or focused solely on respiratory distress syndrome.14 The numerous reports cited in support of active management of ICP-affected pregnancies are flawed by lack of control populations, failure to adjust for the background stillbirth rate, or failure to exclude cases with comorbidities known to be independently associated with higher stillbirth rates.
Assigning ICP as a cause of a stillbirth should be an attribution by exclusion. To determine the cause of a stillbirth, a detailed review of clinical, postmortem, and placental pathology data from the Stillbirth Collaborative Research Network should be used.15 The stillbirth etiology reviewer must document the presence of comorbid conditions known to be independent risk factors for stillbirth, such as obesity, advanced maternal age, pregestational diabetes or hypertension, or being a member of an ethnic minority group.16-18 Retrospective controlled and uncontrolled studies ascribing stillbirth in pregnancies to ICP include cases affected by comorbid conditions known to increase risk of stillbirth.19,20