Human Reproduction, Vol. 14, No. 9, 2249-2251,
September 1999
© 1999 European Society of Human Reproduction and Embryology
Recurrent cholestasis following ovarian hyperstimulation syndrome: Case report
Division of Women's and Children's Health, Guy's, King's and St Thomas's School of Medicine, London, UK
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Abstract |
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This is a case report illustrating a patient who developed recurrent cholestasis during a twin pregnancy following in-vitro fertilization (IVF) treatment. On the first occasion cholestasis developed unusually in the first trimester, and on the second occasion, it presented in the way that obstetric cholestasis (OC) is commonly seen in the third trimester.
Key words: genetic predisposition/obstetric cholestasis/ovarian hyperstimulation syndrome/twin pregnancy
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Introduction |
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Obstetric cholestasis (OC) is unique to pregnancy and although it seems to be becoming more common its exact incidence is unknown. It typically presents during the third trimester of pregnancy. Characteristically the first symptom is pruritus and this is associated with abnormal liver function tests and raised serum bile acids (Nelson-Piercy, 1997
). The disease usually resolves spontaneously, with resolution of pruritus and abnormal liver function tests within a few days following delivery (Bondu and Vaucher, 1997). The exact pathogenesis is not known. There are many theories and one is a possible predisposition to developing cholestasis in the presence of elevated oestrogen concentrations. Progestogens may also play a role (Bacq et al., 1997). OC appears to have a genetic component. Thirty three percent of cases in the UK have a family history suggestive of the condition (Williamson et al., 1998), and there have been pedigrees published which demonstrate sex-limited dominant inheritance (Reyes et al., 1976; Hirvioja and Kivinen, 1993). A subgroup of women with cholestasis of pregnancy have a family history of benign recurrent intrahepatic cholestasis (BRIC), a rare autosomal recessive condition in which affected individuals have episodes of cholestasis at times of stress. A small number of these women have cholestasis of pregnancy as the sole manifestation of BRIC (de Pagter et al., 1976). The following report describes an unusual case of this disease presenting early in a twin pregnancy following in-vitro fertilization (IVF).
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Case report |
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A 34 year old Caucasian nullipara with a history of infertility due to her husband's azoospermia underwent a cycle of ovulation induction and intracytoplasmic sperm injection (ICSI) using her husband's spermatozoa surgically retrieved from the testis. Her treatment commenced with 1.5 ampoules (75 IU equivalent) of highly purified urinary follicle stimulating hormone (FSH) (Metrodin HP®; Serono, Welwyn Garden City, UK). Following 9 days of ovulation induction her serum oestradiol concentration was 955 pg/ml and oocytes were retrieved on day 14 of stimulation following administration of 10 000 IU of human chorionic gonadotrophin (HCG). Fourteen ovarian follicles were aspirated under transvaginal ultrasound control and 12 mature (metaphase II) oocytes were obtained. Ten oocytes fertilized normally following ICSI and two 4-cell embryos were replaced. Following luteal support with progesterone (Cyclogest®; Shire, Andover, UK) 400 mg/day for 14 days, a urine pregnancy test was positive. At this time (4 weeks gestation), she developed abdominal distension with ascites. Enlarged ovaries (size) and fluid in the Pouch of Douglas were noted on ultrasound examination. A diagnosis of moderate ovarian hyperstimulation syndrome (OHSS) was made and she was admitted to hospital for observation and supportive management, which included prophylactic TED stockings and s.c. heparin (5000 IU twice daily), adequate oral and intravenous hydration, and administration of intravenous 5% albumin solution. During admission her liver function tests became slightly abnormal [alanine transaminase (ALT) 65 IU/l] (see Figure 1
). She improved with conservative management and was discharged after 7 days when her symptoms had subsided. Ultrasound scans at 6 and 8 weeks gestation confirmed a viable twin intrauterine pregnancy and normal ovaries. At 9 weeks, she started to complain of severe itching, especially on her arms, palms and the soles of her feet (a characteristic feature of OC). Her liver function tests were abnormal, her ALT was 215 IU/l (normal non-pregnant range <55 IU/l) and rose to a maximum concentration of 250 IU/l. In addition, her serum bile acids were 166 µmol/l (normal range <17 µmol/l) (Figure 1). There was no previous history of liver disease. A diagnosis of cholestasis was made, having excluded other liver pathology (liver was normal on ultrasound examination, serology for hepatitis A, B and C were negative and mitochondrial and smooth muscle antibodies were negative). She was treated symptomatically with chlorpheniramine maleate (Piriton®; Stafford-Miller, Welwyn Garden City, UK). Her symptoms resolved spontaneously associated with normalization of her biochemistry by about 12 weeks gestation (Figure 1) without specific treatment with urso-deoxy cholic acid (UDCA).
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Her pregnancy progressed normally until she presented to the antenatal clinic at 32 weeks gestation with hypertension (blood pressure 160/100) and proteinuria (+++ on urinalysis). At this time she was admitted to hospital for further investigation and observation. Her blood pressure remained elevated but her renal and liver function tests initially were normal. Her treatment commenced with methyldopa 250 mg orally three times a day and she received dexamethasone 12 mg i.m. on two occasions 12 h apart to promote fetal lung maturation. The 24 h urine collection revealed a total protein excretion of 4.29 g/24 h and her blood pressure stabilized with medication. Serial ultrasound examinations had shown a normal growth pattern for both twins. At 32 weeks gestation the umbilical artery Doppler velocity waveform revealed a reduced end diastolic flow in twin 2. Increasing dosages of methyldopa were required to control the patient's blood pressure (maximum 750 mg three times a day). At 34 weeks gestation she again developed pruritus and her liver function became abnormal with raised serum bile acids (Figure 1
). The differential diagnosis of her abnormal liver function tests included pre-eclampsia (which is not normally associated with itching), recurrent OC or an adverse effect of methyldopa which is known to cause hepatotoxicity, although not usually in such a short space of time (Smith and Piercy, 1995). However, due to this latter possibility, her anti-hypertensive treatment was changed to labetolol. Her liver function continued to deteriorate over the following days. At 34 + 2 weeks gestation a decision was made to deliver by Caesarean section due to the further deterioration of Doppler waveforms of the umbilical artery of twin 2. Twin 1 was delivered cephalic (birth weight 1760 g) and twin 2 breech (birth weight 1210 g). Both babies had good Apgar scores at delivery with normal cord pH. They were transferred to the neonatal unit where they did well.
During the postnatal period the patient recovered well, with gradual normalization of her biochemistry (Figure 1), a reduction in bile acids, and cessation of her pruritus. She was discharged with her daughters 13 days following delivery.
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Discussion |
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This case is unusual. Liver dysfunction has been reported in cases of OHSS following IVF and is thought to be due to elevated oestrogen concentrations (Balasch et al., 1990
; Shimono et al., 1998) and possibly a state of circulatory dysfunction (Balasch et al., 1998). However, there have been no reports of OC developing as a complication of OHSS. OC presents typically in the third trimester, but occasionally has been observed in the second trimester of pregnancy (Bacq, 1993). It does not usually remit spontaneously prior to delivery and it is very unusual in the first trimester. OC has a relatively higher incidence in twin pregnancies, possibly due to the greater increase in serum oestrogen concentration compared with singleton pregnancies (Gonzalez et al., 1989). We believe the initial high ALT at 9 weeks gestation was due to hyperstimulation. There was a delay of 4 weeks following recovery from OHSS syndrome before typical features of cholestasis developed. This episode remitted spontaneously, but we believe that this and the subsequent presentation with OC at 34 weeks could be due to a genetic predisposition to cholestasis, and that this may be a response to high concentrations of circulating oestrogen (or HCG). The other two possible explanations for the recurrence of abnormal liver function tests at 34 weeks in this case are methyldopa hepatotoxicity and pre-eclampsia, neither of which is normally associated with pruritus. Methyldopa treatment may be associated with abnormal liver function tests, but this is rare and usually appears at least 4 weeks after commencement of treatment (Moses et al., 1989; Smith and Piercy, 1995). We propose that this woman has a genetic predisposition to develop cholestasis and that this developed on two separate occasions in her twin pregnancy: initially in the first trimester, secondary to abnormally high oestrogen concentrations following OHSS, and subsequently in the third trimester as in the typical case of OC. We propose that serum bile acids are checked, in addition to liver function tests, in cases of OHSS with pruritus.
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Acknowledgments |
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We thank Mr I.L.C. Fergusson, Consultant Obstetrician and Gynaecologist, Guy's and St Thomas's Hospital Trust, for permission to report on his patient, and Dr Cath Williamson for her helpful comments.
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Notes |
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1 To whom correspondence should be addressed
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References |
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Balasch, J., Fabregues, F. and Arroyo, V. (1998) Peripheral arterial vasodilation hypothesis: a new insight into the pathogenesis of ovarian hyperstimulation syndrome. Hum. Reprod., 13, 2718–2730.
Bondu, F. and Vaucher, E. (1997) Cholestasis in pregnancy. A pure cytolytic form. Presse Med., 26, 161–162.
de Pagter, A.G.F., van Berge Henegouwen, G.P., Ten Bokkel Huinink, J.A. et al. (1976) Familial benign recurrent intrahepatic cholestasis; interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives? Gastroenterology, 71, 202–207.[Web of Science][Medline]
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Submitted on March 18, 1999; accepted on June 10, 1999.
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