Dr Henderson is Director of Maternal Fetal Medicine at Lincoln Medical and Mental Health Center and Professor of Clinical Obstetrics and Gynecology at Weill Cornell Medical College.
Two experts debate whether early delivery and active management are appropriate care in women with intrahepatic cholestasis
Yes. The only known way to reduce risk of stillbirth is with early delivery.
Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of stillbirth, and the only known way to reduce this risk is early delivery. The rationale is 3-fold: 1) incidence of stillbirth in ICP is higher than in the general pregnant population; 2) ICP-associated stillbirths cluster toward the end of the third trimester; and 3) early delivery reduces the ICP-related perinatal mortality rate.
Compared to patients without ICP, those affected by ICP have a higher stillbirth rate. The stillbirth rate at 37 weeks’ gestation and beyond for the entire population in the United States is approximately 0.1% to 0.3% (1–3 per 1000).1,2 It is lower than the term stillbirth rate in ICP that was published by Henderson et al. Their study reported a 1.2% (4/331) term stillbirth rate attributed to ICP with expectant management.3 This was calculated after excluding cases of ICP with comorbidities such as diabetes, preeclampsia, abruption, intrauterine growth restriction, and congenital fetal anomalies. Puljic et al. studied more than 1.6 million singleton pregnancies between 34 and 40 weeks’ gestation and compared the stillbirth rate in those with and without ICP.4 They found a significantly higher risk of stillbirth in those with ICP compared to the unaffected population. It persisted for pregnancies between 32 and 40 weeks’ gestation. In a prospective cohort study evaluating patients affected by ICP with total bile acid concentrations ³ 40 Î¼mol/L, Geenes et al., after adjusting for confounders, found a higher incidence of stillbirth in the population with ICP compared to the unaffected controls.5
Stillbirths in ICP cluster toward the end of the third trimester. More than 20 years ago, a striking case series of stillbirths attributed to ICP described obstetric outcomes of 8 women with 13 pregnancies affected with ICP. Twelve of the pregnancies were managed expectantly. Eight of the pregnancies resulted in stillbirth, and the gestational ages at death were: 37, 39, 32, 37 and 37 weeks, with 3 more listed as “at term.”6 Williamson et al. reported their findings in 227 women with 352 total pregnancies affected by ICP. Of these pregnancies, 5.7% (20/352) had an intrauterine death in a singleton pregnancy. The median gestational age when death occurred was 38 weeks (IQR 2.5) with 10% (2/20) occurring before 37 weeks’ gestation.7 In the aforementioned prospective study by Geenes et al., which had a 1.5% (10/664) incidence of stillbirth with ICP, the median gestational age at delivery for the cases with ICP and stillbirth was 36 weeks ± 2 days (IQR 35 ± 4 to 38 ± 1 days). Six of the 10 stillbirths occurred before 37 weeks’ gestation. Of these 10 stillbirths, 2 were to mothers with preeclampsia, 2 had gestational diabetes, and 2 had nonspecified complications. The authors clarified that no stillborn fetus was small for gestational age. Three stillbirths were large for gestational age; none of these were from mothers with gestational diabetes.5 Kawakita et al. had 4 stillbirths in 26 patients with ICP and a total bile acid concentration ³ 100 Î¼mol/L. These stillbirths occurred at 37 1/7, 35 3/7, 24 1/7, and 35 5/7 weeks’ gestation. None of the stillbirths were affected by congenital abnormalities. The one stillbirth at 24 1/7 weeks’ gestation had a normal karyotype and occurred in a mother who had elevated transaminases prior to pregnancy.8 Alsulyman et al. reported 2 stillbirths in 79 patients with ICP who were managed expectantly. The mean gestational age at delivery was 38.5 ± 1.9 weeks for the cohort, and the 2 stillbirths occurred at 36 to 37 weeks’ gestation. Both were appropriately grown with no gross abnormalities.9
Early delivery is the only known intervention that reduces the risk of stillbirth. This practice was recommended more than 40 years ago by Reid et al., who reported 5 stillbirths in 56 pregnancies affected by ICP.10 Subsequently, they adopted a practice of inducing labor at term that led to a decrease in their hospital’s ICP-related perinatal mortality rate from 107 per 1000 to 35 per 1000.11 Several other studies soon followed that demonstrated the effect of early delivery on lowering the perinatal mortality rate in ICP. Rioseco et al. reviewed 320 pregnancies with ICP during a time when their practice was to deliver at 38 weeks’ gestation. They found this led to similar perinatal mortality rates between the ICP affected and unaffected populations. In the cohort of patients with ICP, there were 4 stillbirths (1.3% [4/320]), which occurred between 33 and 38 weeks’ gestation. None of the mothers had obstetrical complications nor did the fetuses have growth abnormalities.12 Roncaglia et al. studied 206 pregnancies with ICP that occurred during a time when they induced patients with ICP at 37 weeks’ gestation; there were no stillbirths. Those managed with early delivery had a significantly lower fetal death rate compared to their historical cohort of patients with ICP who were managed expectantly.13 Turunen et al. studied 687 pregnancies with ICP and compared them to 1374 unaffected controls.14 A proxy for early delivery, the labor induction rate was higher in the cohort with ICP compared to controls. There was no statistical difference in the incidence of stillbirth between the 2 groups. Kenyon et al. reported no stillbirths in 70 pregnancies with ICP that were managed with a protocol that offered elective delivery at 37–38 weeks’ gestation.15 Of these patients, 76% had labor induced. Rook et al., whose clinical practice was to deliver at approximately 37 weeks’ gestation, reported no stillbirths in 101 women with ICP. The average gestational age at delivery was 37 ± 1.2 weeks, and 87% were induced.16
We evaluated 122 patients with ICP when our practice was to deliver at 37 weeks’ gestation. The average gestational age at delivery for our cohort was 36.7 ± 2.1 weeks. Elective delivery occurred in 86.9% and spontaneous labor occurred in 13.1%. One stillbirth occurred at 30 weeks’ gestation.17
Lo et al. meticulously calculated the optimal gestational age for delivery in women with ICP. After accounting for neonatal mortality and morbidities associated with early delivery and the risk of stillbirth with ICP, they demonstrated the optimal time to deliver patients with ICP is at 36 weeks’ gestation.18
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.
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
However, one recent study did consider comorbidities in ICP-affected pregnancies.21 This was a review of a retrospective multisite cohort of 233 symptomatic women with total bile acids (TBA) levels that ranged from 0 Î¼mol/L to > 100 Î¼mol/L. While the authors found the prevalence of maternal comorbid stillbirth risk factors was not affected by the severity of the disease, it is notable that all 4 stillbirths in the cohort occurred in pregnancies most severely affected by ICP as designated by TBA levels > 100 Î¼mol/L. Although the findings in this study are certainly suggestive of an association between elevated TBA and fetal demise, as in many previous reviews of large data sets, critical relevant obstetric information is missing. In particular, no data are provided concerning gestational age or existence of comorbid conditions complicating the pregnancies that ended in stillbirth. No information is provided about the use of active management of ICP-affected pregnancies during the 2009 to 2014 study period.
Active management of ICP has its foundation in reports published between 1964 and 2014 that consisted of only 20 unexplained term stillbirths including 6 pregnancies affected by cardiovascular comorbidities.22-24 A review of the published literature finds no evidence to reject the null hypothesis that there is no difference in stillbirth rates for pregnancies affected and unaffected by ICP.8
In contrast, there is robust evidence that when compared to full-term (FT) infants (39 to 42 weeks’ gestation), ET (37 to 39 weeks’ gestation) and LPT infants (incorrectly dated 34–35 and 36 weeks’ gestation) are at increased risk for short-term respiratory morbidity, admission to neonatal intensive care units, and for the first 8 to 9 years of life, lower lung function as measured by a spirometer.25,26 When compared to FT infants, ET infants are at increased risk for lower cognitive ability; importantly, this is a finding that persists into adulthood.27,28 Several reports indicate that LPT and ET infants are at increased risk for needing special education, achieving less education, and having poorer cognitive abilities than FT infants.29-31 After controlling for socioeconomic confounders, investigators found persistent differences in neurocognitive abilities among LPT and ET children as manifested by generally performing less well on cognitive and language tests than their FT-born counterparts.32 This altered neurocognitive function seems to continue into adulthood as measured by poorer episodic memory performance.33
Whereas there is no evidence to support ICP as an independent risk factor for unexplained term stillbirth, robust data exist that when compared to FT infants born before 39 weeks’ gestation, LPT infants delivered at 34 to 36 weeks and ET infants delivered at 37 to 38 weeks are at increased risk for short- and long-term adverse outcomes.34
1. Abedin P, Weaver JB, Egginton E. Intrahepatic cholestasis of pregnancy: prevalence and ethnic distribution. Etn Health.1999;4:435-437
2. Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 2006;26:527-532
3. Roszkowski I, Pisarek-Miedzinska D. Jaundice in pregnancy. II. Clinical course of pre-pregnancy and delivery and condition of neonate. Am J Obstet Gynecol .1968;101:500-503.
4. MacDorman MF, Kirmeyer SE, Wilson EC. Fetal and perinatal morality, United States, 2013. National Vital Statistics Report Vol 64, no 8, Hyattsville, MD: National Center for Health Statistics, 2015
5. DelkeI, Hyatt R, Feinkind L, Minkoff H. Avoidable causes of perinatal death at or after term pregnancy in an inner-city hospital: Medical versus social. Am J Obstet Gynecol. 1988;159:562-566
6. Reddy UM, Laughon SK, Sun L, Troendle J, Willinger M, Zhang J. Prepregnancy risks factors for antepartum stillbirth in the United States. Obstet Gynecol. 2010:116:1119-1126
7. Gray R, Quigley M, Hockley G, Kurinczuk J, Goldarce M, Brocklehurst P. Caesarean delivery and risk of stillbirth in subsequent pregnancy: a retrospective cohort study in an English population. BJOG; 2007:114:264-270
8. Bahtiyar MO, Julien S, Robinson JN, et al. Prior cesarean delivery is not associated with an increased risk of stillbirth in a subsequent pregnancy: analysis of U.S. perinatal mortality data, 1995-1997. Am J Obstet Gynecol. 2006;195(5):1373
9. Qui Zhong-da, Wang Qi-nan, Liu Yue-han, Maio He-Zhang. Intrahepatic Cholestasis of Pregnancy Clinical analysis and follow-up of 22 Cases . Chinese Medical Journal 1983 96(12):902-906
10. Reid R, Ivey KJ, Rencoret, Storey B. Fetal Complications of obstetric cholestasis. Br Med K 1976;1:870-872
11. Henderson, C.E., Shah, R.R., Gottimukkala, S., Ferreira, K.K., Hamaoui, A., Mercado, R. Primum non nocere: how active management became modus operandi for intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol. 2014:211:189–196
12. Rioseco AJ. Ivankovec MD, Manzur A, Hamed F, Kato SR, Parer JT, Germain AM. Intrahepatic cholestasis of pregnancy: A retrospective case-control study of perinatal outcome. Am J Obstet Gynecol. 1994;170:890-895
13. Spong CY, Mercer BM, D’Alton M, Kilpatrick S, Blackwell S, Saade G. Timing of indicated late-preterm and early-term birth. Obstet Gynecol 2011;118:323–333.
14. Gouyon JB, Vintejoux A, Sagot P, Burguet A, Quantin C, Ferdynus C, Burgundy Perinatal Network. Neonatal outcome associated with singleton birth at 34-41 weeks of gestation. International journal of epidemiology. 2010;39:769-776
15. Dudley DH, Goldenberg R, Conway D, et al. A new system for determining the causes of stillbirth. Obstet Gynecol. 2010;116:254-260
16. Flenady V, Koopmans L, Middleton P, et al. Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet. 2011;377:1331-1340
17. Gardosi J, Madurasinghe V, Williams M, Mailk A, Francis A. Maternal and fetal risk factors for stillbirth. BMJ 2013;346:f108
18. Fretts RG. Etiology and prevention of stillbirth. Am J Obstet Gynecol 2005; 193, 1923-1935
19. Geens V, Chappell LC, Sneed PT, Steer PJ, Knight M, Williamson C. Association of Severe Intrahepatic Cholestasis of Pregnancy with Adverse Pregnancy Outcomes: A Prospective Population-Based Case-Control Study. Hepatology 2014;49:1482-1491
20. Puljic A, Kim E, Page J, et al. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol .2015;212:667.e1-5
21. Kawakita T, Parikh LI, Ramsey PS, et al. Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gyneol 2015;214:570.e1-8
22. Alsulyman OM, Ouzounian JG, Ames-Castrol M, Goodwin TM. Intrahepatic Cholestasis of pregnancy: perinatal outcome associated with expectant management. Am J Obstetric Gynecol. 1996:175;957-960
23. Berg B, Helm G, Petersohn L, Tryding. Cholestasis of Pregnancy. Acta Obstet Gynecol Scand 1986 65:107-113
24. Laatikainen T, Ikonen E. Fetal Prognosis in Obstetric Hepatoisis. Ann Chir Gynaecol Fenn 1975;64(3):155-164
25. Kitcha SJ, Watkins WJ, Lowe J, Henderson AJ, Katecha S. Effect of early-term birth on respiratory symptomssyptoms and lung function in childhood and adolescence. Pediatri Pulmonol 2016; doi: 10.1002/ppul;/23448
26. Harju M, Keski-Nisula L, Georgiadis L, RÃ¤isÃ¤nen S, Gissler M, Heinonen S. 20143 The burden of childhood asthma and late preterm and early term births. J Pediatr 2014;164(2):295-299.
27. Poulsen, G, Wolke D, Kurinczuk JJ, et al. Gestational age and cognitive ability in early childhood: a population-based cohort study. Paediatirc and Perinatal Epidemiology 2013;27,371-379
28. Sengupta S, Carrion V, Shelton J, et al. JAMA Pediatr 2013:167(1):1053-1059
29. Moster D, Lie RT. Moster D, Markestad T. Long-term medical and social consequences of preterm birth NEJM 2008;359:262-273
30. Mathiasen R, Hansen BM, Nybo Anderson AM, Forman JL, Greisen G. Gestational Age and Basic School Achievements: a National Follow up Study in Denmark. Pediatirics 2010;126(6)e1553-e1561
31. Quigley MA, Polusen G, Boyle E, et al. Early term and late preterm birth are associated with poor school performance at 5 years: a cohort study. Arch Dis Child Fetal Neonatal Ed. 2012;97:F167-F173
32. Chan E, Leong P, Malouf R, Quigley. Long-term cognitive and school outcomes for late-preterm and early-term births: a systematic review. Child: care, health and development. 2015: 42;297-312.
33. Heinon K, Eriksson JG, Lahti J, et al. Late Preterm Birth and Neurocognitive Performance in Late Adulthood: A Birth Cohort Study. Pediatrics. 2015;135:(4)e2014-3556
34. Hibbard JU, Wilkins I, Sun L, et al. Consortium on Safe Labor. Respiratory morbidity in late preterm births. JAMA. 2010;304:419-415.
35. Kapellou O, Counsell SJ, Kennea N, et al. Abnormal cortical development after premature birth shown by altered allometric scaling of brain growth. PLoS Medicine. 2006;3(8):1382-1390.
36. Morzurkewich E, Chilimigras J, Koepke E, Keeton K, King VJ. Indications for induction of labor: a best-evidence review. BJOG. 2009; 626-636.