LAUSR

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. 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. 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, 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% and can be as high as 30%-40% in patients with cirrhosis of any cause. 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, 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. Abbreviation: WD, Wilson disease.