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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Kuopio University Hospital, Kuopio, Finland.
Address reprint requests to: Seppo Heinonen, MD, PhD Department of Obstetrics and Gynecology Kuopio University Hospital 70211 Kuopio Finland E-mail: seppo.heinonen{at}kuh.fi
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Abstract |
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Methods: We analyzed 91 women with singleton pregnancies complicated by cholestasis who gave birth at Kuopio University Hospital from January 1990 to December 1996. Logistic regression analysis was used to compare pregnancy outcomes of this group with those of the general obstetric population (n = 16,818).
Results: Women of relatively advanced age (over 35 years) were at increased risk of developing intrahepatic cholestasis. Affected pregnant women delivered by cesarean significantly more often (25.3%) than the general obstetric population (15.8%). Intrahepatic cholestasis increased the low basic risk of preterm delivery and the need for neonatal care in the general population (odds ratio [OR] 2.73; 95% confidence interval [CI] 1.50, 4.95 and OR 2.15; 95% CI 1.21, 3.83, respectively). Otherwise, the courses of pregnancy were comparable in both groups.
Conclusion: Intrahepatic cholestasis has an adverse effect on fetal development, and affected pregnancies merit closer surveillance. Delivery of infants when maturity is reached may minimize the risk of adverse outcomes.
Intrahepatic cholestasis is reported infrequently in most countries except for China, Bolivia, and Scandinavia. It carries a substantial recurrence risk and has a tendency toward familial clustering.1,2 Its pathogenesis is likely to involve a genetic hypersensitivity to estrogen, and autosomal transmission has been suggested.3,4 Many treatments involving charcoal, dexamethasone, and ursodeoxycholic acid have been proposed for maternal medical therapy, but none of these is ideal.5–7 Intrahepatic cholestasis has been associated with increased fetal mortality and morbidity, probably because of retained bile salts in the placental compartment.8–11 A general protocol for following affected pregnancies has not been established, and fetal death from cholestasis is occasionally a sudden obstetric event that is not predictable by conventional nonstress test (NST) and ultrasonography.9 This study was done to evaluate the fetal consequences of intrahepatic cholestasis in a Finnish population receiving modern obstetric care.
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Materials and Methods |
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Patients with intrahepatic cholestasis were identified in maternity care units after questioning about itching. The diagnosis was based on clinical examinations (generalized pruritus in the absence of any dermatologic condition), laboratory results showing a cholestatic pattern (serum aspartate and alanine transferase exceeding 40 U/L and serum total bile acids exceeding 8 µmol/L) that returned to normal after delivery with no signs of viral hepatitis (negative results in assays for hepatitis B surface antigen and antihepatitis A and C antibodies), and normal ultrasonography of the liver and biliary tract. None of our subjects had liver biopsies; however, in our area, liver function tests were done to evaluate the causes of stillbirth to exclude the ascertainment bias that would occur if an affected case had gone undiagnosed and resulted in fetal death. All women with preeclampsia were excluded (eight cases and 672 controls) because a hypertensive disorder likely would have a greater influence on the course of pregnancy than the pregnancy-associated hepatic disorder.
Subjects in this study took no drugs other than antihistamines (hydroxyzine, 25 mg once a day) and cholestyramine (4 g twice a day) to relieve symptoms, and they underwent careful weekly outpatient clinical monitoring. The testing scheme included an NST, amniotic fluid (AF) volume assessment using the four-quadrant amniotic fluid index (AFI),12 and liver function tests. Testing was considered nonreassuring when the NST was nonreactive,13 the AFI was less than 5 cm, or liver function indices were at levels greater than ten times normal. Extreme elevation of liver function test results combined with abnormal fetal heart rate (FHR) or AFI necessitated hospitalization for induction if immediate operative delivery was not elected. If liver function test results were only moderately elevated, either a contraction stress test or a biophysical profile was used as a backup in cases of nonreactive or suspicious FHR and when the AFI was less than 5 cm. In affected pregnancies, labor was induced routinely at 38–40 weeks’ gestation unless nonreassuring antepartum testing was recorded earlier. Demographic data and pregnancy outcome measures were collected by the delivery team.
The following definitions were used to record pregnancy outcomes: preterm birth, delivery before 37 weeks’ gestation; preeclampsia, repeated blood pressure measurements exceeding 149/90 mmHg with proteinuria exceeding 0.5 g/day; and low birth weight (LBW), birth weight less than 2500 g. Infants were considered small for gestational age (SGA) when the sex- and age-adjusted birth weight was below the tenth percentile according to the normal tables for our population. If a subject had two abnormalities, such as LBW and preterm delivery, each was considered an independent outcome and the subject was included in both categories.
Statistical differences between subjects and controls were evaluated using 
2 tests (dichotomous variables), and Fisher exact test was applied when the minimal estimated expected value was less than five. P < .05 was considered statistically significant. Continuous variables were analyzed using a two-tailed, pooled t test. Possible confounding variables were identified from background data, obstetric risk factors, and health behaviors. Multivariate analysis of significant or nearly significant effects (P < .1) was based on multiple logistic regression analysis (BMDP Statistical Software Inc., Los Angeles, CA). Confidence intervals were evaluated at 95%.
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Results |
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shows the distribution of maternal risk factors. The ratio of primigravidas was similar between groups. When women with intrahepatic cholestasis were compared with the general obstetric population, maternal risk factors were similar with the exception of advanced maternal age, number of previous miscarriages, interval since previous delivery, and use of an intrauterine device (IUD) before pregnancy.
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summarizes the frequencies of various pregnancy and delivery complications. Pregnancy-induced hypertension occurred significantly more often in the study group than in the controls (data not shown), but these pregnancies were excluded on the basis of our inclusion criteria. Overall, pregnancy outcomes were similar between the groups with the exception of the mode of delivery. Women with intrahepatic cholestasis had cesarean deliveries significantly more often than the general population, whereas no statistically significant difference was found between the groups in the number of operative vaginal deliveries. Thirteen affected women had a cesarean before labor and ten during the first or second stage of labor. Of these 23 women, five had abdominal delivery for fetal reasons according to the clinical judgment of the attending physician. The proportion of female infants in the study group was greater than in the control group, although this difference did not reach statistical significance. Cervical ripening or labor induction was done in 66 study subjects (72.5%) and in 2776 women (16.5%) in the general obstetric population (P < .001). In the study group, 16 inductions (17.6%) led to successful vaginal deliveries, whereas labor was induced before 37 weeks’ gestation in only four cases because of preterm premature rupture of membranes.
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compares the pregnancy outcomes in the two groups after controlling for the obstetric risk factors investigated in this study. Delivery before 37 weeks’ gestation was found to be 2.73 times more likely to involve cholestasis complications. Accordingly, the rate of admission to a neonatal unit was significantly higher for women with intrahepatic cholestasis, with a relative risk of 2.15. The adjusted risks of LBW and SGA births were comparable. Associations between perinatal or fetal death, low Apgar scores, and fetal acidosis at delivery did not vary between the groups.
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Discussion |
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We found that the women who developed intrahepatic cholestasis of pregnancy were older than the unaffected controls. They also tended to have longer intervals since their previous deliveries, histories of IUD use, and more frequent miscarriages compared with the controls. All of these risk factors are likely to have strong associations with advanced maternal age. Furthermore, a hepatic disorder in a previous pregnancy may make these women favor IUD use over oral contraceptives.16 Using multiple regression analysis, we found that affected women had a significantly higher frequency of preterm delivery, which in turn led to an increased need for intensive neonatal care. In vitro studies have indicated that contractile activity of the myometrium in response to oxytocin is significantly higher in women with cholestasis than in controls.17 In addition, continuous intravenous infusion of cholic acids into fetal lambs caused preterm delivery.18 The slight reduction in the mean birth weight in our study group could be explained in part by the high proportion of female fetuses. Women with intrahepatic cholestasis of pregnancy also had larger placentas than the reference group. The reason for this remains unresolved. Otherwise, pregnancy outcomes were comparable with those in the general obstetric population. Using the general population for comparison of outcomes is less than ideal, although it can put the overall results into perspective. To control for possible confounding factors, we applied multiple regression analysis. Hence, the results are not biased by an unequal distribution of risk factors for adverse pregnancy outcomes, and a cause-and-effect relation can be established.
Other investigators have reported a greater incidence of complications in intrahepatic cholestasis involving fetal distress and perinatal mortality.5,19 Recently, Rioseco et al10 found that intrahepatic cholestasis was associated with a two-fold increase in the incidence of AF meconium and a three-fold increase in the incidence of preterm delivery. In their study, active intervention enabled them to ameliorate possible adverse perinatal outcomes by lowering the incidence of stillbirth and abnormal intrapartum FHR. In our study, the incidence of meconium passage and the stillbirth rate were comparable to those in the general obstetric population. This improvement in perinatal mortality and morbidity was perhaps brought about by increased fetal surveillance combined with liver function tests and careful timing of delivery to avoid fetal compromise and death. Obstetric cholestasis can be a progressive process, and an upward trend in liver function test results may indicate that the fetus is at risk of death and requires immediate delivery.
Acceptable upper limits of liver function test results are a dilemma for obstetricians. If expectant management lasts too long and an infant is asphyxiated, the obstetrician is criticized for inaction. If the obstetrician decides to forestall asphyxia by immediate induction and cesarean delivery, the criticism may be unnecessary interference. Further, a genetic, metabolic predisposition may play a role in pathogenesis, thereby affecting severity of the disease and the overall outcome. A hereditary pattern has been described in women with cholestasis of pregnancy, and autosomal dominant transmission has been suggested.3,4 The mutation responsible for the illness may vary according to the population studied, thus explaining the less severe phenotypes found in Scandinavia than in Chile.
The consequences of intrahepatic cholestasis primarily affect the mother, with discomfort from pruritus, occasional mild jaundice, and nausea. Although there is no long-term hepatic injury to the mother, it is advisable that patients with intrahepatic cholestasis be monitored for fetal effects. We found that pregnancies affected by intrahepatic cholestasis are of concern mainly because of the increased rate of spontaneous preterm delivery. Normal fetal growth suggests that there is no chronic uteroplacental insufficiency, and late fetal loss is uncommon in modern obstetric practice.
Management is based on obstetric assessment of the fetus and its well-being, cervical favorability, and fetal size. Liver function test results at high extremes or with rising trends may be helpful in predicting the severity of the condition. Careful timing of delivery is usually the only active therapy required in singleton pregnancies to achieve a normal outcome. Future genetic studies may provide a better understanding of the pathogenetic mechanisms of cholestasis and new options for treatment.
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Footnotes |
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Received October 21, 1998. Received in revised form January 11, 1999. Accepted January 28, 1999.
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References |
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2. Berg B, Helm G, Petersohn L, Tryrding N. Cholestasis of pregnancy: Clinical and laboratory studies. Acta Obstet Gynecol Scand 1986;65:107–13.[Medline]
3. Holzbach RT, Sivak DA, Braun WE. Familial recurrent intrahepatic cholestasis of pregnancy: A genetic study providing evidence for transmission of a sex-limited, dominant trait. Gastroenterology 1983;85:175–9.[Medline]
4. Hirvioja ML, Kivinen S. Inheritance of intrahepatic cholestasis of pregnancy in one kindred. Clin Genet 1993;43:315–7.[Medline]
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6. Kaaja RJ, Kontula KK, Raiha A, Laatikainen T. Treatment of cholestasis of pregnancy with peroral activated charcoal. A preliminary study. Scand J Gastroenterol 1994;29:178–81.[Medline]
7. Davies MH, da Silva RC, Jones SR, Weaver JB, Elias E. Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid. Gut 1995;37: 580–4.
8. Fisk NM, Sotrey GN. Fetal outcome in obstetric cholestasis. Br J Obstet Gynaecol 1988;95:1137–43.[Medline]
9. Alsulyman OM, Ouzounian JG, Ames-Castro M, Goodwin TM. Intrahepatic cholestasis of pregnancy: Perinatal outcome associated with expectant management. Am J Obstet Gynecol 1996;175: 957–60.[Medline]
10. Rioseco AJ, Ivankovic MB, Manzur A, Hamed F, Kato SR, Parer JT, et al. Intrahepatic cholestasis of pregnancy: A retrospective case-control study of perinatal outcome. Am J Obstet Gynecol 1994;170: 890–5.[Medline]
11. Johnson P, Samisoe G, Gustafson A. Studies in cholestasis of pregnancy with special reference to clinical aspects and liver function tests. Acta Obstet Gynecol Scand Suppl 1975;123:823–8.
12. Phelan JP, Ahn MO, Smith CV, Rutherford SE, Anderson E. Amniotic fluid index measurements during pregnancy. J Reprod Med 1987;32:601–4.[Medline]
13. FIGO News. Guidelines for the use of fetal monitoring. Int J Gynaecol Obstet 1987;25:159–67.
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15. Heikkinen J, Mäentausta O, Ylöstalo P, Jänne 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;88:240–5.[Medline]
16. Lindberg MC. Hepatobiliary complications of oral contraceptives. J Gen Intern Med 1992;7:199–209.[Medline]
17. Israel EJ, Guzman ML, Campos GA. Maximal response to oxytocin of the isolated myometrium from pregnant patients with intrahepatic cholestasis. Acta Obstet Gynecol Scand 1986;65:581–2.[Medline]
18. Campos GA, Guerra FA, Israel EJ. Effects of cholic acid infusion in fetal lambs. Acta Obstet Gynecol Scand 1986;65:23–6.[Medline]
19. Reid R, Ivey KJ, Rencoret RH, Storey B. Fetal complications of obstetric cholestasis. BMJ 1976;1:870–2.
This article has been cited by other articles:
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  E. M. F. Berkley, K. K. Leslie, S. Arora, C. Qualls, and J. C. Dunkelberg Chronic Hepatitis C in Pregnancy Obstet. Gynecol., August 1, 2008; 112(2): 304 - 310. [Abstract] [Full Text] [PDF]
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