Pregnancy Outcomes in Late Onset Pompe Disease and Enzyme Replacement Therapy

There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated. Reproductive history, course of pregnancy, use of Enzyme replacement therapy (ERT), PD symptoms, and outcomes of each pregnancy were obtained through a questionnaire. Among 20 subjects that reported one or more pregnancies, one subject conceived while on ERT and continued therapy through two normal pregnancies with worsening of weakness during pregnancy and improvement postpartum. While fertility was not affected, pregnancy may worsen symptoms, or cause initial symptoms to arise. Complications with pregnancy or birth were not higher, except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2-0.7%). Given small sample size and possible bias of respondents being only women who have been pregnant, further data may be needed to better analyze the effects of pregnancy on PD, and the effects of ERT on pregnancy outcomes.

Pompe disease [2]. In general, events acting as metabolic stressors, such as pregnancy are implicated as disease modifiers. For example, in a much-studied lysosomal storage disorder, Gaucher disease, pregnancy increases the risk of acute bone crises, even in otherwise asymptomatic patients [3]. However, similar studies regarding the impact of pregnancy are needed for LOPD. There is only limited information available as guidelines for clinicians in counseling women with Pompe disease who are planning to become pregnant. Currently, data used to counsel female patients with Pompe disease are derived from other muscular dystrophies, because neither obstetric risk, nor complications of pregnancy have been studied or reported in depth in LOPD. It has been shown that in other muscular dystrophies, such as fascioscapulohumeral dystrophy (FSHD), the rates for low birth weight and total operative deliveries were statistically higher than the national rates in the general population. In addition, worsening of muscle weakness was observed in 24% of gestations and did not usually resolve after delivery [4,5].
The course of Pompe disease has been significantly altered with the advent of enzyme replacement therapy (ERT). The mannose targeted recombinant human alpha glucosidase improves cardiac and skeletal muscle involvement [6,7]. Better outcomes are usually achieved when ERT is started early, prior to progressive muscle damage [8]. However, the skeletal muscle response has been more variable than cardiac muscle. In LOPD, ERT was shown to improve muscle strength with improved 6-minute walk test results [9]. However, often with a delayed diagnosis, and most variable presentation, the data derived from clinical studies may not reflect the long term and true disease outcomes. Thus, the information derived from the natural history of patients treated with ERT will be vital for clinicians to decide when to start therapy and how to follow treated patients with LOPD. ERT has been available commercially for the past decade, and alglucosidase alfa (Lumizyme® ) was approved by the Food and Drug Administration (FDA) in 2010 for the treatment of patients with LOPD. It has been classified as Category C for pregnancy, alglucosidase alfa was recommended to be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. There were no studies of alglucosidase alfa in pregnant women during the drug development phase. In animal reproduction studies, no effects on embryo-fetal development were observed in mice or rabbits given daily administration of alglucosidase alfa at the recommended human bi-weekly dose during the period of organogenesis. An increase in mortality was observed in pups when alglucosidase alfa was administered every other day in mice during the period of organogenesis through lactation at the recommended human bi-weekly dose [10].
While there are few sporadic case reports of pregnancy outcomes in Pompe disease patients who have continued ERT through the pregnancy with some complications, there is no extensive data available about the use of alglucosidase alfa during pregnancy or the effects on pregnancy outcomes [11][12][13][14][15][16]. This study specifically focuses on female patients with LOPD, to characterize the obstetric history and concomitant problems in females with Pompe disease, exploring the disease progression in patients who have been pregnant including the impact of ERT on the outcomes of pregnancy and the fetus. The results are expected to help clinicians in counseling and caring for women with Pompe disease, who are planning to become pregnant, and during the pregnancy.

Results
The demographics and clinical characteristics of patients with LOPD, including diagnostic modality, presentation, and disease progression in relationship to the pregnancy history are summarized in Table 1. Among 25 female patients with Pompe disease, the mean age of disease onset was 33.8 years (range 7-66 years), and the mean age at diagnosis was 42.1 years (range 24-60 years). The most common diagnostic method was muscle biopsy (20/25), followed by molecular testing (17/25). Only three patients were diagnosed through noninvasive methods and one patient underwent a liver biopsy. In the majority of patients (21/23), the diagnosis of Pompe disease was made after the completion of all pregnancies. The presentation of Pompe disease was variable. In addition to the most common complaint of proximal muscle weakness with the inability to climb stairs or rise from a squatting position, some presented with nonspecific symptoms such as fatigue and flu-like symptoms. Three patients presented with shortness of breath. The disease progression was ascertained through current use of assistive ambulation. At the time when the surveys were completed, more than half of the patients (14/25) reported the use of assistive devices for ambulation, and one patient was wheelchair bound. Only three patients reported respiratory compromise either with decreased exercise capacity or shortness of breath, and none of the patients received respiratory support, neither invasive nor noninvasive ventilation. Among the 25 subjects, 3 reported infertility, and assisted reproductive technology was utilized 1 in 1 patient recently diagnosed with Pompe disease, who elected cryopreservation of embryos prior 2 to commencing ERT. There were 7 (12.07%) spontaneous first trimester miscarriages, 50 (86.2%) live 3 births (including one pair of twins), and 2 (3.4%) stillbirths. Of the 52 births, the majority (80.8%) 4 were vaginal deliveries and 10 (19.2%) were Cesarean sections. The preterm birth rate was 13.46% 5 (7/52) and low birth weight rate was 7.7% (4/52). One patient had prolonged recovery from general 6 anesthesia as a complication. Only one infant was born with a congenital defect, multi-cystic kidneys, 7 and the mother was not exposed to ERT before or during pregnancy. The majority of patients (20/23)   (Table 2).

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Pompe disease while the anesthesia complications were higher in incidence (5% for study subjects 31 compared to 0.1% for the national average) (Figure 1).

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For the pregnancy and fetal outcomes, all but two pregnancies resulted in a healthy newborn.

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There was one full term unexplained still birth and one still birth at 24 weeks gestation secondary to 34 a staphylococcal infection. One fetus had a right multi-cystic kidney which spontaneously resolved 35 (Figure 1). Gender and sex may have an effect on pathophysiology of many disease states, such as autoimmune, cardiovascular, and neurological disorders, but may also affect therapeutic outcomes by having an influence on the distribution and efficacy of pharmaceuticals. In addition, gender-related health behavior and choices may overall impact disease progression and outcomes [17]. In this report, we assessed a cohort of female patients with LOPD recruited from two different 48 centers in the US. This cohort includes patients both treatment naïve or on ERT, and those who have 49 been pregnant and/or are contemplating pregnancy.
It is now established that the initial diagnosis of LOPD is significantly delayed, often decades

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In this study, two patients conceived while receiving alglucosidase alfa and one patient was 110 started on ERT during pregnancy. There were no reports of adverse effects of ERT use in the four 111 fetuses exposed during pregnancy. This cohort also demonstrates that patients and/or clinicians may 112 have a preference to withhold therapy during a pregnancy. This decision could be based on the 113 scarcity or the lack of data on the effects of alglucosidase alfa on the developing fetus. One other 114 concern for the use of ERT during pregnancy could be the potential drug related immune

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In this observational case review study, 25 female subjects with a confirmed diagnosis (by mutation analysis, enzymatic assay, or both) of Pompe disease, age 18 years and over who were the review of medical records.
After enrollment, patients were asked to complete a survey or were interviewed in person by the investigator(s). The questionnaire assessed the following: decision to become pregnant, fertility

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First experience with enzyme replacement therapy during pregnancy and lactation in Pompe disease.