The Outcomes and Experience of Pregnancy in Limb Girdle Muscular Dystrophy Type R9

Abstract

Introduction:

Published information about the experiences of pregnancy in limb girdle muscular dystrophy (LGMD) is limited and does not specify LGMD type, limiting utility. We describe the experience and outcomes of pregnancy in a cohort of women with LGMDR9.

Methods:

All women 18 years of age or older with a genetic and clinical diagnosis of LGMDR9 who are enrolled in the University of Iowa Wellstone dystroglycanopathy natural history study (clinicaltrials.gov NCT00313677) were invited to complete a questionnaire about their pregnancy experiences, including questions about pregnancy complications, muscle symptoms experienced during pregnancy, and post-partum course.

Results:

A total of 22 women responded to the survey. Thirteen women reported 26 live births. The majority of pregnancies that resulted in a live birth were uncomplicated (n=19, 73%), and most infants had no complications (n=25, 96%). The rates of assisted vaginal delivery (n=9, 35%) and induction of labor (n=18, 70%) were both significantly higher than the national average. Almost half of pregnancies (n=11, 42%) resulted in increased weakness during pregnancy; only 1 returned to pre-pregnancy baseline.

Discussion:

The data presented here suggest that women with LGMDR9 who are considering a pregnancy should be counseled that they might have a higher likelihood of assisted vaginal delivery and could experience progression of weakness. These results are generally consistent with previous reports, but future studies of pregnancy in defined subtypes of LGMD will be required to confirm these findings and determine if risks vary by genotype.

Introduction

Limb girdle muscular dystrophy type R9 (LGMDR9, previously LGMD2I) is an autosomal recessive disorder caused by mutations in the fukutin-related protein (FKRP) gene.¹ FKRP encodes a protein required for the post-translational glycosylation of α-dystroglycan, which is critical for membrane stability.^2,3 LGMDR9 patients experience progressive weakness on a continuum of severity, with loss of ambulation occurring over a wide age range,from the teens to well into adulthood.^4,5 A founder mutation, c.826C>A, is present in almost all patients with LGMDR9 either as a compound heterozygous or homozygous mutation.⁶ Individuals who are homozygous for this variant generally have a milder phenotype than those who have other genotypes.⁷

The course of pregnancy has been described for several neuromuscular disorders, including fascioscapulohumeral muscular dystrophy (FSHD), myotonic dystrophy (DM1/DM2), and mixed or unspecified LGMD subtypes.^8–11 Most of these are small series. Many women in these previous series experienced an increase in weakness, which often did not return to pre-pregnancy baseline. These reports also identified an increased risk for pregnancy complications, including cesarean delivery, assisted vaginal delivery, and peripartum hemorrhage.^9,11

We describe the course and outcomes of pregnancy for a cohort of women with LGMDR9. This disease-specific information will allow more accurate counseling for women with LGMDR9 who are considering pregnancy.

Methods

A 26 question survey was created by modifying a survey previously used to collect information about the pregnancy experiences and outcomes of women with FSHD.⁸ Eight questions were retained from that survey because they could be applicable to both FSHD and to LGMDR9, ten questions were modified to better fit participants with LGMDR9, and four questions were removed as they were not pertinent to our study. Questions addressed diagnostic history, pregnancy complications, pregnancy outcomes, the course of symptoms during pregnancy, return of symptoms to baseline after pregnancy, and post-partum course. Surveys were administered using the Research Electronic Data Capture (REDCap), and are shown in the supplemental materials.^12,13 Survey questions were designed to offer all potential outcomes for a given questions to avoid suggesting an outcome. For example, when asking about strength during pregnancy, options included getting weaker, staying the same, or getting stronger.

All women 18 years of age or older with a genetic and clinical diagnosis of LGMDR9 who are enrolled in the University of Iowa Wellstone dystroglycanopathy natural history study as of October 2019 were invited to participate. Potential participants were sent an email message describing the study that included a link to the survey on REDCap. A reminder email message was sent two weeks later to those who had not responded. Those who did not respond within three weeks of the second email were considered non-respondents. If the survey was started but responses were incomplete or unclear, the study coordinator (CS) contacted the participant for clarification or to request completion. If a survey was incomplete due to a pregnancy loss before 20 weeks’ gestation (indicated in the survey or noted in the medical history from the parent project), there was no follow-up contact. Only one survey was incomplete due to pregnancy loss before 20 weeks, and that data only counted towards the total number of pregnancies. Surveys included identifying data to allow results to be tied to medical information in the parent study.

For analyses, we grouped respondents’ age at self-reported onset of weakness into groups with onset at <10 years, ≥10 to <20 years, and ≥20 years of age.

Descriptive statistics included calculation of means, standard deviations, medians, and 95% confidence intervals. Two-sided t-tests were used to compare ages of respondents and non-respondents, and the ages of those with and without pregnancies. Fisher’s exact test was used to compare genotype categories and age at onset of weakness categories of respondents and non-respondents, those with a pregnancy and without a pregnancy, and those who did and did not experience worsening of weakness during pregnancy.

Standard Protocol Approvals, Registration, and Patient Consents:

Institutional Review Board approval was obtained for all recruitment and data collection for this study. Written informed consent was obtained from all patients. The dystroglycanopathy natural history study may be found on clinicaltrials.gov (NCT00313677).

Results

Surveys were sent to 32 women and 22 women (69%) completed the survey, as shown in Figure 1. Demographic information for those who did and did not complete the survey are summarized in Table 1. There were no significant differences between respondents and non-respondents, or between those with and without a pregnancy, with respect to age or genotype. We note that only one participant-respondent with a compound heterozygous genotype had a pregnancy carried to term.

Figure 1:

Flow diagram showing subject inclusion

Table 1.

Demographics of women invited to participate

	By Survey Response status				By Pregnancy status, among survey responders
	Responder n=22	Non-responder n=10	Difference (95% CI)	p-value	Had Pregnancy n=14	No Pregnancy n=8	Difference (95% CI)	p-value
FKRP genotype
c.826C>A homozygous	17 (77%)	6 (60%)	17% (−18%, 52%)	0.40	12 (86%)	5 (63%)	23% (−15%, 61%)	0.31
Age at survey, years
Mean (SD)	43.8 (10.7)	42.2 (10.2)	1.6 (−6.6, 9.8)	0.69	46.6 (9.2)	38.8 (11.9)	7.8 (−1.7, 17.2)	0.10
Range	19.8-63.2	25.4-54.9			35.1-63.2	19.8-58.0

CI= Confidence Interval FKRP= fukutin-related protein SD= Standard deviation

We analyzed 26 of 34 pregnancies from fourteen women, as 8 pregnancies resulted in spontaneous abortion (miscarriage), all by 20 weeks’ gestation (Table 2). Two participants became pregnant with in vitro fertilization. Self-reported onset of LGMD-related weakness in those with a pregnancy ranged from early childhood to 48 years old. Nine participants did not know they had LGMD prior to pregnancy.

Table 2.

Pregnancy experience in women with LGMDR9

	N=26 (%)	95% CI	National %
Miscarriage	8 (24%)a	10, 44	10-15%15
Cesarean delivery	3 (12%)	3, 34	31.6%14
Spontaneous vaginal delivery	14 (54%)	33, 74	65.1%17
Vacuum- or Forceps-assisted delivery	9 (35%)	17, 57	2.5%17, 0.5%17
Induced labor	18 (70%)	43, 88	27.1%14
Any complications of pregnancy in those with a live birth	7 (27%)	12, 52
Any infant complications	1 (4%)	0, 28
Became weaker during pregnancy	11 (42%)
Weakness did not return to baseline	10 (91%)
Muscle pain and cramps worsened during pregnancy	2 (8%)
More frequent falls during pregnancy	4 (15%)
Fall frequency did not return to baseline	3 (75%)
Lost function during pregnancy	7 (27%)
Function did not return to baseline	5 (71%)

CI= Confidence interval

^aMiscarriage percentage from 34 total pregnancies

We explored factors associated with choosing to have a pregnancy. There was no significant difference in age at onset of LGMD-related weakness between those with a pregnancy and those without a pregnancy (Table 1). However, three participants reported that they chose not to attempt to conceive because of their diagnosis of LGMDR9; these three participants were similar to the rest of the participant population and were ambulatory into adulthood. Five participants who had a pregnancy reported that symptoms related to muscular dystrophy during their pregnancy affected their decision to have future pregnancies, and none of these participants had an additional pregnancy. The most common reason given was the progression of weakness they experienced during their pregnancy resulting in concern about further progression with future pregnancies. They also reported difficulty caring for their children due to weakness.

The majority of the pregnancies that resulted in a live birth were uncomplicated, and the infants were also healthy, as summarized in Table 2. Complications of pregnancy included preterm labor (n=1), preterm birth (n=1), blood transfusion after delivery (n=1), premature rupture of membranes (n=2), high blood pressure (n=2), breech presentation (n=2), and peripartum hemorrhage (n=3), and the infant complication was 35 week gestation associated with fetal distress and feeding difficulties. Spontaneous vaginal delivery was the most common delivery method. Eighteen pregnancies had an induction of labor, with 50% due to being past the estimated date of delivery (“due date”).

Women reported that weakness worsened in 42% of pregnancies that resulted in a live birth (Table 2). Many also noted an increase in falls or loss of function (such as climbing stairs or getting up from a sitting position or from the floor). Of those who reported progression of weakness, only one returned to her pre-pregnancy baseline. We found no significant relationship between the age at onset of weakness and the likelihood of a worsening of weakness during pregnancy. Age at completion of the survey was similar for those with (mean 42.94 years, range 35.89-51.91 years) and without progression of weakness (mean 51.04 years, range 35.43-63.62 years). Five participants reported that they did not have loss of function with first pregnancies but did with subsequent pregnancies. Age at time of pregnancy, however, was not associated with progression of weakness. The mean age at delivery for those with pregnancy-associated weakness was 27 +/− 3.6 years, compared to 26 +/− 5.2 years for those without progression of weakness.

Discussion

A woman’s decision to have a pregnancy was not affected by genotype or age at onset of weakness (as indicators of disease severity) in this cohort, however several women reported choosing not to have a pregnancy or not to have future pregnancies due to the LGMD diagnosis or symptoms during a pregnancy. We note that some women were pre-symptomatic or minimally symptomatic and unaware of their diagnosis at the time of their pregnancy. Most previous reports about pregnancies in neuromuscular diseases focused on the experience of pregnancy, however 6 of 48 women with FSHD reported that their disease played a role in their decision to not have a pregnancy.⁸

The rates of miscarriage and need for cesarean delivery in our LGMDR9 cohort were similar to national averages, as shown in Table 2. However, considering the national average to be the true value, percentages of those requiring induction of labor and assisted vaginal deliveries were significantly higher than the national averages (outside of our 95% CI).^8–10,14 Higher rates of assisted vaginal deliveries were also reported for other types of muscular dystrophy, summarized in Table 3.^10–13 Reported outcomes are highly variable across diseases and series, likely related to small sample sizes and perhaps to disease specific factors and obstetric practice variation. Both skeletal and smooth muscles are required during labor and delivery and the dystrophin-dystroglycan complex is present in both types of muscle, likely contributing to the increased need for assisted delivery.¹⁶

Table 3.

Pregnancy experiences in LGMDR9 compared with other muscular dystrophies

	LGMD type R9 (current cohort)	LGMD11	LGMD10	DM1 and DM211	DM1 and DM29	FSHD11	FSHD10	FSHD8	National average
# women	22	22	9	74	280	13	11	38	-
# pregnancies	34	31	12	176	375	29	26	105	-
Miscarriage	8 (24%)	5.9%	0	27 (15%)	33%	10.3%	3 (13%)	16.2%	10-15%15
Cesarean delivery (%)	3 (12%)	31%	3 (25%)	43 (24%)	NA	7.7%	2 (9%)	23%	31.6%14
Assisted deliveries (%)	9 (34%)	17.2%	2 (17%)	20 (11%)	NA	15.4%	4 (17%)	27%	3.0 %17
Uncomplicated completed pregnancies	19 (73%)	93.1%	100%	NA	NA	96.2%	100%	NA	-
	LGMD type R9 (current cohort)	LGMD11	LGMD10	DM1 and DM211	DM1 and DM29	FSHD11	FSHD10	FSHD8	National average
Worsened muscle weakness	11 (42%)	54%	56%	14%	30-60%	12%	3 (27%)	24%	-
Healthy babies	25 (96%)	96%	8 (75%)	92.1%	64%	100%	21 (91%)	Same as national avg	-
Labor induction	18 (69%)	NA	NA	NA	NA	NA	NA	NA	27.1%14

LGMD= Limb girdle muscular dystrophy DM1/DM2= myotonic dystrophies type 1 and 2 FSHD= fascioscapulohumeral muscular dystrophy

The majority of infants in this series were healthy, consistent with other LGMD series (Table 3). The health problems reported in infants born to women with LGMD do not appear to have any common pathophysiology, and are likely sporadic occurrences.^10,11 As LGMDR9 and most of the other LGMDs are autosomal recessive, the infants are not expected to have any specific risks outside of maternal factors.

Although women with LGMDR9 have a high likelihood of having a completed pregnancy resulting in a healthy infant, changes in weight, center of gravity, and hormonal changes can all impact motor function during pregnancy. About half of the pregnancies reported here resulted in a worsening of muscle weakness that usually did not return to pre-pregnancy baseline after delivery, similar to previously reported results in cohorts of women with LGMD.^11,10 Objective quantification of strength is lacking due to the retrospective nature of this study. Anecdotally, women reported more rapid progression of weakness during pregnancy than was typical for them. Many also reported a loss of specific functions and increased falling, which support their feeling of increased weakness. LGMDR9 is typically slowly progressive, so it is notable that so many women recall worsening during pregnancy. It is unclear what predisposes some women to have progression of muscle weakness during pregnancy. The small numbers of participants in this and previous series make it difficult to identify specific associations with progression of weakness. Similarly, we did not find an association between pregnancy-associated weakness and duration of disease, and our numbers are too small to explore FKRP genotype associations. Finally, we found no association between age at time of pregnancy and pregnancy-associated progression of weakness. Other potential variables not explored in our analysis might include pre-pregnancy weight or BMI and activity level before and during pregnancy. It is of interest that pregnancy-associated muscle weakness was also reported in other types of muscular dystrophy (Table 3), though most reported rates were lower than those for LGMD.^10–13 This lack of specificity suggests that this phenomenon is not related to the specific biology of the muscular dystrophy, and raises the possibility that it might be modifiable if we had greater knowledge of risk factors. Additional series will be required to clarify predictors of pregnancy-associated progression of weakness.

Our study has several limitations, inherent in a retrospective study in a rare disease. None of the women in this study had a pregnancy during the natural history study, so reports regarding strength are subjective. The mean age at completion of the survey was 43.3 years, with mean time of 19 years between pregnancy and survey completion, introducing the possibility of inaccurate recall. However, age at survey completion was similar in those with and without reported progression of weakness, which makes recall bias less likely as an explanation for our results. Our study is also limited by small cohort size. We had limited genotypic variability in this series, so results might generalize with greatest confidence to women who are homozygous for the c.826C>A mutation. We note that we found no significant differences between the respondents with pregnancies and those who did not respond or did not have a pregnancy, providing some confidence regarding generalizability.

The information presented here will aid in counseling women with LGMDR9 who are considering a pregnancy. Our results suggest that a subset of women with LGMDR9 will experience increased weakness during pregnancy and this might not return to baseline after delivery. Our data also suggest that women with LGMDR9 have a higher likelihood of requiring induction of labor and assisted vaginal delivery compared to national averages. Despite these observations, most women had uncomplicated pregnancies and delivered healthy infants. Future studies of pregnancy in defined subtypes of LGMD will be required to confirm these findings and determine if risks vary by genotype.

Abbreviations:

FSHD

fascioscapulohumeral muscular dystrophy

FKRP

fukutin-related protein

LGMDR9

Limb girdle muscular dystrophy type R9

DM1/DM2

myotonic dystrophy

REDCap

Research Electronic Data Capture