Intrahepatic cholestasis of pregnancy and timing of delivery.

Just Accepted by The Journal of Maternal-Fetal & Neonatal Medicine Intrahepatic cholestasis of pregnancy and timing of delivery Jamie O Lo, MD; Brian L Shaffer, MD; Allison Allen, MD; Sarah E Little MD; Yvonne W. Cheng, MD, PhD; Aaron B. Caughey, MD, PhD doi: 10.3109/14767058.2014.984605 Abstract

J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Biblioteka Uniwersytetu Warszawskiego on 11/26/14 For personal use only.

Objective: We examined the morbidities from delivery at earlier gestational ages versus intrauterine fetal demise (IUFD) for women with intrahepatic cholestasis of pregnancy (ICP) to determine the optimal gestational age for delivery. Methods: A decision-analytic model was created to compare delivery at 35 through 38 weeks gestation for different delivery strategies: (1) empiric steroids; (2) steroids if fetal lung maturity (FLM) negative; (3) wait a week and retest if FLM negative; or (4) deliver immediately. Literature review identified 18 studies that estimated IUFD in ICP; we used the mean rate, 1.74%, and assumed a uniform distribution from 34 to 40 weeks gestation. Large cohort data was used to calculate neonatal morbidity rates at each gestational age. Maternal and neonatal quality-adjusted life years (QALYs) were combined. Univariate sensitivity and Monte Carlo analyses were performed to test for robustness. Results: Immediate delivery at 36 weeks without FLM testing and steroid administration was the optimal strategy as compared to delivery at 36 weeks with steroids (+47 QALYs) and as compared to immediate delivery at 35 weeks (+210 QALYs). Our results were robust up to a 30% increase in the rate of IUFD. Conclusion: Immediate delivery at 36 weeks in women with ICP is the optimal delivery strategy.

© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.

Intrahepatic cholestasis of pregnancy and timing of delivery

Authors: Jamie O Lo, MD (1); Brian L Shaffer, MD (1); Allison Allen, MD (1); Sarah E Little


MD (2); Yvonne W. Cheng, MD, PhD (3); Aaron B. Caughey, MD, PhD (1)

Affiliations: Department of Obstetrics & Gynecology, (1) Oregon Health & Science University, Portland, OR; (2) Harvard University, Boston, MA; and (3) University of California, San Francisco, San Francisco, CA

Corresponding author: Jamie Lo, MD, 3181 SW Sam Jackson Park Rd, Mail code L458, Portland, OR 97239. Telephone (503) 679-2025, Fax: (503) 494-5296. Email: [email protected]

Financial disclosure statement: No investigators have any affiliations or financial involvements that conflict with the material presented in this report.

Word Count: Abstract: 200 Text (excluding abstract): 2211

Short Title: Obstetric cholestasis of pregnancy – A decision analysis Abstract Objective: We examined the morbidities from delivery at earlier gestational ages versus intrauterine fetal demise (IUFD) for women with intrahepatic cholestasis of pregnancy (ICP) to determine the optimal gestational age for delivery.

Methods: A decision-analytic model was created to compare delivery at 35 through 38 weeks gestation for different delivery strategies: (1) empiric steroids; (2) steroids if fetal lung maturity (FLM) negative; (3) wait a week and retest if FLM negative; or (4) deliver immediately. Literature review identified 18 studies that


estimated IUFD in ICP; we used the mean rate, 1.74%, and assumed a uniform distribution from 34 to 40 weeks gestation. Large cohort data was used to calculate neonatal morbidity rates at each gestational age. Maternal and neonatal quality-adjusted life years (QALYs) were combined. Univariate sensitivity and Monte Carlo analyses were performed to test for robustness.

Results: Immediate delivery at 36 weeks without FLM testing and steroid administration was the optimal strategy as compared to delivery at 36 weeks with steroids (+47 QALYs) and as compared to immediate delivery at 35 weeks (+210 QALYs). Our results were robust up to a 30% increase in the rate of IUFD. Conclusion: Immediate delivery at 36 weeks in women with ICP is the optimal delivery strategy.

Keywords: Cholestasis, pregnancy, late preterm delivery, gestational age, intrahepatic cholestasis, decision analytic model

Introduction: Intrahepatic cholestasis of pregnancy (ICP) is one of the most common liver disorders of pregnancy affecting 0.7% of women of Northern European ancestry1 and up to 5% of Chilean women2. It is characterized by pruritus and impaired release of bile from hepatic cells resulting in bile accumulation in the liver and in a small proportion of women, abnormal liver function. Affected women have a favorable long term prognosis with no long term hepatic sequelae. In contrast, this disorder is associated with significant fetal risk including an increased risk of

spontaneous premature delivery, fetal arrhythmia, fetal asphyxia, meconium-stained amniotic fluid, and fetal death3. In addition, untreated ICP is associated with perinatal mortality risks of up to 2%4,5. The underlying mechanism and pathophysiology of fetal death is unknown.


Although many clinicians perform non-stress tests or biophysical profile assessments6,7, standard fetal surveillance has not been found to be predictive of intrauterine fetal demise (IUFD)3,8,9. Most IUFD occurs late in pregnancy with a large majority (~90 percent) after 37 weeks gestation, thus early term delivery (37-38 weeks’ gestation) is commonly employed10. However, early delivery increases the risk for neonatal morbidity and may require admission to the neonatal intensive care unit. Some have proposed corticosteroid administration prior to a planned early term delivery to limit neonatal respiratory morbidity11. Hence, the decision and timing of delivery with or without administration of corticosteroids must balance the risk of late preterm or early term neonatal morbidity against the ongoing risk of IUFD.

There are no randomized trials evaluating the optimal gestational age for delivery and there is no consensus whether delivery should occur at 37 or 38 weeks of gestation, or even earlier4,8. As such, we designed a decision-analytic model to determine the optimal gestational age for delivery of women with ICP by accounting for optimization of both maternal and neonatal outcomes.

Materials and Methods: A decision-analytic model was designed using TreeAgePro 2012 software (TreeAge Software Inc, Williamstown, Mass). Our model (Figure 1) compared delivery in women with ICP at 35 to 38 weeks gestation with four different delivery strategies: (1) delivery 48 hours after steroid

administration; (2) amniocentesis with steroid administration if fetal lung maturity is negative with delivery 48 hours after steroids; (3) amniocentesis with re-testing in one week if fetal lung maturity is negative; or (4) immediate delivery. This study was exempt from Institutional


Review Board approval.

In our model, the neonatal outcomes studied included IUFD, respiratory distress syndrome (RDS), cerebral palsy (CP), necrotizing enterocolitis (NEC) and the absence of major neonatal morbidity. The risk for these neonatal outcomes was defined by gestational age and was adjusted appropriately in the setting of receiving corticosteroids. Given the favorable maternal prognosis of ICP, maternal outcomes were not incorporated into the model.

The baseline probability estimates used in our model are shown in Table 1. Neonatal death (NND), IUFD, RDS, NEC, CP, and the effect of corticosteroids were obtained from the literature12-13. Reported NND rates were limited to 36 weeks gestation, thus later gestational ages were extrapolated assuming exponential decay consistent with the progression seen in other term pregnancies. To establish a baseline incidence of IUFD, a literature review identified 18 studies3,4,6-8,10,11,13,15-22 that estimated IUFD in the setting of ICP. A mean IUFD rate of 1.74% was calculated and a uniform IUFD rate distribution over 35 to 38 weeks was assumed. The percentage of CP classified as moderate or severe was determined using United Kingdom data from 1984 to 1999 which accounted only for children with known moderate or severe impairment12. The long-term effect of near-term steroids has not been well studied, thus the model did not include any complications or morbidity to steroid administration. In addition, the sensitivity and specificity of fetal lung maturity (FLM) was determined based on either a

lecithin/sphingomyelin (L/S) ratio >2 or a phosphatidylglycerol/sphingomyelin (PG/S) ratio >0.0223.


We assumed a hypothetical cohort of 10,000 women with ICP to determine maternal and infant outcomes from the four strategies. The primary outcome of our study was total quality-adjusted life years (QALYs), which accounted for both maternal and neonatal QALYs. A QALY is a measure of the value of health outcomes, including both life expectancy and utility, a measure of the quality of remaining life years. Utility is an interval scale from 0 to 1, with 0 representing death and 1 signifying perfect health. A utility is multiplied by the number of life years to calculate a QALY; a year of life lived in perfect health is worth 1 QALY (1 Year of Life × 1 Utility value = 1 QALY) and a year of life lived in less than perfect health is worth less than 1.

Quality-adjusted life years were generated accounting for both the mother and neonate. A 3% discount rate was assumed when calculating the QALYs24. Maternal life expectancy was determined by assuming an average maternal age of 25. At each strategy, including scenario and gestational age, the strategy with the greatest number of QALYs was considered optimal. The estimated utilities used in our model were derived from data available in the literature (Table 1). An estimated utility of having a child with CP was extrapolated from the published utility (0.81) of having a child with Down syndrome25. The maternal utility (0.92) for a neonatal demise was determined using the published utility for women undergoing miscarriage25.

The robustness of our model and baseline assumptions was determined by performing univariate sensitivity analyses using TreeAge Pro 2012 (TreeAge, Cambridge, MA). Our analyses were

completed by using a range of baseline probabilities found in the literature or from our best clinical estimations. Aggregate variables for univariate sensitivity analysis were created, which varied neonatal outcomes (probability of NND, IUFD, RDS, NEC, and CP) simultaneously while


maintaining baseline proportions.

Multivariate sensitivity analysis was performed to test the robustness of the model to simultaneous multivariable changes in probability and utility inputs using a Monte Carlo simulation with 1,000 trials. A beta distribution, the multivariate equivalent of a binomial distribution, was used for probability estimates and standard deviations were derived from the literature.

Results: As expected, our model demonstrated that there were greater adverse neonatal outcomes with delivery at the earlier gestational ages. Table 2 shows the absolute numbers of neonatal adverse outcomes by delivery strategy and gestational age for a hypothetical cohort of 10,000 women with ICP. In our model, although there was a higher rate of neonatal morbidity associated with immediate 36 week delivery, compared with 36 weeks after corticosteroids or immediate 37 week delivery, there was a lower incidence of IUFD. In a hypothetical cohort of 10,000 women with ICP, the incidence of IUFD is 58 with immediate delivery at 36 weeks, 66 with delivery at 36 weeks after corticosteroids, 29 with immediate delivery at 35 weeks, and 87 with immediate delivery at 37 weeks (Table 2).

The relative weights of these adverse outcomes were then factored in as QALYs. Immediate delivery at 36 weeks without FLM testing and steroid administration was the optimal strategy, at an incremental gain of 263 QALYs as compared to delivery at 36 2/7 weeks after steroids, an incremental gain of 550 QALYs as

compared to immediate delivery at 35 weeks, and an incremental gain of 677 QALYs as compared to immediate delivery at 37 weeks.


Robustness of the model was tested by varying the baseline probabilities. Our sensitivity analysis demonstrated that our results were robust up to a 30% increase in the IUFD rate above which the preferred gestation for delivery became 35 weeks gestation. The model was robust up to a rate of 60% lower than the baseline value, under which a 38 week delivery with no amniocentesis or antenatal steroids was favored. The 36 week delivery was robust up to a 255% increase in the NND rate above which a 38 week delivery was preferred. The Monte Carlo analysis revealed that immediate delivery at 36 weeks gestation with no FLM testing or steroid administration was the best strategy in 74.1% of trials. Further, based on these assessments, we can be 95% confident that delivery at or before 37 weeks is optimal.

Discussion: Our results suggest that immediate delivery at 36 weeks gestation with no FLM testing and no corticosteroid administration was the optimal strategy compared to delivery at a later gestation or delivery after FLM testing or administration of corticosteroids. Complications of late preterm birth or early term birth, especially after 36 weeks gestation generally have a lower risk of neonatal morbidity. When considering the tradeoffs, while there is a higher association of neonatal morbidity with delivery at 36 versus at 37 weeks gestation or later, there is a decreased risk of IUFD. Applying a modified number needed to treat (NNT) in this clinical scenario, the number of RDS cases that would occur after IOL at 36 weeks to prevent one IUFD would be 6 cases at 36 weeks; however, less than one case of RDS would occur (0.46 cases) if IOL was delayed until 37 weeks. Additionally, in our model, we found that the marginal benefit of antenatal corticosteroids was outweighed by the potential IUFDs caused by the 48

hour delay for administration. Similarly, we found no advantage to fetal lung maturity testing because such management could lead to further delay in delivery.


The optimal strategy was determined on the basis of combined maternal and neonatal QALYs. The difference between QALYs between the four different strategies was relatively small, but remained robust despite the range of values used for our key data inputs. The “robustness” of a decision-analytic model determines the variation when different probabilities are tested by sensitivity analysis in the optimal strategy. One of the specific strengths of our study included the use of univariate and multivariable sensitivity analyses, varying inputs over wide ranges, and confirmed the robustness of our results.

Ideally, a randomized, controlled trial would be designed to answer the question of optimal gestational age for delivery in women with ICP. However, this is unlikely to be feasible given the sample size required to achieve adequate power to determine the best strategy. For example, to find a 50% reduction in the most common outcome, RDS by delivery at a different gestational age, 2,800 patients would be needed, when considering the need for Bonferroni correction, this number increases to 3,976. The numbers needed to identify a difference in stillbirth would be considerable higher. Thus, while the intent of our study is not to replace a randomized controlled trial, when none are available, decision analysis can provide insight to difficult clinical questions. The purpose of this model is to assist clinicians by demonstrating the potential relative risks and benefits of the four different strategies in a concrete, specific fashion. Although these results are associated with some degree of uncertainty, a strategy of either a delivery prior to 36 weeks or a

delayed delivery beyond 36 weeks is not optimal in regard to maternal and neonatal outcomes; delivery at 36 weeks’ gestation leads to the optimal QALYs given our assumptions.


Despite the importance of these findings, our study is not without limitations. Similar to other decision analyses, our model simplifies the clinical situation. After determining the ideal strategy, we did not assess the QALYs for the clinical scenario of betamethasone administration 48 hours prior to delivery; this may be the optimal strategy as this was not in the original study design. There is also no published QALY for term IUFD, so we utilized the value published for miscarriage. While this may underestimate the impact of such an event at term, over one’s life it affords the best available estimate and would bias our results to an earlier timing for delivery. Further, we did not explore all potential delivery strategies for patients with ICP and did not include strategies for delivery after 38 weeks’ gestation or prior to 35 weeks’ gestation. As demonstrated by our model, even the 48-hour delay in delivery secondary to corticosteroid administration was associated with increased risk of IUFD. Therefore, it is likely that strategies including delivery after 38 weeks would be less favorable and result in a higher rate of IUFD. In addition, we also did not include the small risks associated with amniocentesis as these risks are infrequent and accounting for them would only further support our findings30. We did not consider a strategy of inpatient expectant management with non-stress tests or biophysical profiles as previous studies have demonstrated that standard fetal surveillance is not reliably predictive of IUFD as the pathophysiology does not appear to be consistent with that of placental insufficiency and may be an acute event8,9. Although ICP is associated with increased spontaneous preterm birth, the incidence is not clearly defined in the literature and thus we did not incorporate this in our model31,32. Lastly, our model did not include any complications or

morbidity to antenatal corticosteroid administration as the long-term effect of near-term steroids has not been well studied and the existing literature is inconsistent.


Our decision-analytic model provides one answer to a difficult clinical question which, to our knowledge, was previously unanswered by other research methods. This work can assist decision making and support and streamline current clinical practices. The findings of our study have demonstrated that immediate delivery at 36 weeks’ gestation without amniocentesis or corticosteroid administration optimizes neonatal morbidity and mortality in the woman with ICP.

References: 1. Abedin P, Weaver JB, Egginton E. Intrahepatic cholestasis of pregnancy: Prevalence and


ethnic distribution. Ethn Health. 1999;4:35-37. 2. Germain A, Carvajal JA, Glasinovic JC, et al. Intrahepatic cholestasis of pregnancy. An intriguing pregnancy specific disorder. J Soc Gynecol Invest. 2002;9:10-14. 3. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology. 2004;40:467-474. 4. Rioseco AJ, Ivankovic MB, Manzur A, et al. Intrahepatic cholestasis of pregnancy: A retrospective case-control study of perinatal outcome. Am J Obstet Gynecol 1994;170:890-895. 5. Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol. 2000;33:1012–1021. 6. Kenyon AP, Piercy CN, Girling J, et al. Obstetric cholestasis, outcome with active management: a series of 70 cases. BJOG. 2002; 109:282. 7. Heinonen S, Kirkinen P. Pregnancy outcome with intrahepatic cholestasis. Obstet Gynecol. 1999; 94:189. 8. Fisk NM, Storey GNB. Fetal outcome in obstetric cholestasis. Br J Obstet Gynaecol. 1988;95:1137-1143. 9. Londero F, San Marco L. Intrahepatic cholestasis of pregnancy: are we really able to predict fetal outcome? Am J Obstet Gynecol. 1997;177:1274.

10. Williamson C, Hems LM, Goulis DG, et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG. 2004;111:676. 11. Stutchfield P, Whitaker R, Russell I, et al. Antenatal Betamethasone and the incidence of


neonatal respiratory distress after elective cesarean section: a pragmatic randomized trial BMJ. 2005 September 24; 331(7518): 662. 12. Surman G, Newdick H, King A, Davenport H, Kurinezuk JJ. 4Child: Four Counties Database of Cerebral Palsy, Vision Loss and Health Loss in Children. Annual Report 2009, including data for births 1984 to 2003. Oxford: National Perinatal Epidemiology Unit. 2009. ISSN 1749-9674. 13. Roberts D, Dalziel S: Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;3:CD004454. 14. Robertson PA, Sniderman SH, Laros RK, Jr. Neonatal morbidity according to gestational age and birth weight from five tertiary care centers in the United States, 1983 through 1986. Am J Obstet Gynecol 1992;166:162-1641, discussion 41-45. 15. Bacq Y, Sapey T, Brechot MC, Pierre F, Fignon A, Dubois F. Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology. 1997;26(2):358-64. 16. Jain R, Suri V, Chopra S, Chawla YK, Kohli KK. Obstetric cholestasis: outcome with active management. J Obstet Gynaecol Res. 2013;39(5):953-959. 17. Reid R, Ivey KJ, Rencoret RH, Storey B. Fetal complications of obstetric cholestasis. Br Med J. 1976. 1(6014):870-872. 18. Johnson WG, Baskett TF. Obstetric cholestasis. A 14 year review. Am J Obstet Gynecol. 1979;133(3):299-301.

19. Heikkinen J, Maentausta O, Ylostalo P, Janne O. Changes in serum bile acid concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy and in pregnant women with itching. Br J Obstet Gynaecol. 1981;88(3):240-


245. 20. Alsuyman OM, Ouzounian JG, Ames-Castro M, Goodwin TM. Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management. Am J Obstet Gynecol. 1996;175(4 Pt 1):957-960. 21. Palma J; Reyes H, Ribalta J, et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol. 1997;27(6):1022-1028. 22. Shaw D, Frohlich J, Wittmann BA, Willms M. A prospective study of 18 patients with cholestasis of pregnancy. Am J Obstet Gynecol. 1982;142(6 Pt 1):621-625. 23. Herbert WN, Chapman JF: Clinical and economic considerations associated with testing for fetal lung maturity. Am J Obstet Gynecol. 1986;155:820-823. 24. Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost-effectiveness in health and medicine. New York (NY): Oxford University Press; 1996. 25. Kuppermann M, Nease RF, Learman LA, et al. Procedure –related miscarriages and Down syndrome-affected births: Implications for prenatal testing based on woemn’s preferences. Obstet Gynecol. 2000;96:511-516. 26. Life Expectancy Project. Available at htt;://www.lifeexpectancy.com/index/shtml, accessed April 25, 2005.

27. Saigal S, Stoskopf BL, Feeny D, et al. Differences in preferences for neonatal outcomes among health care professionals, parents, and adolescents. JAMA. 1999;281:1991-1997. 28. Copper RL, Goldenberg RL, Creasy RK, et al. A multicenter study of preterm birth


weight and gestational age-specific neonatal mortaility. Am J Obstet Gynecol. 1993;168:78-84. 29. CCDC Website. Available at: http://www.cdc.gov/nchs/data/dvs/LEWK3_2009.pdf 30. Stark CM, Smith RS, Lagrandeur RM, et al. Need for urgent delivery after third-trimester amniocentesis. Obstet Gynecol 2000; 95:48-50. 31. Williamson C, Geenes V. Intrahepatic Cholestasis of Pregnancy. Obstet Gynecol. 2014;124(1):120-133. 32. Geenes V, Chappell LC, Seed 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;59(4):1482-91.

Table and Figure Legends


Table 1. Probability Estimates, Life Expectancy, & Utility Estimates

Table 2. Decision Analysis Results: QALYs and Outcomes per 10,000 Pregnant Women with Intrahepatic Cholestasis

Figure 1. Simplified decision analytic model showing four delivery strategies. Arms were created for 35, 36, 37, and 38 weeks of gestational age. Amnio = amniocentesis. FLM = fetal lung maturity testing. Steroids = steroid administration. RDS = respiratory distress syndrome. CP = cerebral palsy. NEC = necrotizing enterocolitis. ROM = rupture of membranes.

Table 1. Probability Estimates, Life Expectancy, & Utility Estimates


Variable

Probability

Reference

Cerebral palsy at 35 weeks

0.0051

12


0.0031

12


0.0025

12


0.0013

12


0.0009

12

Necrotizing enterocolitis at 35 weeks

0.011

14


0.009

14


0.0063

14


0.003667

14


0.001

14

Intraventricular hemorrhage at 35 weeks

0

14


0

14


0

14


0

14


0

14

Respiratory distress syndrome at 35 weeks

0.064

14


0.033

14


0.004

14


0.004

14


0.003

14

Neonatal Death at 35 weeks

0.008

28


0.005

28


0.00442

28


0.00294

28


0.00195

28

Intrauterine fetal demise at 35 weeks with ICP

0.0021

3,4,6-8,10,11,13,15-22


0.0042

3,4,6-8,10,11,13,15-22


0.0062

3,4,6-8,10,11,13,15-22


0.0083

3,4,6-8,10,11,13,15-22


0.0104

3,4,6-8,10,11,13,15-22

Sensitivity of fetal lung maturity testing

0.851

23

Specificity of fetal lung maturity testing

0.843

23

Odds Ratio of Respiratory Distress Syndrome

0.66

13

Odds Ratio of Necrotizing Enterocolitis

0.46

13

Odds Ratio of Neonatal Death

1.00

-

Odds Ratio of Intraventricular Hemorrhage

0.54

13

Probability of CP being severe

0.29

12

Probability CP being moderate

0.15

12

Value

Reference

1

-

Losing a Child (stillbirth or neonatal death)

0.92

25

Having a child with cerebral palsy

0.81

25


Corticosteroids Administered

Variable Utility Maternal Healthy Child

Neonatal Healthy

1

-

Having moderate cerebral palsy

0.90

27

Having severe cerebral palsy

0.30

27

Maternal

56.00

29

Neonatal

77.90

29

Neonate with severe cerebral palsy

28.70

26

Neonate with moderate cerebral palsy

62.00

26

Life expectancies

Table 2. Decision Analysis Results: QALYs and Outcomes per 10,000 Pregnant Women with Intrahepatic Cholestasis


STRATEGY

QALYs

IUFD

RDS

CP

No Complications

35 wks, no amnio, +steroids

56.5381

37

430

50

9357

35 wks, + amnio, no steroids (FLM mature)

56.5403

44

111

46

9624

35 wks, + amnio, + steroids

56.5590

31

491

50

9257

35 wks, no amnio, no steroids

56.5640

29

638

50

9105

36 wks, no amnio, + steroids

56.5616

66

219

31

9595


56.5330

77

53

29

9710


56.5833

60

244

31

9538


56.5879

58

328

31

9449


56.4937

95

26

25

9782


56.4607

109

8

23

9762


56.5159

88

29

25

9758


56.5202

87

40

25

9743


56.4820

87

28

13

9780


56.4192

139

11

12

9780


56.4597

124

26

13

9791


56.4862

116

40

13

9767

Bold text indicates optimal strategy “+” Indicates procedure performed FLM – Fetal Lung Maturity


Intrahepatic cholestasis of pregnancy.

Management of intrahepatic cholestasis in pregnancy.

Management of intrahepatic cholestasis in pregnancy.

Uterine contractility in intrahepatic cholestasis of pregnancy.

The treatment of intrahepatic cholestasis of pregnancy by dexamethasone.

Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy.

Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy.

The role of interleukin-17 in intrahepatic cholestasis of pregnancy.

Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy.

Prevalence of intrahepatic cholestasis of pregnancy in La Paz, Bolivia.

The molecular genetics of intrahepatic cholestasis of pregnancy.

Menopause after a history of intrahepatic cholestasis of pregnancy.

Induction for intrahepatic cholestasis of pregnancy: why we'll never know.

Primum non nocere: stillbirth rate in intrahepatic cholestasis of pregnancy.

Fetal complications due to intrahepatic cholestasis of pregnancy.

Epomediol ameliorates pruritus in patients with intrahepatic cholestasis of pregnancy.

Placental proteome alterations in women with intrahepatic cholestasis of pregnancy.

Impaired fetal myocardial deformation in intrahepatic cholestasis of pregnancy.

MRP3.

Intrahepatic cholestasis of pregnancy and acute fatty liver of pregnancy. An unusual but favorable association?

Pregnancy outcomes and prognostic factors in patients with intrahepatic cholestasis of pregnancy.

Dermatological Diseases Associated with Pregnancy: Pemphigoid Gestationis, Polymorphic Eruption of Pregnancy, Intrahepatic Cholestasis of Pregnancy, and Atopic Eruption of Pregnancy.

Disopyramide-induced intrahepatic cholestasis.

Can routine laboratory parameters predict adverse pregnancy outcomes in intrahepatic cholestasis of pregnancy?