J Neurol (1992) 239 : 26-30

Journal of

Neurology © Springer-Verlag1992

Pregnancy and spinal muscular atrophy Sabine Rudnik-Schfneborn 1, Klaus Zerres 1, Jaakko Ignatius 2, and Marcella Rietschel 1 11nstitut far Humangenetik der Universit~it, Wilhelmstrasse 31, W-5300 Bonn 1, Federal Republic of Germany 2Department of Medical Genetics V~iest61iitto, Helsinki, Finland Received January 14, 1991 / Accepted May 2, 1991

Summary. W e investigated the course and outcome of pregnancy and its influence on muscle weakness in 12 females with proximal spinal muscular atrophy (SMA) who delivered a total of 17 infants when aged 18-32 years. In 4 females the S M A clearly followed an autosomal recessive m o d e of inheritance. The disease was autosomal dominantly inherited in 2 patients; the other 6 were sporadic cases. Ages of onset of S M A ranged from 8 months to 29 years; all the females learned to walk, and 10 out of 12 are still ambulatory aged 30-60 years. Pregnancy and delivery were complicated in 10 out of 12 patients by p r e m a t u r e labour (4), prolonged labour (3) and delayed p o s t p a r t u m recovery (6). Caesarean section was p e r f o r m e d in 3 cases. No deleterious effects on fetal outcome could be detected. Exacerbation of muscle weakness after the second trimester of pregnancy was experienced by 8 females: 5 noticed a persistent deterioration of SMA; in 3 muscle weakness worsened temporarily during pregnancy and was followed by m a r k e d improvem e n t in the puerperium. The psychological perceptions, in retrospect, of 10 females concerning their decision to have children were evaluated. Key words: Spinal muscular atrophy - Pregnancy Muscle weakness - Psychological perceptions

Introduction Proximal spinal muscular atrophies (SMA) are a group of inherited neuromuscular disorder that are characterized by selective anterior horn cell degeneration. The symptoms are progressive muscle weakness and atrophy with a m a r k e d variation in age of onset and clinical severity. Proximal S M A is the second most c o m m o n autosomal recessively inherited disorder after cystic fibrosis, with an estimated incidence of i in 10000 children. The acute form represents the main cause of heritable infant mortality. Patients with a chronic course of proximal S M A have an early age of onset in infancy or youth and m a y remain ambulatory for decades. A u t o s o m a l dominant inherited SMA in childhood is rare (less than 2%), whereOffprint requests to: S. Rudnik-Sch/Sneborn

as about 30% of the cases with adult-onset S M A are considered to follow an autosomal dominant trait [3]. W o m e n afflicted with progressive muscular weakness since childhood are unlikely to decide to have children. To our knowledge there have been only two reports on pregnancy in SMA. Dietz and Gigon [1] reported one female suffering f r o m severe but chronic S M A who gave birth to four children. Laffargue et al. [2] described a 20year-old patient with W e r d n i g - H o f f m a n n ' s disease who delivered a healthy boy. Consulting w o m e n mainly worry about questions concerning potential complications in pregnancy and the unknown influence of pregnancy on muscle weakness and vice versa. They also fear a possible recurrence risk of S M A in their children, although this risk is usually very small in cases without a family history (below 1%). Sterilization and termination of pregnancy are frequent decisions due to the lack of information and experience.

Patients and methods Within our study on classification and genetics of proximal SMA [4-6] in 270 patients, we investigated retrospectively the influence of pregnancy in 10 women who delivered 14 children when aged 18-32 years. Three additional deliveries in 2 women with proximal SMA have been documented in Finland by one of us (J. I.). Initially, detailed clinical histories (milestones of de,~elopment, age of onset, ability to walk, impairment of functions) from all patients were obtained. The diagnosis of SMA has been evaluated on the basis of neurological examinations, with electrophysiological and in most cases histological investigations. Medical reports and information about family history were available in all cases. In a second step we interviewed 12 women with an age of onset of SMA between 8 months and 29 years regarding their pregnancies and deliveries. Two different questionnaires were put together: the first was to find out whether there were pregnancy complications, abnormal deliveries and a temporary or persistant influence on muscle weakness. In the second questionnaire 10 females from the German study were asked how they considered their decision for children in retrospect.

Results Clinical c o u r s e

The ages of onset of the 12 patients with proximal S M A ranged from 8 months to 29 years, corresponding to the childhood, juvenile or adolescent onset type of SMA.

27 70

•

Unable to walk (wheel- chair) [ ] Walking with support

60

* Deliveries

[ ] Walking difficulties 50-

..,,.

[ ] Without symptoms

(u 4 0 -

~9 -9

30*o"

20

*9

~9

*o" ~cF

10 254

55

901

203

I

902

72

82

I

212

l

1

-9

135

I

*o"

*d' *o"

Fig. 1. Clinical course with regard to walking ability in 12 females with chronic spinal muscular atrophy (SMA) who delivered a total of 17 infants (* age at childbirth and gender of infants indicated in each column)

~9

134

I

124

I

108

I

Patients

Table 1. Pregnancy and delivery in 7 females with childhood onset spinal muscular atrophy (SMA) (age of onset < 10 years) - obstetric history and influence on muscle weakness Case no. (family history)

Age of onset

Age at childbirth (years)

Pregnancy course and outcome

Influence on muscle weakness

254

8months

32

No deterioration but development of contractions due to inactivity

55

1.5 years

18 20

Premature labour and cervical incompetence beginning at 26 weeks' gestation; premature delivery at 36 weeks; prolonged postpartum recovery Vaginal bleeding at 7th month and prolonged labour in the 2nd pregnancy

901 (sister affected)

2.5 years

21 28

Caesarean section at term due to breech presentation in the 1st pregnancy; normal pregnancy and delivery in the 2nd pregnancy; prolonged recovery for about i year after delivery

203

3 years

24

902

5 years

27

Normal pregnancy; prolonged labour requiring forceps delivery Premature contractions at 32 weeks' gestation, elective caesarean section at 38 weeks (fetal breech presentation); prolonged recovery for about i year

72

6 years

30

9 years

27 31

82 (brother affected)

Normal pregnancy, no spontaneous delivery possible (caesarean section at 39 weeks' gestation); prolonged postpartum recovery Normal pregnancy and delivery in the 1st pregnancy; prolonged labour lasting more than 20 h in the 2nd pregnancy

A l l p a t i e n t s h a d l e a r n e d to w a l k a n d 10 o u t o f 12 a r e still a m b u l a t o r y at an age of 3 0 - 6 0 y e a r s (Fig. 1). M u s c l e w e a k n e s s was c h a r a c t e r i z e d b y slow p r o g r e s sion with l o n g - l a s t i n g stability, p a r t i c u l a r l y in t h e 7 earlyo n s e t cases ( T a b l e 1). T h e s e 7 f e m a l e s h a d t h e i r first s y m p t o m s in t h e first d e c a d e of life a n d w e r e p r e s u m e d to h a v e a b a d p r o g n o s i s . U n e x p e c t e d l y , t h e y all s h o w e d a benign course of the disease; walking without support was still p o s s i b l e at an age o f 3 0 - 5 4 years. Life e x p e c t a n c y is p r o b a b l y n o t m u c h r e d u c e d - if at all - b u t is u n p r e d i c t a b l e at t h e t i m e o f diagnosis. T h e r e m a i n i n g 5 f e m a l e s h a d an age o f o n s e t in the late s e c o n d o r in t h e t h i r d d e c a d e o f life a n d s h o w e d a

Deterioration of SMA in both pregnancies (beginning in the 3rd trimester) probably due to increasing weight; improvement immediately after deliveries No influence in the 1st pregnancy Marked excerbation (walking difficulties, climbing) during the last weeks of the 2nd pregnancy, some improvement after delivery, but ability to walk only for short distances Worsening of muscle weakness after delivery especially of upper extremities Worsening of walking ability after 20 weeks' gestation, confined to wheelchair for the rest of pregnancy, loss of head control during the last weeks; improvement within I year after delivery, all functions regained as before pregnancy Muscle weakness worsened with increasing weight, complete improvement during puerperium No influence

m o r e p r o n o u n c e d p r o g r e s s i o n o f w e a k n e s s . W i t h i n this g r o u p - a g e d 4 3 - 6 0 y e a r s at t h e t i m e o f this r e p o r t ; t h e m e a n age (51 y e a r s ) is t h e r e f o r e significantly h i g h e r t h a n in t h e e a r l y - o n s e t g r o u p (38 y e a r s ) - 4 p a t i e n t s lost t h e i r ability to w a l k w i t h o u t aid at an age o f 2 5 - 5 2 years. T w o w o m e n (nos. 135 a n d 134) b e c a m e c h a i r b o u n d 25 y e a r s a f t e r t h e first s y m p t o m s .

Genetic aspects A p o s i t i v e f a m i l y h i s t o r y was r e p o r t e d in 6 of t h e 12 f e m a l e s : 4 w o m e n h a d s i m i l a r l y a f f e c t e d siblings (sister of no. 901, b r o t h e r o f no. 82, sisters nos. 134 a n d 135)

28 Table 2. Pregnancy and delivery in 5 females with juvenile and adolescent onset SMA (> 10 years) - obstetric history and influence on muscle weakness Case no. (family history)

Age of onset (years)

Age at childbirth (years)

Pregnancy course and outcome

Influence on muscle weakness

212

12

22 25 (son affected)

Prolonged labour in the 1st pregnancy and prolonged postpartum recovery; rupture of membranes at 36 weeks' gestation of the 2nd pregnancy, premature infant Normal pregnancy and delivery

First subjective symptoms (unable to run and jump) recognized after 2nd delivery

Normal pregnancy and delivery Premature labour in both pregnancies; prolonged recovery after the first pregnancy

Three years later difficulties in climbing stairs Clinical onset of SMA (problems in climbing stairs, waddling gait) in the 1st pregnancy (4th-5th month); marked deterioration of muscle weakness during the 2nd pregnancy Marked muscular atrophy of the left thigh; first walking difficulties after delivery

27

135 16 (sisters affected) 134 17 124 22

108

18 22 (father and son affected) 24 29

29

~

Prematurelabourmainlyin the 2nd trimester; prolongedrecoveryin puerperiumfor 2 years

No influence

remature delivery

~

~~o'] Caesarean

V///////.//.,,,,.I section Obstetric -~//////////////~%5qProlonged complications ~ ~ 7 ~ 1 labor ~

35&/o Prolonged postpartum .... i] recovery

.

'

Influence on muscle weakness

No. of deliveries

"~ ~o Premature ..... i] labor

I

I

0

2

,

I

~ ~ g / [ ] ~._~6&/1o

,

4

I

6

,

I

8

,

t

,

10

I

12

Permanentdeterioration 35°/' of muscle strength

Exacerbationof SMA in pregnancy .... with ensuing improvement

il

and healthy parents. In these families the S M A obviously follows an autosomal recessive pattern of inheritance, which is to be expected in the childhood and juvenile onset form. Two offspring of 2 females (nos. 124, 212) also developed SMA, thus indicating an autosomal dominant m o d e of transmission. The father of patient 124 and her first son revealed muscle weakness at the age of 30 and 8 years respectively. The second son of patient 212 showed first symptoms of S M A at the age of 28 years; no further affected family m e m b e r s were known.

Obstetric complications Case reports with regard to pregnancy course, delivery and the influence on muscle weakness are listed in Tables I and 2. In summary, obstetrical problems were reported on 13 out of 17 deliveries (76%) in this study (Fig. 2). P r e m a t u r e labour in the second and third trimester was recorded in 4 w o m e n in 6 pregnancies, resulting in p r e t e r m births in 2 cases. Prolonged labour due to weakness of trunk muscles occurred in 4 deliveries of 3 females and led to a forceps delivery in 1. Caesarean

,

I

14

,

I

16

Fig. 2. Obstetric complications and exacerbation of muscle weakness in 17 deliveries of 12 females with proximal SMA

section was p e r f o r m e d in 3 cases: in 2 cases elective section was chosen because of breech presentation of the fetus; 1 infant was born by caesarean section because spontaneous delivery was impossible. Delayed recovery p o s t p a r t u m was experienced by 6 w o m e n who needed months or even 1-2 years (nos. 901, 902, 108) to recover after delivery. Not only muscle weakness due to S M A but also involuntary inactivity in pregnancy is assumed to contribute to the prolonged recovery. Altogether, pregnancies and deliveries were complicated in 10 patients (83%), while only 2 affected w o m e n (nos. 134, 135) with an age of onset of 16 and 17 years had uneventful pregnancies without any complaints.

Influence on muscle weakness Muscle weakness worsened temporarily in 3 w o m e n (4 pregnancies), probably as a result of the increasing weight during the last months of pregnancy, and in these cases was followed by a m a r k e d i m p r o v e m e n t in the puerperium. In 3 cases there was transient but prolonged worsening of S M A associated with pregnancy lasting at

29 least several months, sometimes even years after delivery. One patient (no. 902) who was able to walk unaided before was confined to a wheelchair for the second half of her pregnancy, and she even lost head control during the last few weeks. She slowly regained the functions she had had before pregnancy within 1-2 years postpartum. Five females (42%) including both patients with the dominant form of SMA claimed their pregnancies (6) were responsible for a permanent exacerbation of SMA. Deterioration of muscle strength of the first symptoms of SMA were noticed during or immediately after pregnancy and did not improve by the time of our investigation (7-35 years after delivery). The transient or persistent exacerbation did not lead to immobility during or after pregnancy (exception: patient 902), and the long-term course was still mild in almost all cases. However, the majority of mothers needed assistance in caring for their families at least for a certain period.

Outcome The infants delivered (10 females, 7 males) were described as healthy at birth and developed normally. The 15 offspring of patients with a supposed autosomal recessively inherited SMA have been alive and well and ranged in age from 5 months - 35 years at the time of this report. The affected sons of patients 124 and 212 only showed mild signs of SMA at the age of 10 and 38 years respectively; walking and running were still possible. Diagnosis of SMA was supported by clinical and electrophysiological features.

Psychological aspects The questionnaire concerning the personal attitudes towards having children of their own was sent to 10 families in the German study. It was intended to evaluate the positive aspects of pregnancy in SMA (e.g. fulfilled family life, new perspectives and tasks, activity and distraction) as well as negative arguments against having children (e.g. over-exertion, possible recurrence risk, worsening of muscle weakness). Five females with an age of onset below 17 years decided to give birth to their own children, 2 of whom (nos. 55, 203) would have considered their offspring to be able to manage life with SMA as well. Unplanned pregnancies while being aware of SMA were reported in 2 cases (nos. 82, 134). Three patients had no subjective symptoms up to their first or second pregnancy, so that they had not been faced with this problem. The question "What would you personally advise women with SMA who think about having children?" was answered by 9 females. The majority (5) of them emphasized the great personal value of raising children who were mostly born against medical advice, particularly in 3 early-onset cases (nos. 254, 55,203). The abovementioned positive attitudes expressed by these patients with an onset at age less than 10 years could be related

to the stability of disease, the more of less uneventful deliveries and healthy children. Two women would advise against a patient having her own children, to avoid even the slightest risk of transmitting SMA; the son of patient 212 developed SMA as well; the other patient (no. 108) underwent sterilization after the diagnosis of SMA. Patient 124 felt responsible for her affected son, but, nevertheless, she would rather decide in favour of than against having children. Patient 72 was not in a position to give any advice as her daugther was only a few months old, so she would call her life a "fulfilled exertion".

Discussion

The results of our study suggest a high incidence of obstetrical problems in SMA, which are normally easily treated. No deleterious effects on fetal outcome and development could be confirmed. Recovery after delivery might be delayed, as half of the mothers reported, but in most cases function seemed to be regained sufficiently. Exacerbation of muscle weakness after the second trimester of pregnancy was experienced by the majority (8) of the patients, with lasting disability in 5 (40%) of them. The most striking and consistent deterioration was found in females with a possible autosomal dominant pattern of SMA. Considering the patients with a presumed autosomal recessively inherited SMA we were unable to establish any relation between severity of the disease and a worsening influence of future pregnancies on SMA. It is remarkable that in 5 out of 7 women with an early age of onset of SMA in the first decade of life pregnancy did not promote progression of weakness. No birth order effect could be detected. The patient described by Dietz and Gigon [1] was severely handicapped with her first walking difficulties in her 3rd year of life. Though being chairbound and totally helpless she completed four pregnancies successfully. The infants were born by caesarean section and appeared normal; 3 of them showed a striking hypotonia at birth. One boy died at the age of 3 years suffering from acute myeloic leukaemia and cerebral palsy. The other children were healthy at the age of 3 years, 2 years and several months respectively. The main problems in the successive pregnancies were related to recurrent urinary tract infections necessitating a nephrectomy after the third delivery. The caesarean sections were followed by severe respiratory distress, but the patient recovered soon in the puerperium. The pregnancy of the female presented by Laffargue et al. [2] was well tolerated, despite the severe physical handicap and the reduced respiratory function. The child was born in the 35th week of gestation by caesarean section. The authors could not see any lasting deterioration of SMA during or after pregnancy. In conclusion, pregnancy may have a deleterious effect in SMA as has been documented in detail. Neither age of onset nor course of the disease are useful criteria

30 for predicting any possible aggravation of S M A in pregnancy. W o m e n suffering f r o m proximal S M A who intend to have a family should be informed that preserved abilities might be lost on account of pregnancy and delivery, at least for a certain time, and that assistance in caring for the family could be necessary. Despite the physical burden, the positive aspects of satisfied family life p r e d o m i n a t e d for nearly all females in their retrospective view. T h e y generally would not shrink from raising children on their own. W e believe our investigation (apparently the first with a large series) into the influence of pregnancy in chronic S M A is an important contribution to adequate counselling of w o m e n with SMA. Because of the limited n u m b e r of published reports further studies are necessary to estimate the influence of pregnancy in S M A and other neuromuscular diseases.

Acknowledgement. The study was supported by the Deutsche Forschungsgemeinschaft (Ze 205/2-2).

References 1. Dietz U, Gigon U (1989) Schwangerschaft und Geburt bei chronischer Vorderhornl~ision. Z Geburtshilfe Perinatol 193:155158 2. Laffargue F, Boulot P, Lafont L, Jonquet O, Hedon B, Viala JL (1990) Association maladie de Werdnig-Hoffman et grossesse: ~t propos d'un cas exceptionnel. J Gynecol Obstet Biol Reprod 19 : 321-323 3. Pearn J (1978) Autosomal dominant spinal muscular atrophy. J Neurol Sci 38 : 263-275 4. Rudnik-Sch6neborn S (1990) Proximale spinale Muskelatrophien des frfihen Kindesalters - Diagnostik, Differentialdiagnose und Klassifikation. Medical thesis, University of Bonn 5. Weingarten-Happe A (1990) Klassifikation spinaler Muskelatrophien anhand klinisch-genetischer Kriterien unter besonderer Bert~cksichtigung der proximalen chronischen Formen. Medical thesis, University of Bonn 6. Zerres K (1989) Klassifikation und Genetik spinaler Muskelatrophien. Thieme, Stuttgart NewYork