Pregnancy in Wilson disease
Authors: Atoosa Rabiee, James P.A. Hamilton
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article On Page 1261 Abbreviation WD Wilson disease In this issue of hepatology, Pfeiffenberger et al.1 report on pregnancy in Wilson disease (WD). This is a detailed analysis of a large cohort of pregnant woman with WD and will become a useful reference for this unique challenge of patient care. WD is caused by autosomal recessive mutations of ATP7B. The gene, located on chromosome 13q14, encodes an intracellular copper‐transporting P‐type adenosine triphosphatase. ATP7B is critical for the incorporation of dietary copper into ceruloplasmin and biliary copper excretion. Mutation in this gene results in defective synthesis of ceruloplasmin, impaired copper excretion into bile, and copper accumulation in the liver, brain, and other tissues.2 Clinical symptoms can vary from asymptomatic to chronic liver disease, neuropsychiatric disease, acute liver failure, or combinations of these problems. Treatment includes use of the chelating agents D‐penicillamine and trientine, which increase urinary copper excretion, or zinc salts, which affect intestinal copper absorption. There is a heterogeneous body of data regarding WD and pregnancy, which, prior to the current study, has been limited to small series and case reports.3 While there are numerous reports of successful pregnancies in WD, fetal demise and maternal death from liver disease have been described. Successful treatment of WD during pregnancy has also been reported, but the safety of the medications is not well studied. Teratogenicity has been linked with chelation therapies in animal models and patients. Overchelation and copper deficiency are risk factors for impaired fetal development. Despite current societal guidelines advocating continuing treatment during pregnancy,5 some patients decide to stop therapy while pregnant. The current study was designed to analyze fetal and maternal outcomes and therapeutic effects in WD. Specifically, the study addresses three major concerns: (1) what is the risk of miscarriage in treated and untreated WD patients, (2) can WD worsen during pregnancy, and (3) are chelating agents during pregnancy safe? The study included 136 patients and 282 pregnancies over 40 years from three medical centers in Germany and Vienna, Austria, all of which have expertise in WD. Hepatic WD was present in a majority of patients (54%), and 31% of pregnancies occurred in patients not previously diagnosed with WD. Twenty‐eight percent of the patients in the study had cirrhosis. The spontaneous abortion rate in the general population is 10%‐20%7 and can be as high as 30%‐40% in patients with cirrhosis of any cause.8 In this study, 26% of the pregnancies resulted in miscarriage. Interestingly, in patients previously diagnosed with WD, neurologic WD was most commonly associated with spontaneous abortions. Cirrhosis (80 pregnancies) and portal hypertension (34 pregnancies) were not associated with an increased risk of spontaneous abortion compared to other WD presentations. This may be due to decreased fertility rate and underrepresentation of this group in pregnant patients. Untreated WD has been associated with oligomenorrhea and amenorrhea,9 indicating some degree of hormonal dysregulation in women with WD. In this study, spontaneous abortions occurred in 41% of 86 patients without a prior diagnosis of WD, and these miscarriages were significantly more common than in patients with hepatic or mixed presentations of WD. This study was not designed to determine how frequent infertility or difficulty with conception occurs in WD, and the hypothalamic–pituitary–ovarian axis in neurologic WD is not well studied. Treatment with zinc and D‐penicillamine resulted in lower spontaneous abortion rates (10% and 17%, respectively) compared to undiagnosed patients or those who stopped treatment (36%). The rate of spontaneous abortion was similar (27%) in trientine‐treated and treatment‐naive patients. Although the rate of abortions in trientine‐treated patients was the highest of those patients on therapy, it was not statistically significant. This finding was attributed to the retrospective nature of the study, in which drug selection was not randomized and many patients had been converted to trientine from D‐penicillamine. Liver function became abnormal during 16 pregnancies in 12 patients (6% of total pregnancies). Two of these patients were not previously diagnosed with WD. The liver problems ranged from abnormal liver enzymes to cholestasis and coagulopathy. These patients were treated with chelators or zinc. There were four spontaneous abortions in this group, and liver function improved after delivery in all of the patients. New onset of neurologic symptoms was rare in the cohort (3 patients), and the symptoms did not improve after delivery. Fourteen patients with a known diagnosis of WD who stopped their treatment did not experience worsening neurologic or hepatic symptoms during pregnancy. There was a total of seven birth defects (3%), and only one occurred in the trientine group. This rate is comparable to that in the general population. The practical data presented by Pfeiffenberger and colleagues clearly demonstrate that undiagnosed and untreated WD disease results in higher rates of spontaneous abortion. Hepatic WD (and liver disease in general) can increase testosterone, decrease estradiol, and result in impaired ovarian function. This may explain the high rates of spontaneous abortion in untreated WD patients. The direct effects of copper in the ovaries and the placenta are not known, but ATP7B is expressed in these locations. In addition, patients with neurologic WD were found to have the highest risk of miscarriage in treated patients. Although deterioration of liver function was more common in WD patients with liver disease, this was still uncommon and was reversible after delivery. Worsening of neurologic symptoms was also quite uncommon and was not reversible. Overall, the number of patients in whom some form of maternal demise occurred was low, which is good news for the WD community. Another important aspect of this study was that treatment of WD did not increase the risk of spontaneous abortion. Treatment with zinc salts had the lowest risk of miscarriage, so it would appear that the ideal WD patient to conceive would be one who has been successfully chelated and is on zinc maintenance. Finally, in this large study, chelation therapy resulted in no increase in the rate of birth defects compared to the general population. The authors also offer practical recommendations regarding dose adjustment for chelating agents, to avoid the concern of overchelation and copper deficiency, which has been associated with birth defects. One caveat is that patients who are initially diagnosed during pregnancy should be started on a standard dose of chelating agents given the high copper burden. This study provides clear evidence that WD patients should continue treatment with close monitoring of liver function, urinary copper, and neurologic symptoms during pregnancy as maternal and fetal outcomes can be affected by undiagnosed or untreated disease. Given the large number of pregnant WD patients in the cohort and the length of time over which the data were collected, it is not likely that a study of this magnitude will be replicated any time soon. This study provides valuable information regarding the risk of spontaneous abortion in WD, the risk of maternal decompensation, and the safety of chelating agents during pregnancy. Information reported in this issue of hepatology may be useful for providers of preconception counseling of patients with WD.