Abstract
PURPOSE:
Congenital myotonic dystrophy (CDM) results in hypotonia and acute respiratory distress at birth. Previous studies show that prolonged periods of intubation (>4 weeks) correlate with increased mortality rates. The objective is to describe the use and duration of respiratory support in newborns with CDM and how these relate to mortality.
METHODS:
A retrospective chart review was performed at a tertiary pediatric hospital among children with confirmed diagnosis of CDM. The main outcome measures were: mortality, duration of invasive mechanical ventilation (IMV) and non-invasive partial pressure ventilation (NIPPV), along with long-term use of respiratory support and equipment.
RESULTS:
A total of 18 subjects met inclusion criteria, 83%.f which had documented respiratory distress at birth, 39%.equired NIPPV, and 50%.equired intubation in the neonatal period. The earliest NIPPV was initiated at day one of life, and the latest extubation to NIPPV was at 17 days of life.
CONCLUSION:
This cohort required IMV for shorter periods with earlier transitions to NIPPV which suggests a possible change in practice and earlier transition to NIPPV recently. Further data are needed to determine if there is a possible correlation between the need for NIPPV/IMV and mortality rates.
Introduction
Congenital myotonic dystrophy (CDM) is a muscular disorder that presents in the neonatal period, affecting 1 in 47,619 live births [1]. CDM results from a mutation in the DM1 protein kinase (DMPK) gene at locus 19q13.3 and produces an abnormal expansion of cytosine-thymine-guanine (CTG) repeats. This expansion results in genetic anticipation, with the number of repeats increasing in successive generations. A higher number of repeats is associated with an earlier clinical presentation and more symptomatic phenotype. Infants with CDM can have greater than 1,000 CTG repeats.
Clinically, CDM can result in hypotonia and respiratory insufficiency at birth [1, 2]. Other clinical manifestations include a tent shaped mouth, poor suck, high arched palate, and talipes equinus. Infants with mild presentations may demonstrate hypotonia only, whereas the most severely affected can have respiratory distress, dysphagia, and gastrointestinal motility dysfunction [1, 2]. The degree of respiratory distress varies and in severe cases requires invasive mechanical ventilation (IMV) for survival [1–3].
Previous research dating back to 1989 demonstrated a prolonged need for IMV in infants with CDM and increased mortality in those requiring IMV for greater than 28 days [2, 3]. Based on this prior research, some infants with prolonged IMV needs have been withdrawn from life support [1, 3]. Other studies have called this association between prolonged IMV and increased mortality into question, but no study to date has been able to conclusively confirm or refute this finding [1, 4]. Additionally, recent case studies have demonstrated success with using non-invasive positive pressure ventilation (NIPPV) in this population, potentially decreasing need/length of IMV, but no studies to date have described the respiratory needs or mortality of these patients after the first few months of life [5].
The primary aim of this descriptive study was to characterize the respiratory support utilized in the neonatal period by infants with CDM and explore its associations with mortality. The secondary aim was to determine if respiratory support or other risk factors in the neonatal period were associated with adverse respiratory outcomes within two years of birth in children with CDM.
Methods
This is a retrospective case series of children with CDM seen at Seattle Children’s Hospital from January 2005 to December 2017 in the NICU and/or in the outpatient clinic. Subjects were identified if they had been coded as having myotonic disorders in the electronic health record. Subjects were included if they had documentation of 1) clinical CDM symptoms including respiratory distress, hypotonia, or difficulty feeding in the neonatal period and 2) genetically confirmed diagnosis of myotonic dystrophy.
Demographic data, delivery information, initial and subsequent hospitalizations, and need for respiratory assistive devices/support (e.g., suction, cough assist, pulse oximetry, or oxygen) in the first two years of life were gleaned from subjects’ medical records by the first author. Primary outcomes included use of respiratory support (including oxygen, IMV, and NIPPV) at birth, duration of respiratory support, and mortality within the first 2 years of life. Secondary outcomes included the use of respiratory assistive devices, number of hospitalizations, number of subsequent IMV events (defined as at least 48 hours after initial extubation and up to 2 years of age), and apnea hypopnea index (AHI) from a polysomnogram (sleep study) after 1 month of age and up to 2 years of age. Potential predictors of respiratory support in the neonatal period were also collected and included: Apgar scores at 1, 5, and 10 minutes, number of CTG repeats, gestational age (prematurity < 37 weeks), pregnancy complications, maternal age, and chest x-ray findings in the neonatal period.
Subjects were categorically stratified into two groups: those who required moderate to high levels of respiratory support (IMV, NIPPV) and those who required little to no respiratory support (oxygen, nothing). Associations were explored between predictive factors of levels of respiratory support as well as between levels of respiratory support and outcomes.
Data are presented as median (interquartile range) or n (%.. Continuous data were compared using the Wilcoxon rank-sum test and categorical data were compared using Fisher’s exact test. All tests were two-sided and p-values < 0.05 were considered statistically significant. Data were analyzed using SAS 9.4 (SAS Institute Inc, Cary, NC).
Results
A total of 18 infants were identified, 15 with over 1000 CTG repeats (one with 570 repeats and 2 with missing data). Of the 18 infants, 56%.ere born prematurely, 61%.ere born via cesarean section, and 94%.ad mothers diagnosed with myotonic dystrophy (DM) after the infant was diagnosed with CDM. Half of the subjects required IMV in the first 24 hours of life and 11%.equired NIPPV in the first 48 hours of life. Five subjects successfully transitioned from IMV to NIPPV by 3 weeks of life. The longest duration of IMV was greater than 2 years (via tracheostomy) and the longest duration of NIPPV was 75 days. Two subjects died during the period of observation; one required IMV for 26 days and died in the first month of life from respiratory complications of CDM, and the other died at 19 months from an unknown cause (Table 1).
Clinical details of 18 infants with congenital myotonic dystrophy
Clinical details of 18 infants with congenital myotonic dystrophy
Key: unk = unknown; N/A = not applicable.
Respiratory outcomes, as they relate to level of respiratory intervention required, are described in Table 2. Subjects who required neonatal intervention were more likely to require subsequent intubation (27%.s 0%, p < 0.51), had longer initial hospital stays (p < 0.23), and an increased number of hospitalizations in the first 2 years of life (p < 0.4). All 3 subjects requiring subsequent intubation transitioned from IMV to NIPPV: one child was intubated within one month, the other two were intubated related to critical illness around one year of age. Subjects who required neonatal intervention also were more likely to utilize more respiratory assistive devices at home after the first month of life. Finally, subjects who required intervention in the neonatal period were more likely to have an abnormal AHI (72%.s 14%, p < 0.2) on sleep study. These findings are descriptive as none of them reached statistical significance (p < 0.05).
Respiratory outcomes within 2 years of birth based on level of respiratory support in first month of life
Data are presented as median (IQR) or n (%..
Potential predictors of respiratory outcomes stratified by level of respiratory intervention are described in Table 3. Subjects who required neonatal intervention when compared to those who did not had lower median gestational ages (34 vs 39 weeks, p < 0.05), higher median number of CTG repeats (1,475 vs 1,000, p < 0.07), mothers with lower median ages (25 vs 37 years old, p < 0.06) and more reported pregnancy complications (91%.s 43%, p < 0.05). They were also more likely to have abnormal chest X-ray findings (73%.s 14%, p < 0.44), most commonly with low lung volume or diaphragmatic asymmetry.
Predictors of level of respiratory support in the first month of life
Data are presented as median (IQR) or n (%..
In our cohort, subjects born at younger gestational ages required more respiratory support in the neonatal period as compared to prior studies [5, 6]. Potential explanations for this include smaller size, less muscle strength (affecting both inspiratory and expiratory effort), and less mature respiratory systems. Subjects needing neonatal respiratory support tended to have higher number of CTG repeats, reflecting increased severity of initial presentation. An increased awareness and early genetic testing may help providers anticipate the level of support needed. These findings are in accordance with more recent studies showing there is no clear association between duration of IMV or NIPPV and mortality, as previously reported by Rutherford et al. (1989); though more studies with larger samples sizes are needed to confirm this finding [4, 8]. Lastly, subjects who required intervention at birth typically had more hospital and intensive care admissions in the first two years of life than subjects who did not. This information may be helpful in discussions with families who have infants with newly diagnosed CDM.
Most subjects in this study weaned from IMV within three months, which is sooner than an average of > 100 days as reported in prior studies [1, 9]. Subjects in this study were extubated to NIPPV more quickly than the previously reported ranges spanning 55 to > 140 days [4, 9]. Of the 5 subjects in this cohort transitioned from IMV to NIPPV, 4 were transitioned within one week of initiation of IMV. This may reflect increasing comfort levels among providers while using NIPPV in the infant population, especially as the technology surrounding NIPVV (masks, modes, device settings) have improved over time [10, 11]. Another novel finding was that over half of the subjects were born via cesarean section. This is not surprising; failure to progress during all three phases of labor is documented in mothers with the known diagnosis of DM as well as mothers diagnosed after their child was diagnosed with CDM [12].
To the knowledge of the authors, this study is the first to report on long term respiratory equipment needs of children with CDM. Patients who require more support at birth utilize more respiratory assistive devices within the first two years of life. This information is valuable to providers caring for infants with CDM to best monitor these patients and provide anticipatory guidance to their families. Infants who require more support at birth also are more at risk for having abnormal sleep studies, with a clinically significant AHI. Treatment of sleep apnea has been associated with improved cognitive function in adults with CDM [13]. This needs further study among children with CDM.
There are several limitations to this study. First, this was a retrospective chart review, which yielded incomplete data for several subjects. The majority of missing data were in subjects who did not require neonatal intervention, limiting the ability to compare outcomes and predictors between groups. The subject number is low due to the rarity of this condition, yielding insufficient data to interpret and resulting in descriptive results. This study included subjects ultimately referred to a single tertiary institution, which may have led to some referral and regional biases.
Conclusion
Congenital myotonic dystrophy is a rare autosomal dominant disorder resulting in hypotonia and respiratory distress at birth that can be life threatening. This study demonstrated that infants who require NIPPV/IMV at birth have a higher number of CTG repeats; they also have abnormal sleep studies and utilize more respiratory assistive devices over their first two years of life. This information may provide guidance to clinicians counseling these families. In addition, this study is the first to report successful early transition from IMV to NIPPV in infants with CDM. Given advancements of NIPPV, improved management of infants requiring IMV, and a lack of association between NIPPV/IMV and mortality, the authors challenge the current paradigm linking prolonged IMV with high mortality in children with CDM. Providers caring for infants with CDM should be aware of these treatment advances, and incorporate this evolving landscape into their medical decision-making and discussions with families.
Ethical considerations
This study was approved by the Seattle Children’s Hospital Institutional Review Board (IRB). Given the study design, no consent of human subjects was required.
Conflict of interest
None of the authors has any conflict of interest to disclose.