Compared to results from a nationwide Japanese birth cohort study , we found no differences in frequency of natural conception, term delivery, or complications of newborns among pregnant GNE myopathy patients. However, the prevalence of threatened abortion was higher in post-onset pregnancies among GNE myopathy patients compared to the general population. Notably, the prevalence of CS, especially emergency CS, was lower in all pregnancies (i.e. pre- and post-onset deliveries) among GNE myopathy patients compared to the general population.
Threatened abortion is defined as pregnancy-related bloody vaginal discharge that occurs during the first half of a pregnancy and is accompanied by abdominal pain which may present as intermittent cramps . This complication was noted relatively frequently among pregnancies of GNE myopathy patients, especially in post-onset pregnancies, compared to the general Japanese population. Maternal factors such as age, diabetes, thyroid disease, obesity, alcohol use, tobacco use, and illicit drug use are reported to increase the risk of threatened abortion . No differences in age and prevalence of diabetes were found between pregnant GNE myopathy patients and women of the Japanese nationwide cohort study. Theoretically, vaginal bleeding may occur in pregnant women who have a tendency to bleed. Some case reports have indicated a relationship between thrombocytopenia and GNE myopathy  or GNE mutations . Platelet desialylation level is reportedly associated with thrombocytopenia in septic patients . Based on these findings, we analyzed responses regarding thrombocytopenia and low platelet counts from 12 participants who had threatened abortion. Two of the participants had a past history of thrombocytopenia and a bleeding tendency, which may have been the cause of threatened abortion. While a high prevalence of thrombocytopenia could be related to a high frequency of threatened abortion in GNE myopathy patients, this remains speculative and a better understanding of the prevalence and risks of threatened abortion is needed. Threatened abortion is associated with preterm labor, low birth weight, preeclampsia, preterm PROM, placental abruption, and intrauterine growth restriction . However, neither the prevalence of threatened premature delivery nor the incidence of complications was high among GNE myopathy patients with threatened abortion in this study, possibly due to appropriate management.
The frequency of CS, especially emergency CS, was lower among GNE myopathy patients with all pregnancies (i.e. pre- and post-onset deliveries) compared to the general Japanese population. While over-rigidity of soft tissues in the lower birth canal is considered one of the causes leading to emergency CS , this may not be the case in patients with muscle weakness. The low frequency of CS may reflect the characteristics of pregnancies among GNE myopathy patients, although no significant difference was observed among those with post-onset deliveries compared to the general population, likely due to the small sample size. Conversely, the frequency of CS before the 37th gestational week is reportedly higher in patients with spinal muscular atrophy due to reduced lung function, and in some patients, pregnancy cannot be completed to term . Most of our patients became pregnant pre-onset or in the early stage of GNE myopathy, and none lost ambulation at pregnancy. The prevalence of CS might vary in patients with advanced-stage GNE myopathy who have reduced respiratory function.
The impact of pregnancy or delivery on disease progression is a matter of great significance. A total of 7 patients were previously reported to have developed GNE myopathy during pregnancy [11–13]. Interestingly, in the present survey, none of the patients reported experiencing the first symptoms of GNE myopathy during pregnancy, while 6 did within a year after delivery. Among pregnancies after disease onset, roughly one-fifth of participants felt their disease progression accelerated after delivery, which was more frequent than those who felt their disease progression accelerated during pregnancy. This may suggest a tendency to develop GNE myopathy or accelerate disease progression within a year after delivery. We hypothesized that loss of sialic acid due to breastfeeding might be a risk factor, but no difference was found in subjective disease progression in breastfeeding participants compared to formula or mixed feeding participants. Breastfeeding participants had a higher frequency of developing disease within a year after delivery; however, the analyzed sample size was too small to draw conclusions. Reportedly, mean serum sialic acid concentration is significantly higher during pregnancy and decreases after delivery in healthy individuals . A rapid decline in sialic acid concentration after delivery might trigger disease progression. In women with carnitine deficiency syndrome, carnitine supplementation is recommended during pregnancy as carnitine concentrations markedly decrease during gestation . Sialic acid supplementation might help prevent deterioration of the disease due to pregnancy. However, sialic acid concentrations during pregnancy and postpartum need to be carefully monitored, as the level of sialic acid at 12 weeks postpartum is reported to be still higher than that of non-pregnant females  and the influence of the mode of feeding on serum sialic acid concentration have not been examined. As for the influence of pregnancy on the disease course of other neuromuscular disorders, roughly half of patients with limb-girdle muscular dystrophy, one-third of those with spinal muscular atrophy, and one fifth of those with Charcot-Marie-Tooth disease reported deterioration of symptoms during pregnancy . In another report, one-third of patients with myasthenia gravis (MG) experienced worsening of symptoms in the first trimester or postpartum, and in 15% of cases, pregnancy preceded the onset of MG. This may be explained by changes in the immune system and/or a decrease inα-fetoprotein following delivery, as well as stress and sleep deprivation . The disease course of neuromuscular disorders including GNE myopathy is highly variable and unpredictable, making it difficult to examine the correlation with pregnancy. Moreover, other factors may affect the onset or subjective progression of symptoms, such as an increase in housework and childrearing, which might lead to a higher awareness of muscle weakness, as well as the lack of rest and sleep, which could accelerate disease progression. Monitoring of biomarkers or frequent scoring of muscle weakness will be needed to acquire more information.
This study has some limitations. First, the sample size was small, and thus the range of the 95% CI was wide and hindered the detection of significant differences. Nonetheless, it is difficult to obtain a large sample of patients with this very rare disease, and the present study represents one of the largest surveys of pregnancy in GNE myopathy patients. Second, we analyzed self-reported data. Self-reported data are not objective, and given that the mean respondent age was 17 years older than the mean maternal age, participants could have forgotten or had difficulty recalling their conditions during pregnancy. Third, there may have been selection bias, since those with severe phenotypes may have been more prone to participate in the national registry. Notwithstanding these potential limitations, we believe that this first and largest survey of pregnancy in Japanese GNE myopathy patients would be helpful for future patients who desire to get pregnant and for doctors responsible for managing their pregnancies.