The Impact of Pregnancy on Myotonic Dystrophy: A Registry-Based Study

Abbreviations

INTRODUCTION

The myotonic dystrophies are autosomal dominant, multisystemic disorders due to either a CTG repeat in the DMPK gene (myotonic dystrophy type-1; DM1) [1–3] or a CCTG repeat in the CNBP (ZNF9) gene (myotonic dystrophy type-2; DM2) [4–6]. Both DM1 and DM2 cause muscle weakness, delayed muscle relaxation (myotonia), and early onset cataracts [7, 8]. In addition, both disorders may affect the heart, cognition, and other body systems [9]. Genetic anticipation can lead to expansion in the CTG repeat in DM1. In DM1, genetic anticipation can lead to children with earlier, and more life-altering symptoms than their affected mother. In these cases, mothers with classical or mild DM1 may have children who present with severe symptoms developing in infancy or childhood, known as congenital DM1 or childhood DM1 [8]. In DM2, clinical symptoms associated with the disease do not typically occur until early adulthood or later.

Neuromuscular disease can complicate pregnancy. Maternal weakness, concern over passing a disease to a child, peripartum anesthesia risks, and neonatal complications are common concerns [10]. DM patients are at increased risk of reproductive complications. In prior obstetrical surveys, patients with DM1 had a higher rate of spontaneous abortions, polyhydramnios, ectopic pregnancies, placenta previa, and preterm labor [11]. Pregnant DM2 patients have a higher rate of urinary tract infections and preterm labor [11, 12]. Anecdotally, DM patients often report that their symptoms worsen or begin during pregnancy. In a series of 42 patients with DM2, 21% of women reported developing their initial symptoms during pregnancy [12].

This study builds on prior research by utilizing a large cohort of women with DM to identify the outcomes, complications, and changes in symptoms associated with pregnancy. In addition, this study utilizes the Myotonic Dystrophy Health Index-Short Form (MDHI-SF) to retrospectively estimate the impact pregnancy has on disease burden in DM [9]. Approval for this study was obtained through the local institutional review board and an ethical approval process through both registries.

METHODS

RESULTS

From the combined registries, 217 women returned the survey (144 from MDF registry, 73 from national registry) for a 40.0% response rate. 152 (70%) of these women reported that they had been pregnant at least once. The demographic information, number of pregnancies, and abortions/miscarriage rates for both DM1 and DM2 are provided in Table 1.

There were 375 total pregnancies: 290 reported pregnancies from 152 women with DM1 and 70 reported pregnancies from 122 women with DM2. Fifteen pregnancies were reported from DM woman who did not know (n = 5) or did not report (n = 1) what type of myotonic dystrophy they had. A total of 48.9% (49.6% for DM1 and 50% for DM2) of women reported developing some clinical symptoms of DM prior to their first pregnancy, 37.6% (36.3% DM1 and 40.9% DM2) did not have any symptoms prior to their first pregnancy, and 10.6% (12.4 DM1 and 0 for DM2) were unsure.

Assistive reproductive technology (e.g., hormone therapy, in vitro fertilization) was reported during pregnancy in DM. During their first pregnancy, 18.1% (DM1:19.8% , DM2:13.6%) of women used in vitro fertilization, but only 6.9% (DM1:6.9% , DM2:9.1%) of women reported using pre-implantation diagnosis. 34.1% of the pregnancies that used in vitro fertilization resulted in a child with DM. 12.1% of women with DM1 and zero percent of women with DM2 utilized hormone therapy in their first pregnancy.

Of the DM1 initial pregnancies carried to term, 36.2% of the children had a combination of feeding problems, breathing problems, hypotonia, or clubfoot at birth, which may be considered congenital DM1[8].

Women with DM experienced a high rate of pregnancy complications (Table 2). During the first pregnancy, 10.4% of women reporting pre-eclampsia and 13.9% of women reporting peripartum hemorrhage. Comparing women with DM1 and DM2, pre-eclampsia was more common in DM2 (13.6% vs 9.5%), while polyhydramnios (25% vs 0.0%) and pre-term labor (31.0% vs 13.6%) were more common in DM1 (Table 2). Polyhydramnios has been specifically associated with congenital DM, which may explain why this is only reported in women with DM1 [14].

Among those DM1 women who had a child with neonatal complications of myotonic dystrophy during the first pregnancy, 49% went on to have a second pregnancy. The outcome of the second pregnancy in these cases resulted in a child with myotonic dystrophy 44% of the time, 33% of these subsequent pregnancies had neonatal complications of myotonic dystrophy.

Women with DM reported that select symptoms progressed during pregnancy. In some cases, these symptoms did not return to baseline six months after pregnancy. When evaluating DM1 participants, the prevalence of mobility limitations (p <  0.001), activity limitations (p = 0.008), pain (p = 0.021), emotional issues (p = 0.041), and myotonia (p = 0.045) increased when comparing results prior to pregnancy with after pregnancy (Fig. 1A). In women with DM1, there was a significant increase in the impact of mobility limitations (p <  0.001), activity limitations (p = 0.001), fatigue (p = 0.043), pain (p = 0.019),emotional issues (p = 0.002) and myotonia (p = 0.039) from pre-pregnancy to after pregnancy (Fig. 1B).

In DM2, women reported that activity limitations (p = 0.044) were more prevalent after pregnancy (Fig. 2A). In DM2, there was a significant increase in the impact of mobility limitations (p = 0.009), activity limitations (p = 0.035), fatigue (p = 0.003), communication difficulties (p = 0.043), and sleep impairment (p = 0.016) after pregnancy (compared to prior to pregnancy) (Fig. 2B).

DISCUSSION

This study highlights the possible complications and outcomes associated with pregnancy in DM. Our DM participants had a higher total miscarriage rate (DM1:32.1% , DM2:37.1%) than the national average of 16.9% [15]. DM rates of preeclampsia (10.4%) and peripartum hemorrhage (13.9%) were also elevated compared to the national rates of 3.4% and 2.9% , respectively [16, 17].

Women with DM were more likely to use reproductive technology (35%) than the national average (12%) [18]. Prior studies have shown that women with DM1 may have diminished ovarian reserve and less favorable outcome with in vitro fertilization, though it is possible for women with DM1 to successfully complete in vitro fertilization [19–21]. While 18.1% of woman used in vitro fertilization during their first pregnancy, only 6.6% used pre-implantation diagnosis. When properly utilized, a combination of in vitro fertilization, genetic testing, and selective implantation can be used to significantly reduce or even prevent the transmission of DM between generations. The low use of pre-implantation diagnosis may have been the result of the mother being unaware of her own diagnosis, personal preference, financial concerns, or a lack of awareness among fertility specialists.

Those participants responding to the survey reported that up to 36.2% of initial DM1 pregnancies carried to term resulted in a child with congenital DM. While this percentage of congenital DM births is higher than previously reported [7], we suspect that this was due in part to a sampling bias and the utilization of only registry participants.

This study identifies a possible risk of disease progression during pregnancy; especially in activity limitation and mobility, fatigue, and pain. In these symptoms, disease burden advanced during pregnancy and did not return to the pre-pregnancy state after 6 months.

The highest reported complication rates were associated with the first DM pregnancy. Similarly, the percentage of mothers with DM1 reporting symptoms associated with congenital DM in their child was reduced in subsequent pregnancies. We suspect that these results reflect the possibility that participants with severe complications during their first pregnancy were more likely than those that had minimal complications to avoid subsequent pregnancies.

There are limitations to this study. First, the response rate was relatively low. This is particularly of concern in the interpretation of the responses from DM2 patients, where the number of participants was lower than in DM1. Second, participants were limited to those woman involved in one of the two major United States DM Registries. Results from this study do not include input from DM women outside of these two registries nor does it evaluate cases involving paternal transmission of DM. Though participants were instructed not to, they may have completed the survey in both registries, should they have been members of both. Thirdly, there was no control group, so a similar change in the MDHI-SF can not be compared to those women who were not pregnant. Lastly, this study was retrospective. Participants provided information, which may have been prone to recall bias or potentially DM-associated cognitive dysfunction. Ideally, the reporting of symptoms, complications, and outcomes, including the use of the MDHI-SF, should be performed in a prospective fashion. It is also not known when the mother’s in our study were diagnosed. It is certainly possible that a mother’s knowledge of her own diagnosis of DM1 prior, during, or after her pregnancy played a role in how she retrospectively viewed her symptoms during these time periods. Future prospective studies of pregnancy in DM should beconsidered.

Overall, this study uses patient insight to highlight the risks, complications, and disease progression associated with DM pregnancy. Results from this study provide data regarding possible symptom progression during the course of a DM pregnancy and identifies divergent patterns of symptom progression related to pregnancy in both DM1 and DM2. The information from this research may be utilized by DM patients and family members seeking to better understand the risks and outcomes associated with pregnancy in DM.