Effect of alpha-methyldopa administration during pregnancy on the development of a child's sleep

D. CLINICAL SYMPTOMS IN RELATION TO MIDBRAIN AND BRAINSTEM STRUCTURES

Effect of Alpha-Methyldopa Administration during Pregnancy on the Development of a Child's Sleep Masayuki Shimohira, MD, Jun Kohyama, MD, Yutaka Kawano, MD, Hidenori Suzuki, MD, Masakatsu Ogiso, MD and Yoshihide Iwakawa, MD A male infant was born to a mother who had been suffering from primary hyperaldosteronism with the administration of alpha-methyldopa (MD) during pregnancy. His behavioral development, especially that of sleep, was studied by means of sleep-awake rhythm and polysomnography recordings (PSG) from 2 months to 2 years and 5 months of age. His daily sleep-awake rhythm showed some abnormal pattern. As to the PSG, the proportion of each sleep stage was normal and the two types of body movements (BM) showed various patterns. A paradoxical increase was seen in the twitch movement of some muscles. MD affects the cathecolamine system in the CNS and human sleep. Since the sleep-awake rhythm and BM are thought to be related to the monoaminergic system in the CNS, we assume that his behavior and sleep disorders are the effects of the maternal MD administration during pregnancy. Shimohira M, Kohyama J, Kawano Y, Suzuki H, Ogiso M, Iwakawa Y. Effect of alpha-methyldopa administration during pregnancy on the development of a child's sleep. Brain Dev 1986;8: 416-23

Impairment of the neurotransmitters in the early developing brain has been proved to interfere with the normal maturation of behavior and sleep in later life in experimental animals. Though some people belive that this is the case in human beings, no reliable data have been presented. We report here a 3-year-old boy with an abnormal sleep-awake circadian rhythm during

From the Department of Pediatrics, Tokyo Medical and Dental University, Tokyo.

Key words: Alpha-methyldopa, polysomnography, sleep-awake rhythm, body movement, monoaminergic system, autism. Correspondence address: Dr. Masayuki Shimohira, Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113 Japan.

infancy, who was born to a mother who had been suffering from primary hyperaldosteronism with the administration of alphamethyldopa (MD) in addition to some antihypertensive drugs during the pregnancy. Since MD is known as a drug that acts on the CNS, we attempted to clarify the effects of the disturbance of the monoaminergic system in the early developing brain on the behavioral development, especially that of sleep, by studying this case. Case Report A 3-year-old boy. He was admitted to our hospital just after birth because of tachypnea. His mother had been suffering from primary hyperaldostelonism with hypertrophy of the bilateral adrenal glands since 21 years old. She had taken daily antihypertensive drugs such as

at bir th

pregnanc y

o (l

methyldopa

36w

age 4w

======~~21~5 0"fi:::::::l

s pl rono lacton

r--'

~

t,..iamteren hydr a lazine tr ichlormethia~ide

tremor symptoms tachypnea hyponatremia Jaundice medIcation

MD 2,250 mg, teren 150 mg, chlormethiazide throughout the pregnancy, she cesarean section blood pressure.

-..... ~ ~

Fig 1 Clinical course of the patient and his mother.

phenobarbital

spironolacton 225 mg, triamhydralazine 100 mg and tri4 mg since 21 years old and pregnancy. At 36 weeks of gave delivery by means of because of uncontrollable high

At birth the boy was a small-for-date baby, being 1,905 gm in weight and 30 cm in head circumference. The unbilical cord was slightly edematous and the placenta was macroscopically normal. The Apgar score was 8 pOints. He showed tachypnea , cyanosis of the fingernails and tremor in the extremities (about 8-10 Hz). Clock Hour

2400

1200

T. , male.

Fig 2 Sleepawake rhythm.

Shimohira et al: Effect of alpha-methyldopa 417

hours

Table 1 Laboratory data at birth Blood analysis

Red blood cells

540xlO/mnl

Hemoglobin

12. 0 g/ d I

Hematocrit

65 %

White blood cells band form

segmented

S360/Dull 25 % 39

lymphocytes

36

Na

127.8

K

5.7

CI

113

Ca Glc

8.4 106

Mg

2

T.Bil

4.4

Chest X-Ray

I

shadow

16

Brain CT scan at 7 days old

protein

146

glucose culture;

51 negative

Ph PaCO,

total sleep time

14 Q)

7.295 33.4

E

'';:;

PaO, B. E.

-9.4

Q.

HCO,

15.8

en

88.7

HVA·VMA in urine 9th

normal children mean±SD

normal

Blood Gas

5th

patient

Cerebrospinal fluid cell count 213

13th

da

after birth

t

12

Q) Q)

CRP (-)

3rd

t

no abnormal

Abdominal X - Ray

clear fluid

Biochemistry

.....

18

10

* 0.9+0.5 1.0TO.5 control

*: reference 1.

He showed normal Moro, sucking, rooting, grasping reflexes, and normal muscle tone. Laboratory data showed mild hyponatremia and slight metabolic acidosis. The amounts of HVA in 24-hour urine were slightly low for his age [I]. The tachypnea was transient and the cyanosis soon disappeared. Jaundice appeared on the second day and phototherapy was performed for one day. Sodium bicarbonate, vitamin K2, vitamin B6, and magnesium were administered intravenously. He was also given phenobarbital. These drugs showed no effect on his tremor and in fact, the tremor got worse. It reached the peak in frequency on his second day of life. Then it disappeared gradually within 3 weeks. He was discharged in good condition on the 48th day (Fig I, Table I). His postnatal development was good except for his speech ability. He could speak only a few words at 2 years and 5 months old. Examination at 2 years and 2 months old showed subtle choreic movements in the distal extremities and slight hyperactivity. He was left-handed and his personality was timid, i.e. not manly, which is often seen in autistic children. His family reported that he spent most of the day sleeping until about I year old. We studied his sleep characteristics by means of sleep-awake rhythm recording from 2 months to 2 years and 5 months old, the record being performed by his family. During this recording, his daily total amount of sleep was

418 Brain & Development, Vol 8, No 4,1986

8

6 daytime sleep time

4 2

o

3

6

9 12

months old

Fig 3 Duration of whole day sleep time (mean for a week). Both total and daytime sleep time were longer than in normal children. At 12 months old, the sleep time had become almost normal.

comparable to that of a healthy child during infancy, but his daytime sleep was longer and more frequent. At around 10 or 11 months old, his daytime sleep decreased abruptly to the level of normal children. Until 10 months old, the onset time of night sleep had been irregular and had tended to shift backwards (Figs 2,3). Futhermore, we examined the sleep structures by means of polysomnographical recording (pSG). We performed all night sleep PSGs at 9 months, I year and 6 months, and 2 years and 5 months old, respectively. The PSG consisted of EEG from C4 and P4, horizontal

2

4

3

5

6

8

7

9

10

9m awake

REM 1

2 3 4

\~~nJ\It~\r~tL~L~Jr

GM

.lllil

TM

.,,,r,'M"

,I ""

~illl ,dj'lll~ ~ 1,,"I'I~IIII~IIII, IIIJ 1....1,

I.,

,'"" ......... ~" .,,~iI.,~ ••,.J...,dl..• ,

1y 6m awake

REM 1 2 3 4

~~~ I I~, I~IJ~

GM

II

TM

I"" •• " •• "

IlllllHllil1

1.,,11,

,...... J

I~

,J

,I I ,I ,"'..

I

II

,~".,

1~IILI'i

Iii ,Iii

j'I~~I". ",Ij.,~,

2y 5m awake

REM 1 2

3

4

GM

V\~~ , 111

Jtl,

1lllllidlUI, lililLilllll

11~~'.IIILji II I~ ,

TM

",

male

Fig 5 Percentages of sleep stages.

80

9m

ly6m

2y 5m

10 ~ 60

o

.r. 50

-.:-

\ ~

II 40 § 30 c:

p.

20 10

,

I

"+

1 2 3 4 R total 1 2 3 4 R total 1 2 3 4 R total ...-...... patient

stages of sleep

0- - "'0 control

Fig 6 Gross movements. Gross movements of the patient were almost the same as those of the control children.

Fig 4 Three whole night hypnograms at 9 months, 1 year and 6 months, 2 years and 5 months.

EOG from an electrode attached to the outer canthus, and surface EMGs from the mentalis muscle and 4 or more muscles of the trunk and limbs. The sleep stages were determined each minute on the EEG according to the APSS standard. The body movements were classified in to two types on the basis of their distribution over the body parts and the duration of the movements on the surface EMG recordings. The gross movement (GM) comprised movements of the trunk muscles lasting more than 2 seconds. The twitch movement (TM) was that localized in one muscle lasting less than 0.5 seconds. All three PSGs showed that each SREM occupied about 30% of the whole night sleep, and that slow wave sleep amounted to 1420.6% of the whole night sleep. The proportion of each sleep stage was the same as that in normal children as previously reported [2, 3] (Figs 4, 5). The distribution of GMs against each sleep stage showed an almost normal U-shaped pattern except for the frequency in SREM at 9 months old, which was lower than in S2. In contrast to in normal children, the frequency of

Shimohira et al: Effect of alpha-methyldopa 419

9m

170

1 Y 6m

2 Y 5m

extensor muscles of left arm

9m

160

1 y 6m

2y 5m

1 2 3 4 R total

1 2 3 4 R total

• 150

. ~

0

~ 140 ~ 130 ~

c 120

110 100

1 2 3 4 R total

9I

,, ,

90

s tages of sleep

left anterior tibial muscle

I

80

I I

70

•

I

I

~

60

I

t

I

I

50

+ •

40 30 20

~

9m

ly 6m

] 40 E 2 30 20 10

~.

~.

t

t

1 2 3 4 R total

10

2

3

4 Rtotal 1

e _ patient

2 3 4 R to\al 1

0 --- 0

2

3

R total

stages of sleep

control

Fig 7 Twitch movements in mentalis muscle. The frequency in S1 of the patient was lower than in controls.

..-. pat tent

2 y 5m

ly6m

l::LL~ ~ :~ C'O

1

2 3 4 R total

,

2 3 4 R total

,

2 3 4 R total

4 Rtotal

I 2 3 4

+

R total

s tages of sleep

control (mean ± SD )

( n = 10 )

Fig 9 Twitch movements of the extensor muscles of the left arm and left anterior tibial muscle. Various patterns were seen and a paradoxical increase was also seen in the left anterior tibial muscle.

lef t biceps brachii

9m

t

I 2 3

J. 2 y 5m

50

14 ~'" 12

'E '0

ly6m

9m

";::,

1l

2y5m

§8 c:

6

stages of sleep

right biceps brachii

,y 8m

9m

2 y 5m

l~LLj~t I

2 3 4 R total

I

2 3 4 Rtotal

1 2

3 4 Rtotal

stages of sleep

.......... patient

tcontrol ( mean ±SD ) ( n= 10 )

Fig 8 Twitch movements of bilateral biceps brachii

muscles. A paradoxical increase was seen in the right biceps brachii.

GM in the whole night sleep tended to increase with age especially in SREM (Fig 6). The distribution of TMs in the mentalis muscle against each sleep stage showed a normal V-shaped pattern [3,4], except for the

420 Brain & Development, Vol 8, No 4,1986

F

M L

F

M

L

F

M L

e _ above 700 , 0 --0 50° ~ 70° Fig 10 Freequency of rapid eye movements. F; the first one-third of a whole night sleep time, M; the middle one-third of a whole night sleep time, L; the last one-third of a whole night sleep time. The frequency of REMs in SREM was classified into two types; the rising angles of eye movement on the PSG of 50_70° and above 70°.

frequency in Sl which was lower than that in slow wave sleep. A paradoxical increase in the frequency of TMs in whole night sleep with age was also observed (Fig 7). The distribution of TMs of the other muscle

was variable. A paradoxical increase was also seen in the tibialis anterior muscle (Figs 8, 9). We also analyzed the rapid eye movemenUn SREM, dividing one whole night sleep time into three equal parts. The frequency of REMs was classified into two types according to the rising angle of the eye movement on the PSG recording; 50°-70° and over 70°. The frequency of the REMs in this case showed a normal pattern, increasing gradually from the 1st to the 3rd part of whole night sleep (Fig 10). Discussion During the pregnancy and the perinatal period, there were many risk factors in this case such as maternal hyperaldosteronism, hypertention, small-for-date infant, hyponatremia, metabolic acidosis and hyperbilirubinemia. Most of them improved soon after, but these various risk factors may have caused some dysfunction in the developing brain of this case. Moreover, various antihypertensive drugs which were given to his mother during the pregnancy may have had some effect on the eNS of the baby. Among these drugs, MD is especially worthy of attention. MD is taken up the noradrenergic neurons and converted into the active agonist, alphamethyladrenarine, which depletes endogenous cathecolamines by displacing them at the neuronal storage sites [5, 6]. Futhermore, MD interferes with the synthesis of 5-hydroxytryptamine, noradrenarine and dopamine in the eNS, being a decarboxylase inhibitor. It was also confirmed that MD passes through the placenta into the foetus in a high concentration [7] . The above-mentioned pharmacological characteristics of MD gave us the idea that MD may have caused the interference of the monoaminergic system in the baby's eNS during the early developing period. After the analysis of the clinical symptoms and examination data, we became sure of our hypothesis. Tremor in the early neonatal period is observed even in a normal physiological state, besides in pathological states such as hyponatremia, hypocalcemia and polycythemia. The tremor in our case is assumed to be pathological, because it began just after birth, it was severe and frequent, and it continued for several days without any abnormal laboratory data. In this regard, Bodis et al reported that they observed excessive tremor in several babies

born to mothers on MD therapy during pregnancy, and that they gave atropine sulfate to these "iatrogenic Parkinsonism" , babies and concluded that the tremor was due to the reduction in the dopaminergic tone in favour of the cholinergic tone [8]. This report suggests that the tremor in our case was also due to maternal MD. Some authors reported the body characteristics of newborn infants born to mothers treated with MD [9, 10]. These reports stated that the infants had a relatively small head circumference and that a significant difference in neonatal head circumference was only seen for mothers who had been treated between 16 and 20 weeks gestation. In our case, the head circumference, height and weight were all normal at birth, and have since developed at the standard rates. The body movements (BMs) during sleep seen on PSG are thought to be regulated by the cathecolamine system in the eNS [3,4, 11, 12] . We assume that the disturbance of the BMs in this case also reflects the abnormal monoaminergic tone in the eNS. As to the sleep-awake circadian rhythm, a normal baby sleeps almost all day and night except excretion and feeding, Le., it sleeps polyphasically. At 2 months old our case slept mostly polyphasically and since then the length of daytime sleep became longer and his sleepawake circadian rhythm gradually became adult-like. The circadian rhythm of sleep in rodents was proved to be closely related to the suprachiasmatic nucleus. Ibuka et al reported that the destruction of this nucleus resulted in the permanent abolition of the circadian rhythmicity in the sleep-awake cycle, but the daily total and relative amounts of sleep in this state are compatible to these in intact animals [13] . Other reports showed that the disturbance of the brain cathecolamine system during early life with metanphetamine treatment resulted in the abolition of the behavioral circadian rhythm, but it was transient [14]. From the results of these animal experiments and the clinical observation of our case, we assume that the disturbance of the organization of the sleepawake circadian rhythm during infancy in our case might have some relation to the monoamine impairment in his early life, which case the abolition of the sleep-awake circadian rhythmicity, and recovery might occur in later

Shimohira et al: Effect of alpha-methyldopa 421

life. According to some reports on the effects of MD on newborn animal sleep, MD induced the deprivation of paradoxical sleep cPS) during MD administration and a progressive recovery of the PS-ratio was observed after the cessation of the drug in newborn rats [15]. In newborn kittens, it is the same as in rats, and no significant delay in ponderable growth nor acquisition of stereotyped behavior patterns was seen, but the motor coordination was delayed in these kittens [16]. These reports indicate that MD has an effect on the behavioral development of newborn animals as well as their sleep. The destruction of the brain monoaminergic system in early life by means of a pharmacological method was investigated in more detail by others [17, 18]. The increased locomotion of rats in the neonatal and subsequent periods occurred only when the pharmacological treatment was performed in early life . Active sleep deprived rats with chlorimipramine showed the increase in the frequency of the active sleep time and of the strong jerky body movements in adulthood [18]. These phenomena were speculated to be related to the low level of serotonergic inhibition in the CNS. As mentioned above, the BMs during sleep are thought to be regulated by the doparninergic system, and the frequency of BMs gradually decreases with maturation. Taking all these facts into account, we speculate that the paradoxical increase in the BMs in our case at 2 years and 9 months old reflects the postsynaptic supersensitivity of the dopaminergic system to the effect of the maternal MD. Our case suggested that impairment of the brain monoaminergic system in early life may affect the development of both behavior and sleep in human beings. On the other hand, some people hypothesize that disturbance of the monoaminergic system during the early developing period may be related to the causal factor of child autism [19J Also, it is known that one of the early symptoms of child autism is abnormal development of the sleep-awake rhythm, and that there are some age-dependent clinical symptoms of child autism. In this sense, we think that our case is very valuable for understanding of the pathogenasis of autism, and that it is important to follow up the sleep and behavioral development of this case who had some disturbance of the mono-

422 Brain & Development, Vol 8, No 4, 1986

aminergic system in the CNS in early life . Acknowledgment This work was supported by a grant awarded by the Research Committee on the Developmental Neurologic Approach to Early Infantile Au tism chaired by Dr. M. Segawa. We are very grateful to Dr. J. Yata, Professor of the Department of Pediatrics, Tokyo Medical and Dental University, for his help and advice.

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cleation. Brain Res 1977;122 :33-47. 14. Sato M, Fujikawa Y, Ogawa T, Harada T, Ehara T, Bunan K. Experimental study of behavioral anomalies with metamphetamine. In: Segawa M, ed. Annual Report of the Research Committee on the Developmental Neurobiological Approach of Early Infantile Autism (Tokyo) (in Japanese). Tokyo, 1983:83-7. 15. Juvancz P. The sleep of artificially reared newborn rats, effect of alpha-methyl-dopa treatment on paradixocal sleep and on adult behavior. Acta Physiol Acad Sci Hung 1981 ;57: 87-98. 16. Saucier D, Astic L. Effets de l'alpha-methyl-Dopa sur Ie sommeil du chat nouveau-ne. Evolution comportementale au cours du rer mois postnatal. Psychophamacologia (Berl) 1975 ;42:299-

303. 17. Mirmiran M, Van de Poll NE, Corner MA, Van Oyen HG, Bour HL. Suppression of active sleep by chronic treatment with chlorimipramine during early postnatal development: effects upon adult sleep and behavior in the rat. Brain Res 1981;204:129-46. 18. Mirmiran M, Sholtens J, Van de Poll NE, Uylings HBM, Van der Gugten J, Boar GJ. Effects of experimental suppression of active (REM) sleep during early development upon adult brain and behavior in the rat. Dev Brain Res 1983;7 :27786. 19. Segawa M. Neurological approach to early infantile autism (in Japanese). Hattatsu Shogai Kenkyu (Tokyo) 1979;1:189-200.

Shimohira et al: Effect of alpha-methyldopa 423