60
Neurodevelopment in Late Infancy After Prenatal Exposure to Benzodiazepines - A Prospective Study* By L. Laegreid, Gudrun Hagberg and Anita Lundberg Department of Pediatrics II, University of Göteborg, Gothenburg, Sweden
Growth and neurodevelopment at 6, 10 and 18 months of age have been studied prospectively and longitudinally in aseries of 17 children born to mothers who used benzodiazepines (BZD) in therapeutic doses as their only psychotropic drug throughout pregnancy. The results were compared with a group of 29 children born to mothers without any known use of psychotropic drugs. The BZD-exposed children caught up their low mean birth-weight, at an early stage, whereas the slightly decreased head circumference at birth remained at the same low level. In five infants, a pattern of craniofacial anomalies was found. Deviating neurodevelopmental and clinical symptoms and signs were common. The gross motor development was retarded at 6 and 10 months, but was nearly normal at 18 months. Impaired fine motor functions were found on all foIlow-up occasions. At 18 months, the most prominent finding was a delayed development of pincer grasp. The BZD-exposed children showed deviations in muscle tone and pattern of movements more frequently than children in the reference group. The study suggests that the use of BZD in therapeutic doses throughout pregnancy can have negative effects on the development of children up to 18 months of age. The long-term hazards cannot be evaluated from these results. A further foIlow-up at early school age is needed and is in progress.
Keywords Benzodiazepine use - Childhood - Neurodevelopment - Somatic growth
Introduction For more than 30 years benzodiazepines (BZD) have been prescribed on a large scale for the short- and longterm treatment of mental disease, anxiety states, restlessness, and insomnia (5). In recent years greater knowledge of their pharmacokinetics, neurotransmitter release and turnover, and their effects on cellular metabolism has increased our understanding of the action BZD exerts on the CNS (13). Teratogenic
Received December 21, 1990; accepted January 9, 1991 Neuropediatrics 23 (1992) 60-67 © Hippokrates Verlag Stuttgart
This study is the second part of a prospective, longitudinal study of children born to mothers who used BZD as the only psychotropic drug in prescribed doses throughout pregnancy without the use of street drugs or the abuse of alcohol. In the first part, which deals with the newborn period, a tendency to decreased intrauterine growth, and the symptoms and signs of CNS depression as weIl as CNS hyperirritability were shown (24). The aim ofthe present studywas to evaluate the somatic growth and neurodevelopmental outcome of the infants at 6, 10 and 18 months of age.
Material and methods The data were taken from the following two groups of infants: I) Maternal use of BZD (BZD group) and 11) No known maternal use of psychotropic drugs (reference group).
BZDgrouP From May 1984 to August 1986, the doctors at the general maternity outpatient units, the obstetricians at the two delivery departments and the psychiatrists in Gothenburg were asked to inform pregnant mothers using psychotropic drugs about the study and, if they were willing to participate, to refer them to one of us (LL). The referred mothers were interviewed by one of us (LL) prior to delivery about their use of alcohol, cigarettes and prescribed and non-prescribed drugs during pregnancy. Those mothers who reported the regular use of psychotropic drugs without the use oI street drugs (i. e. cocaine, heroin, marijuana, amphetamines) or the abuse of alcohol were included. In this way, 41 mothers were identified, 20 of whom had consumed BZD. Three used BZD in combination with other psychotropic drugs and one delivered a boy with a Zellweger syndrome; these four were excluded from the study. One of the mothers had twins. The BZD group thus comprised 17 children born to 16 mothers. Fifteen of these mothers used oxazepam (15-60 mg daily) or diazepam (5-30 mg daily) alone or in combination and one mother used lorazepam (5-15 mg daily).
* Supported by grants from the Swedish Medical Research Council (grant No. K90-27P-8465-03A), the First of May Flower Annual Campaign for Childrens Health, the Petter Silfverskiöld Memorial Foundation and the Göteborgs Läkaresällskap Research Foundation.
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Abstract
or other prejudicial properties affecting the future development and behavior of the child are discussed (23). The clinical adverse effects of prenatal BZD exposure on newborns have been reported (11, 24, 42).
Neuropediatrics 23 (1992)
Fetal Benzodiazepine Exposure
Referenee group comprised 29 children born to 29 mothers. These mothers were part of a control group in a study which was conducted in order to estimate the frequency of women using psychoactive drugs during pregnancy (41) and to evaluate the development of their children. The control group was randomly selected from three maternity units in Gothenburg. These mothers were interviewed about their use of alcohol, cigarettes and prescribed and non-prescribed drugs in pregnancy. Their urine sampIes were screened in early pregnancy for metabolites of BZD, marijuana, morphine, heroin, amphetamines, alcohol, phenobarbitone, meprobamate, codeine, propoxyphene, salicylic acid and nicotine. Those mothers whose urine was found to be negative and who were not using psychoactive drugs or suffering from recorded psychiatrie disease served as our reference group.
61
growth charts (18). The health records of one child in the refereuce group could not be traced, and single values (especially head circumference) were not noted in a few children.
Minor eraniofaeial anomalies according to a checklist of 10 craniofacial features (29), were systematically recorded in all children in the newborn period and were then rechecked at the follow-up. The checklist included: short nose with low nasal bridge, uptilted nose, slanting eyes, epicanthic foIds, telecanthus, highly arched palate, low set or otherwise abnormal ears, flat upper lips, full lips, and hypoplastic mandible. All these features were recorded by inspection. A cluster of at least 6 such features was classified as dysmorphism.
Charaeteristies ofmothers and infants All the mothers in the BZD group had been diagnosed as having some psychiatrie disease; anxiety disorder in 14 and depression in 2. All the mothers in the reference group were recorded as being healthy. Slightly fewer mothers in the BZD group than in the reference group lived in a stable pair relationship (75 % vs. 93 %). No difference was found in the rate or type of employment between the two groups of mothers. Compared with the reference group, newborns in the BZD group tended to be wasted (low birth-weight for birth length), had significantly more perinatal complications and significantly deviating neuro-behaviour in the newborn period (24). All the children in the BZD group and the reference group were born at term. All the mothers in the BZD group continued their BZD medication after delivery.
Somatie growth was taken from child health records at the regular checks at 6, 10 and 18 months of age and was measured in standard deviation (SD) scores from the mean of Swedish
12 c:::
~
c....,.
The neurologie assessment according to Touwen was used (37). It comprises 30 items which showed a fair differentiation and an evident developmental sequence. They are grouped into 18 items describing posture and motility, and 12 items describing reactions and responses. The manual with its scoring system was strictly followed. The rooting reflexes and the Moro reaction (head-drop method) items were excluded from the analysis because all the children had reached the final change at 6 months of age and the foot sole response item was
-
16 -
:E u
The neurodevelopmental evaluation was performed by one of us (LL). It comprised two parts, one neurologie assessment and one clinical neurologie examination. The children were examined in their hornes with one or both parents present at a chronological age of 6, 10 and 18 months. The number of children who were examined differed somewhat between the age-groups due to unforeseen difficulties in the time schedule and migration from Gothenburg. One child in each group was lost to evaluation. In the BZD group, 14 children were seen on all three occasions, 1 on two and 1 on one occasion (Fig. 1a). In the reference group, 14 children were seen on all three occasions, 11 on two and 3 on one occasion (Fig. 1b).
28
16 8-
0
~
e::s
Z
8
4-
4
o
0 6
~
ID
Age at follow-up (months)
EI
EI One ehild onee 11 One ehild twiee a Fig. 1
~ 14 ehildren 3 times
W
6
Age at follow-up (months) 3 ehildren onee
111
10 ehildren twiee
m One ehild twiee
~
14 ehildren 3 times
b Number of children assessed at 6, 10 and 18 months of age in a) the BZD group and b) the reference group.
~
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N eurodevelopmental evaluation
L. Laegreid et al
Neuropediatrics 23 (1992)
excluded because of the large intraindividual variation. Three items, the ATNR-imposed reflex, the ATNR-spontaneous reflex and the palmar grasp reflexes, were rescored so that the highest score showed a dissolution of the reflexes. Consequently, a higher score always indicated a more mature development. The mean score for each item and the mean total score for each group of items and each group of children were calculated.
0,1
-0,1
o
V)
'-"
-0,3
Cl)
The elinieal neurologie examination was performed to make an overall assessment. It was considered important to identify treatable conditions, such as visual and auditory defects. The parents frequently wanted advice when the child's development was found to be delayed or its behavior unusual. Developmentally delayed children were given priority at daycare-centers for stimulus. The neurologie examination included the recording of cranial nerve function, squint, museIe tone, walking pattern, tremor, pattern of movements in upper extremities. Hypotonus was considered in the case of unusual posture (frog position) and diminished resistance to passive movements and hypertonus was considered when the resistance was increased in the legs and extensor hypertonus was present. Tremor was noted when attempts to grasp objects were jerky and abortive. Movements in the arms and hands were considered slow when anobvious delay in reach out was observed and stereotype when non-constructive repeated movements without purpose were present. It was not possible to perform a blind evaluation of the children in the BZD group as the mothers had been interviewed about their medication before delivery and were thus known to the investigator. The children in the reference group were, however, blindly evaluated as part of another study (41). The Student's t-test was used to test differences in mean scores and the Chi-square test was used to test differences in proportions. A p-value of ~ 0.05 was considered statistically significant. The study was approved by the Medical Ethics Committee at the University of Göteborg. All the parents gave their informed consent.
~
~
a ~
•
-0,5
Weight Height Head circwnference
-0,7 .....- - . - - - -.......... . - - - - -.......- - - - - . - Birth 6 months 10 months 18 months Fig. 2 Differences in mean standard deviation scores for somatic growth between children in the BZD group and the reference group at birth, 6, 10 and 18 months of age.
creased somatic growth compared with the reference group in all measurements except for height at 6 months (nonsignificant). Figure 2 shows the differences in mean SD scores between the BZD group and the reference group from birth to 18 months of age. The children in the BZD group gradually caught up their low mean birth-weight. At 10 and 18 months of age, the mean SD score for height and weight for the BZD group was 0.1 SD scores below the reference group on average and that of head circumference was 0.3 SD scores below the reference group.
Major maljörmations were present in 2 children; 1 child in the BZD group had a hydronephrosis due to pelvo-urethral stenosis which was treated surgically at the age of two weeks, and 1 child in the reference group had a unilateral cleft lip.
Dysmorphism Results
Somatie irowth The mean SD scores for weight, height and head circumference at 6, 10 and 18 months of age are shown in Table 1. On average, the children in the BZD group had a de-
10 n
Mean
16 27
-0.13 0.24
± 1.18 ± 1.09
17 28
0.05 0.15
Height BZD group Reference group
16 27
0.09 0.06
± 1.21
± 1.28
17 28
0.03 0.19
Head circumference BZD group Reference group
15 24
0.74 0.96
± 1.11 ± 1.18
16 25
0.88 1.17
Weight BZD group Reference group
F==r
IqthS
mors
n
I
was found in 5 of the 17 BZD-exposed infants (29 %). The most common craniofacial anomalies were a short nose with a low nasal bridge (5/5), an uptilted nose (5/5), slanting eyes (4/5), epicanthic folds (5/5), low set or abnormal ears (4/5) and a hypoplastic mandible (4/5). Two infants in the reference group had epicanthic folds (7 %) as the only craniofacial anomaly.
Mean
n
Mean
± 1.23 ± 1.04
17 28
0.29 0.39
± 0.95 ± 1.13
± 1.02
± 1.15
17 28
0.10 0.17
± 0.90 ± 1.09
± 1.09 ± 1.01
16 21
0.85 1.13
± 1.05 ± 1.00
Table 1 Means and standard deviations for somatic growth measured in standard deviation scores for children in the BZD group and the reference group at 6, 10 and 18 months of age.
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62
Fetal Benzodiazepine Exposure
Neuropediatrics 23 (1992)
Neurologie assessment The mean total score for posture and motility was significantly lower in the BZD group than in the reference group on all three follow-up occasions (p ~ 0.001, ~ 0.001 and ~ 0.01, respectively) and the mean total score for reactions and responses at 6 months of age (p ~ 0.05) (Tables 2, 3, 4). The differences decreased with age. Significant differences in mean item scores between the two groups of children were found at 6 months in 14 items, at 10 months in 14 and at 18 months in 1 item (Tables 2, 3, 4). Items with highly significant differences (p ~ 0.001) in mean scores between the 2 groups of children are described below.
nantly asymmetrical movements in their arms (scores 1,2) compared with none in the reference group. Two of 14 infants in the BZD group (14 %) compared with 14/15 of the infants in the reference group (93 %) had symmetrical and voluntary movements (scores 4,5).
Goal-directed motility ofarms and hands: 7/14 infants in the BZD group (50 %) had no goal directed motility in their arms and hands (score 0) and 5/14 (36 %) looked and played with their hands or grasped objects without actually getting hold of them (scores 1, 2) compared with none of the infants in the reference group. One of 14 infants in the BZD group (7 %) was able to hold objects in one or both hands (scores 4,5) as compared with 14/15 infants in the reference group (93 %).
Spontaneous posture ofarms: 11/14 infants in the BZD group (79 %) had apredominant flexion or semiflexion posture in their arms (scores 1, 2) compared with none in the reference group, all of whom showed a more mature development with extension or arbitrary postures (scores 3, 4).
and extended arms (scores 5, 6) compared with 9/15 in the reference group (60 %). 10 months (Table 3)
Spontaneous motility ofthe arms: 11/14 infants
Spontaneous motility oflegs in vertical suspension:1/15 infants in the BZD group (7 %) showed an extension
in the BZD group (79 %) had neonatal alternating or predomi-
pattern in its hip and knees (score 3) and 8/15 infants (53 %)
BZO group n = 14 Mean
SO
Reference group n = 15 Mean SO
Posture and motility Spontaneaus posture of the arms Spontaneaus posture of the legs Spontaneaus motility of the arms Spontaneaus motility of the legs Spontaneaus motility of the legs in vertical position Goal-directed motility of arms and hands Type of voluntary grasping Co-ordination of upper extremities Posture of head, trunk and arms in prone position Locomotion in proneposition Rolling over from supine to prone position Rolling back from prone to supine position Spontaneaus head-lifting in supine position Sitting up Ouration of sitting Posture of the trunk during sitting Standing up Walking Total score
1. 71 2.50 1.93 2.43
0.99*** 0.76 1.07*** 0.51 *
3.33 2.60 4.20 2.87
0.49 0.51 0.56 0.35
2.79 1.00 1. 71 0.64
1.12* 1.30*** 0.61 0.74*
3.67 4.20 2.07 1.40
0.82 0.56 0.80 0.74
2.64 1.86 0.71 0.79 1.07 1.21 1.07 0.93 0.43 0.29
0.74*** 1.46** 0.91 0.89 0.83* 0.89* 1.07* 1.14 0.85 0.61
4.40 3.33 0.73 0.67 1.67 1.93 2.20 1.80 0.60 0.53
1.50 1.40 0.59 0.72 0.49 0.70 1.47 1.32 1.06 0.74
25.71
11.78***
42.20
7.68
Reactions and responses ATN R imposed ATN R spontaoeous Palmar grasp reflex Reaction to push against the shoulders when sitting Following of an object with the eyes and rotation of the head when sitti ng Optical placing reaction of the hands Parachute reaction of arms and hands in prone position Optical placing reaction of the feet Acoustic orientation
0.79 0.71 0.43
0.43 0.47 0.51
0.80 0.80 0.60
0.41 0.41 0.50
0.29
0.47**
1.20
1.08
0.64 0.07
1.01 0.27*
1.40 0.47
1.12 0.64
0.14 0.71 1.57
0.36 0.83 0.51 *
0.53 1.00 1.07
0.64 0.65 0.59
Total score
5.36
2.71 *
7.87
3.64
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Posture ofhead, trunk and arms in prone position: None of the 14 BZD infants supported itself on its hands
6 months (Table 2)
Table 2 Means and standard deviations for total scores and item scores for infants in the BZO group and the reference group at 6 months of age. *p ~ 0.05, **p ~ 0.01, ***p ~ 0.001
63
Neuropediatrics 23 (1992)
L. Laegreid et al BZO group n = 15 Mean
SO
Reference group n = 26 Mean SO
Posture and motility Spontaneous posture of the arms Spontaneous posture of the legs Spontaneous motility of the arms Spontaneous motility of the legs Spontaneous motility of the legs in vertical position Goal-directed motility of arms and hands Type of voluntary grasping Co-ordination of upper extremities Posture of head, trunk and arms in prone position Locomotion in prone position Rolling over from supine to prone position Rolling back from prone to supine position Spontaneous head-Iifting in supine position Sitting up Ouration of sitting Posture of the trunk during sitting Standing up Walking Total score
3.33 3.60 3.53 3.67
0.90** 0.51 * 0.74** 0.49**
3.96 3.92 3.96 4.04
0.20 0.27 0.20 0.34
4.47 4.60 3.40 1.53
0.83*** 0.63** 0.63*** 0.52***
5.58 5.12 4.46 1.96
0.64 0.43 0.86 0.20
5.27 4.27 1.60 1.67 1.80 2.93 3.73 3.00 2.20 1.27
1.10*** 1.10* 0.51 ** 1.18* 0.41 0.46 0.46 0.38 1.32 1.16
6.42 4.81 1.96 2.38 1.92 3.00 3.85 3.19 2.96 1.88
0.86 0.49 0.20 0.70 0.39 0.00 0.46 0.49 1.18 1.07
55.87
9.45***
65.38
5.12
lable 3
Means and standard deviations for total scores and item scores for infants in the BZO group and the reference group at 10 months of age. *p ~ 0.05, **p ~ 0.01, ***p ~ 0.001
Reactions and responses ATNR imposed ATN R spontaneous Palmar grasp reflex Reaction to push against the shoulders when sitting Following of an object with the eyes and rotation of the head when sitting Optical placing reaction of the hands Parachute reaction of arms and hands in prone position Optical placing reaction of the feet Acoustic orientation Total score
1.00 1.00 0.67
0.00 0.00 0.49*
1.00 1.00 0.96
0.00 0.00 0.20
2.73
0.59
2.65
0.63
3.13 1.53
0.83** 0.74
3.69 1.88
0.47 0.43
1.53 1.67 1.93
0.74 0.49 0.26
1.88 1.85 1.85
0.43 0.46 0.37
15.20
3.34
16.77
2.44
had predominantly asymmetrical motility in their legs (score 4) compared with 2/26 in the reference group (8 %). Six of 15 infants in the BZD group (40 %) as compared with 24/26 in the reference group (92 %) had predominantly symmetrical motility or predominantly arbitrary movements (scores 5, 6).
Type ofvoluntary grasping: 1/15 infants in the BZD group (7 %) had a radial palmar grasp (score 2) and 7/15 (470/0) had a scissor grasp (score 3) compared with none in the reference group. None of the infants in the BZD group had a pincer grasp (score 6) compared with 6/26 infants in the reference group (23 %).
group. Six of 15 infants in the BZD group (40 %) lifted their head and thorax part of the time without supporting themselves and part of the time supporting themselves on open hands and extended arms (score 5) compared with 6/26 in the reference group (23 %). Five of 15 infants in the BZD group (33 %) supported themselves on their hands and extended arms exclusively (score 6, 7) compared with 20/26 in the reference group (77 %).
18 months ofage (Table 4)
Type ofvoluntary grasping: 3/16 children in the BZD group (19 %) had a radial palmar grasp (score 2) and 1/16 (6 %) had a scissor grasp (score 3) compared with none of the Co-ordination of upper extremities: 7/15 in- infants in the reference group. Five of 16 children in the BZD fants in the BZD group (47 %) had well-directed movements al- group (31 %) had a pincer grasp (score 6) compared with 22/26 though overshooting occurred repeatedly (score 1) compared children in the reference group (85 %). with 1/26 in the reference group (4 %). Eightof 15 infants in the Clinical neurologie examination (Table 5): The BZD group (53 %) had well-directed arm and hand movements BZD group had a consistently lower proportion of normal find(score 2) compared to 25/26 in the reference group (96 %). ings than the reference group. In practically all the items the differences were statistically significant. At 6 months of age 3 inPosture ofhead, trunk and arms in prone posi- fants were considered to have anormal development, at 10 tion: 4/15 infants in the BZD group (27 %) did not support months 8 infants, and at 18 months 9 infants. Five infants themselves on their elbows or hands (swimming position, showed deviations from normality in muscle tone and pattern of score 4) compared with none of the infants in the reference movements on all three follow-up occasions. Füur of these 5
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64
Fetal Benzodiazepine Exposure
Neuropediatrics 23 (1992)
Table 4
BZO group n = 16 Mean
Reference group n = 26 Mean SO
SO
Posture and motility Spontaneous posture of the arms Spontaneous posture of the legs Spontaneous motility of the arms Spontaneous motility of the legs Spontaneous motility of the legs in vertical position Goal-directed motility of arms and hands Type of voluntary grasping Co-ordination of upper extremities Posture of head, trunk and arms in prone position Locomotion in prone position Rolling over from supine to prone position Rolling back from prone to supine position Spontaneous head-Iifting in supine position Sitting up Ouration of sitting Posture of the trunk during sitting Standing up Walking Total score
4.00 4.00 4.38 4.00
0.00 0.00 0.50 0.00
4.00 4.00 5.00 4.00
0.00 0.00 0.00 0.00
5.56 5.25 4.50 1.94
0.73 0.86 1.51 *** 0.25
5.62 5.42 5.81 2.00
0.57 0.70 0.49 0.00
6.31 4.75 2.00 2.88 2.00 3.00 4.00 3.38 3.88 3.75
0.70 0.58 0.00 0.34 0.00 0.00 0.00 0.50 0.34 0.77
6.69 4.85 2.00 3.00 2.00 3.00 4.00 3.62 3.96 3.96
0.47 0.37 0.00 0.00 0.00 0.00 0.00 0.50 0.20 0.20
72.92
2.08
69.56
5.03**
Reactions and responses ATN R im posed ATN R spontaneous Palmar grasp reflex Reaction to push against the shoulders when sitting Following of an object with the eyes and rotation of the head when sitting Optical placing reaction of the hands Parachute reaction of arms and hands in prone position Optical placing reaction of the feet Acoustic orientation Total score
Table 5
Findings at the clinical examination at 6, 10 and 18 months of age. *p ~ 0.05, **p ~ 0.01, ***p ~ 0.001, BZD group vs reference group
1.00 1.00 1.00
0.00 0.00 0.00
1.00 1.00 1.00
0.00 0.00 0.00
3.00
0.00
3.00
0.00
3.94 2.00
0.25 0.00
3.88 2.00
0.33 0.00
2.00 2.00 2.00
0.00 0.00 0.00
2.00 1.77 1.96
0.00 0.51 0.20
17.94
0.25
17.62
0.64
BZO group 6 months n = 14
18 months n = 16
18 months n = 26
Muscle tone Normal Hypotonus Hypertonus
10* 2 3
10* 3 3
14 1 0
25 1 0
25 1 0
0 0 14
0 0 15
10** 5 1
0 0 15
0 3 23
26 0 0
10 4
11* 4
12* 4
15 0
26 0
26 0
15 0 0
26 0 0
25 1 0
4*** 3 7
Walking pattern Normal Immature No walking
Tremor No Present
Movements Normal Siow Stereotype
6*** 5 3
also showed intention tremor in their hands. A squint was found in 2 children in the BZD group. No child had a severe impairment of vision or hearing.
9** 4 2
9*** 5 2
Discussion
To our knowledge, no prospective, longitudinal study of the pattern of growth and neurodevelopment in children born to mothers who used BZD in therapeutic doses throughout pregnancy has previously been reported.
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Means and standard deviations for total scores and item scores for children in the BZO group and the reference group at 18 months of age. **p ~ 0.01, ***p ~ 0.001
65
Neuropediatrics 23 (1992)
Deviant neurodevelopmental and clinical symptoms and signs were common in the BZD children during their first 18 months of life. The most prominent finding was the significant delay in fine motor function found at all ages. At lower ages, difficulties in reaching out to grasp with poorly controlled arm- and hand-motility were common and, at 18 months, an immature pincer grasp was a frequent finding. At 6 months, a delayed sitting balance and a delay in leg control was obvious. The low muscle tone, often found in the newborn period (24), slowly improved and eventually changed to mild hypertonicity in the legs, but the hypotonicity in the arms remained. In these children independent walking was delayed and they displayed an immature broad gait with abducted arms and flexed elbows. Adverse effects on the fetus and the developing child as a result of the maternal use of BZD in pregnancy have been disputed and are difficult to demonstrate. One of the reasons for this is that BZD is often used in combination with other psychoactive substances (35). By selectively including mothers who used BZD as the single psychotropic drug without the simultaneous use of street drugs or the abuse of alcohol, it was possible to control some of these confounding factors. The neurodevelopmental evaluation of the BZD group could not be performed in a blind manner. However, the assessment was considered to have been performed objectively because the items used, according to Touwen (37), indicated a gradual and protracted developmental course, and the manual for assessment was clear and instructive. In addition, our results were supported by a parallel psychometric test using the Griffiths' Mental Developmental Scales, where the psychologist was unaware of- the group to which the specific child belonged (40). Like ours, this study revealed an impaired fine motor function. All the mothers in the BZD group were longterm, regular users of BZD and had been diagnosed as having a psychiatric disorder. It is well-known that maternal depression causes an important adverse effect on the development of children (6). The vast majority of the mothers in our BZD group were not depressed, however, but suffered from an anxiety disorder. They showed emotional instability, excessive concern, overindulgence and anxiety about their children. Psychic illhealth in mothers may cause a disturbed maternal-childinteraction (32) with the risk of a failure-to-thrive situation (21). The BZD children's growth profile, however, argues against maternal deprivation. The children caught up their low birth-weight and reached a near normal level at 10 months of age. There were no large differences in the social situation between the mothers in the BZD group and the reference group, contrasting to mothers using street drugs or abusing alcohol who live in more disorganized families and poor social environments (30, 39). Children of alcoholic mothers - with or without signs of the fetal alcohol syndrome - have been reported as showing the permanent stunting of postnatal growth (22). Decreased fetal head growth has been associated with fetal exposure to many psychotropic agents such as alcohol, anticonvulsants, heroin and cocaine (2, 28, 30, 39). Small head size in young infants has been reported as being a predictor of poor developmental outcome (12) and may be an indicator of the high-risk status of all drug-exposed infants (3), including those exposed to BZD.
L. Laegreid et al
The presence of several clustered minor anOffialies is considered to be a clue to altered embryonic development (29). In our experience, children excessively exposed to BZD in utero, have a pattern of craniofacial anomalies (23), which was also found in 5 of our 17 BZD children exposed to therapeutic doses of BZD. This finding indicates that BZDs have a teratogenic effect, and this is in agreement with the accepted occurrence of dysmorphic features seen in children after prenatal exposure to alcohol (4) and anticonvulsant drugs (14, 16). Lindahl and Michelson (26) found an association between prenatal insults in form of minor congenital anomalies and neurodevelopmental disturbances. Dissociated gross motor development with an advanced fine motor function and normal general development can be considered to be a constitutional problem (27). The deviant gross motor findings in our BZD-exposed children were transient and parallel to a persistent delay in fine motor functions. Transient abnormal gross motor development during the first 18 months of life combined with delayed fine motor functions have been reported in preterms (10) and high-risk infants (9). The perinatal compromising events found in our BZD group were, however, never of the severe type that has been connected with a poor developmental outcome (43). Both the perinatal complications and the deviating neuro-behavior in the newborn period were thought to be explained by the intoxication and withdrawal symptoms of BZD (24). The gross motor skill in preterm infants matures according to their conceptional age, while the fine motor one is retarded (31) and is considered to be delayed sensorimotor development (34). The more primitive goaldirected motility of arms and hands is thought to be mediated by non-cortical structures, i. e. the basal ganglia, brainstem and cerebellum (7), where the highest concentrations of BZD receptors are found in the newborn (15). In his studies of eye-hand co-ordination in healthy infants, Hoßten (17) found that the capacity to catch a moving object develops at a postnatal age of just 18 weeks. The vast majority of the BZD-exposed infants still had a flexion posture in their arms with no goal-directed motility of arms and hands at 6 months of age. The pincer grasp, i. e. the final type of grasping, is considered to be a typical motor-cortical and corticospinal function, thus requiring the more mature devel
Neurodevelopment in Late Infancy After Prenatal Exposure to Benzodiazepines - A Prospective Study* By L. Laegreid, Gudrun Hagberg and Anita Lundberg Department of Pediatrics II, University of Göteborg, Gothenburg, Sweden
Growth and neurodevelopment at 6, 10 and 18 months of age have been studied prospectively and longitudinally in aseries of 17 children born to mothers who used benzodiazepines (BZD) in therapeutic doses as their only psychotropic drug throughout pregnancy. The results were compared with a group of 29 children born to mothers without any known use of psychotropic drugs. The BZD-exposed children caught up their low mean birth-weight, at an early stage, whereas the slightly decreased head circumference at birth remained at the same low level. In five infants, a pattern of craniofacial anomalies was found. Deviating neurodevelopmental and clinical symptoms and signs were common. The gross motor development was retarded at 6 and 10 months, but was nearly normal at 18 months. Impaired fine motor functions were found on all foIlow-up occasions. At 18 months, the most prominent finding was a delayed development of pincer grasp. The BZD-exposed children showed deviations in muscle tone and pattern of movements more frequently than children in the reference group. The study suggests that the use of BZD in therapeutic doses throughout pregnancy can have negative effects on the development of children up to 18 months of age. The long-term hazards cannot be evaluated from these results. A further foIlow-up at early school age is needed and is in progress.
Keywords Benzodiazepine use - Childhood - Neurodevelopment - Somatic growth
Introduction For more than 30 years benzodiazepines (BZD) have been prescribed on a large scale for the short- and longterm treatment of mental disease, anxiety states, restlessness, and insomnia (5). In recent years greater knowledge of their pharmacokinetics, neurotransmitter release and turnover, and their effects on cellular metabolism has increased our understanding of the action BZD exerts on the CNS (13). Teratogenic
Received December 21, 1990; accepted January 9, 1991 Neuropediatrics 23 (1992) 60-67 © Hippokrates Verlag Stuttgart
This study is the second part of a prospective, longitudinal study of children born to mothers who used BZD as the only psychotropic drug in prescribed doses throughout pregnancy without the use of street drugs or the abuse of alcohol. In the first part, which deals with the newborn period, a tendency to decreased intrauterine growth, and the symptoms and signs of CNS depression as weIl as CNS hyperirritability were shown (24). The aim ofthe present studywas to evaluate the somatic growth and neurodevelopmental outcome of the infants at 6, 10 and 18 months of age.
Material and methods The data were taken from the following two groups of infants: I) Maternal use of BZD (BZD group) and 11) No known maternal use of psychotropic drugs (reference group).
BZDgrouP From May 1984 to August 1986, the doctors at the general maternity outpatient units, the obstetricians at the two delivery departments and the psychiatrists in Gothenburg were asked to inform pregnant mothers using psychotropic drugs about the study and, if they were willing to participate, to refer them to one of us (LL). The referred mothers were interviewed by one of us (LL) prior to delivery about their use of alcohol, cigarettes and prescribed and non-prescribed drugs during pregnancy. Those mothers who reported the regular use of psychotropic drugs without the use oI street drugs (i. e. cocaine, heroin, marijuana, amphetamines) or the abuse of alcohol were included. In this way, 41 mothers were identified, 20 of whom had consumed BZD. Three used BZD in combination with other psychotropic drugs and one delivered a boy with a Zellweger syndrome; these four were excluded from the study. One of the mothers had twins. The BZD group thus comprised 17 children born to 16 mothers. Fifteen of these mothers used oxazepam (15-60 mg daily) or diazepam (5-30 mg daily) alone or in combination and one mother used lorazepam (5-15 mg daily).
* Supported by grants from the Swedish Medical Research Council (grant No. K90-27P-8465-03A), the First of May Flower Annual Campaign for Childrens Health, the Petter Silfverskiöld Memorial Foundation and the Göteborgs Läkaresällskap Research Foundation.
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Abstract
or other prejudicial properties affecting the future development and behavior of the child are discussed (23). The clinical adverse effects of prenatal BZD exposure on newborns have been reported (11, 24, 42).
Neuropediatrics 23 (1992)
Fetal Benzodiazepine Exposure
Referenee group comprised 29 children born to 29 mothers. These mothers were part of a control group in a study which was conducted in order to estimate the frequency of women using psychoactive drugs during pregnancy (41) and to evaluate the development of their children. The control group was randomly selected from three maternity units in Gothenburg. These mothers were interviewed about their use of alcohol, cigarettes and prescribed and non-prescribed drugs in pregnancy. Their urine sampIes were screened in early pregnancy for metabolites of BZD, marijuana, morphine, heroin, amphetamines, alcohol, phenobarbitone, meprobamate, codeine, propoxyphene, salicylic acid and nicotine. Those mothers whose urine was found to be negative and who were not using psychoactive drugs or suffering from recorded psychiatrie disease served as our reference group.
61
growth charts (18). The health records of one child in the refereuce group could not be traced, and single values (especially head circumference) were not noted in a few children.
Minor eraniofaeial anomalies according to a checklist of 10 craniofacial features (29), were systematically recorded in all children in the newborn period and were then rechecked at the follow-up. The checklist included: short nose with low nasal bridge, uptilted nose, slanting eyes, epicanthic foIds, telecanthus, highly arched palate, low set or otherwise abnormal ears, flat upper lips, full lips, and hypoplastic mandible. All these features were recorded by inspection. A cluster of at least 6 such features was classified as dysmorphism.
Charaeteristies ofmothers and infants All the mothers in the BZD group had been diagnosed as having some psychiatrie disease; anxiety disorder in 14 and depression in 2. All the mothers in the reference group were recorded as being healthy. Slightly fewer mothers in the BZD group than in the reference group lived in a stable pair relationship (75 % vs. 93 %). No difference was found in the rate or type of employment between the two groups of mothers. Compared with the reference group, newborns in the BZD group tended to be wasted (low birth-weight for birth length), had significantly more perinatal complications and significantly deviating neuro-behaviour in the newborn period (24). All the children in the BZD group and the reference group were born at term. All the mothers in the BZD group continued their BZD medication after delivery.
Somatie growth was taken from child health records at the regular checks at 6, 10 and 18 months of age and was measured in standard deviation (SD) scores from the mean of Swedish
12 c:::
~
c....,.
The neurologie assessment according to Touwen was used (37). It comprises 30 items which showed a fair differentiation and an evident developmental sequence. They are grouped into 18 items describing posture and motility, and 12 items describing reactions and responses. The manual with its scoring system was strictly followed. The rooting reflexes and the Moro reaction (head-drop method) items were excluded from the analysis because all the children had reached the final change at 6 months of age and the foot sole response item was
-
16 -
:E u
The neurodevelopmental evaluation was performed by one of us (LL). It comprised two parts, one neurologie assessment and one clinical neurologie examination. The children were examined in their hornes with one or both parents present at a chronological age of 6, 10 and 18 months. The number of children who were examined differed somewhat between the age-groups due to unforeseen difficulties in the time schedule and migration from Gothenburg. One child in each group was lost to evaluation. In the BZD group, 14 children were seen on all three occasions, 1 on two and 1 on one occasion (Fig. 1a). In the reference group, 14 children were seen on all three occasions, 11 on two and 3 on one occasion (Fig. 1b).
28
16 8-
0
~
e::s
Z
8
4-
4
o
0 6
~
ID
Age at follow-up (months)
EI
EI One ehild onee 11 One ehild twiee a Fig. 1
~ 14 ehildren 3 times
W
6
Age at follow-up (months) 3 ehildren onee
111
10 ehildren twiee
m One ehild twiee
~
14 ehildren 3 times
b Number of children assessed at 6, 10 and 18 months of age in a) the BZD group and b) the reference group.
~
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N eurodevelopmental evaluation
L. Laegreid et al
Neuropediatrics 23 (1992)
excluded because of the large intraindividual variation. Three items, the ATNR-imposed reflex, the ATNR-spontaneous reflex and the palmar grasp reflexes, were rescored so that the highest score showed a dissolution of the reflexes. Consequently, a higher score always indicated a more mature development. The mean score for each item and the mean total score for each group of items and each group of children were calculated.
0,1
-0,1
o
V)
'-"
-0,3
Cl)
The elinieal neurologie examination was performed to make an overall assessment. It was considered important to identify treatable conditions, such as visual and auditory defects. The parents frequently wanted advice when the child's development was found to be delayed or its behavior unusual. Developmentally delayed children were given priority at daycare-centers for stimulus. The neurologie examination included the recording of cranial nerve function, squint, museIe tone, walking pattern, tremor, pattern of movements in upper extremities. Hypotonus was considered in the case of unusual posture (frog position) and diminished resistance to passive movements and hypertonus was considered when the resistance was increased in the legs and extensor hypertonus was present. Tremor was noted when attempts to grasp objects were jerky and abortive. Movements in the arms and hands were considered slow when anobvious delay in reach out was observed and stereotype when non-constructive repeated movements without purpose were present. It was not possible to perform a blind evaluation of the children in the BZD group as the mothers had been interviewed about their medication before delivery and were thus known to the investigator. The children in the reference group were, however, blindly evaluated as part of another study (41). The Student's t-test was used to test differences in mean scores and the Chi-square test was used to test differences in proportions. A p-value of ~ 0.05 was considered statistically significant. The study was approved by the Medical Ethics Committee at the University of Göteborg. All the parents gave their informed consent.
~
~
a ~
•
-0,5
Weight Height Head circwnference
-0,7 .....- - . - - - -.......... . - - - - -.......- - - - - . - Birth 6 months 10 months 18 months Fig. 2 Differences in mean standard deviation scores for somatic growth between children in the BZD group and the reference group at birth, 6, 10 and 18 months of age.
creased somatic growth compared with the reference group in all measurements except for height at 6 months (nonsignificant). Figure 2 shows the differences in mean SD scores between the BZD group and the reference group from birth to 18 months of age. The children in the BZD group gradually caught up their low mean birth-weight. At 10 and 18 months of age, the mean SD score for height and weight for the BZD group was 0.1 SD scores below the reference group on average and that of head circumference was 0.3 SD scores below the reference group.
Major maljörmations were present in 2 children; 1 child in the BZD group had a hydronephrosis due to pelvo-urethral stenosis which was treated surgically at the age of two weeks, and 1 child in the reference group had a unilateral cleft lip.
Dysmorphism Results
Somatie irowth The mean SD scores for weight, height and head circumference at 6, 10 and 18 months of age are shown in Table 1. On average, the children in the BZD group had a de-
10 n
Mean
16 27
-0.13 0.24
± 1.18 ± 1.09
17 28
0.05 0.15
Height BZD group Reference group
16 27
0.09 0.06
± 1.21
± 1.28
17 28
0.03 0.19
Head circumference BZD group Reference group
15 24
0.74 0.96
± 1.11 ± 1.18
16 25
0.88 1.17
Weight BZD group Reference group
F==r
IqthS
mors
n
I
was found in 5 of the 17 BZD-exposed infants (29 %). The most common craniofacial anomalies were a short nose with a low nasal bridge (5/5), an uptilted nose (5/5), slanting eyes (4/5), epicanthic folds (5/5), low set or abnormal ears (4/5) and a hypoplastic mandible (4/5). Two infants in the reference group had epicanthic folds (7 %) as the only craniofacial anomaly.
Mean
n
Mean
± 1.23 ± 1.04
17 28
0.29 0.39
± 0.95 ± 1.13
± 1.02
± 1.15
17 28
0.10 0.17
± 0.90 ± 1.09
± 1.09 ± 1.01
16 21
0.85 1.13
± 1.05 ± 1.00
Table 1 Means and standard deviations for somatic growth measured in standard deviation scores for children in the BZD group and the reference group at 6, 10 and 18 months of age.
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62
Fetal Benzodiazepine Exposure
Neuropediatrics 23 (1992)
Neurologie assessment The mean total score for posture and motility was significantly lower in the BZD group than in the reference group on all three follow-up occasions (p ~ 0.001, ~ 0.001 and ~ 0.01, respectively) and the mean total score for reactions and responses at 6 months of age (p ~ 0.05) (Tables 2, 3, 4). The differences decreased with age. Significant differences in mean item scores between the two groups of children were found at 6 months in 14 items, at 10 months in 14 and at 18 months in 1 item (Tables 2, 3, 4). Items with highly significant differences (p ~ 0.001) in mean scores between the 2 groups of children are described below.
nantly asymmetrical movements in their arms (scores 1,2) compared with none in the reference group. Two of 14 infants in the BZD group (14 %) compared with 14/15 of the infants in the reference group (93 %) had symmetrical and voluntary movements (scores 4,5).
Goal-directed motility ofarms and hands: 7/14 infants in the BZD group (50 %) had no goal directed motility in their arms and hands (score 0) and 5/14 (36 %) looked and played with their hands or grasped objects without actually getting hold of them (scores 1, 2) compared with none of the infants in the reference group. One of 14 infants in the BZD group (7 %) was able to hold objects in one or both hands (scores 4,5) as compared with 14/15 infants in the reference group (93 %).
Spontaneous posture ofarms: 11/14 infants in the BZD group (79 %) had apredominant flexion or semiflexion posture in their arms (scores 1, 2) compared with none in the reference group, all of whom showed a more mature development with extension or arbitrary postures (scores 3, 4).
and extended arms (scores 5, 6) compared with 9/15 in the reference group (60 %). 10 months (Table 3)
Spontaneous motility ofthe arms: 11/14 infants
Spontaneous motility oflegs in vertical suspension:1/15 infants in the BZD group (7 %) showed an extension
in the BZD group (79 %) had neonatal alternating or predomi-
pattern in its hip and knees (score 3) and 8/15 infants (53 %)
BZO group n = 14 Mean
SO
Reference group n = 15 Mean SO
Posture and motility Spontaneaus posture of the arms Spontaneaus posture of the legs Spontaneaus motility of the arms Spontaneaus motility of the legs Spontaneaus motility of the legs in vertical position Goal-directed motility of arms and hands Type of voluntary grasping Co-ordination of upper extremities Posture of head, trunk and arms in prone position Locomotion in proneposition Rolling over from supine to prone position Rolling back from prone to supine position Spontaneaus head-lifting in supine position Sitting up Ouration of sitting Posture of the trunk during sitting Standing up Walking Total score
1. 71 2.50 1.93 2.43
0.99*** 0.76 1.07*** 0.51 *
3.33 2.60 4.20 2.87
0.49 0.51 0.56 0.35
2.79 1.00 1. 71 0.64
1.12* 1.30*** 0.61 0.74*
3.67 4.20 2.07 1.40
0.82 0.56 0.80 0.74
2.64 1.86 0.71 0.79 1.07 1.21 1.07 0.93 0.43 0.29
0.74*** 1.46** 0.91 0.89 0.83* 0.89* 1.07* 1.14 0.85 0.61
4.40 3.33 0.73 0.67 1.67 1.93 2.20 1.80 0.60 0.53
1.50 1.40 0.59 0.72 0.49 0.70 1.47 1.32 1.06 0.74
25.71
11.78***
42.20
7.68
Reactions and responses ATN R imposed ATN R spontaoeous Palmar grasp reflex Reaction to push against the shoulders when sitting Following of an object with the eyes and rotation of the head when sitti ng Optical placing reaction of the hands Parachute reaction of arms and hands in prone position Optical placing reaction of the feet Acoustic orientation
0.79 0.71 0.43
0.43 0.47 0.51
0.80 0.80 0.60
0.41 0.41 0.50
0.29
0.47**
1.20
1.08
0.64 0.07
1.01 0.27*
1.40 0.47
1.12 0.64
0.14 0.71 1.57
0.36 0.83 0.51 *
0.53 1.00 1.07
0.64 0.65 0.59
Total score
5.36
2.71 *
7.87
3.64
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Posture ofhead, trunk and arms in prone position: None of the 14 BZD infants supported itself on its hands
6 months (Table 2)
Table 2 Means and standard deviations for total scores and item scores for infants in the BZO group and the reference group at 6 months of age. *p ~ 0.05, **p ~ 0.01, ***p ~ 0.001
63
Neuropediatrics 23 (1992)
L. Laegreid et al BZO group n = 15 Mean
SO
Reference group n = 26 Mean SO
Posture and motility Spontaneous posture of the arms Spontaneous posture of the legs Spontaneous motility of the arms Spontaneous motility of the legs Spontaneous motility of the legs in vertical position Goal-directed motility of arms and hands Type of voluntary grasping Co-ordination of upper extremities Posture of head, trunk and arms in prone position Locomotion in prone position Rolling over from supine to prone position Rolling back from prone to supine position Spontaneous head-Iifting in supine position Sitting up Ouration of sitting Posture of the trunk during sitting Standing up Walking Total score
3.33 3.60 3.53 3.67
0.90** 0.51 * 0.74** 0.49**
3.96 3.92 3.96 4.04
0.20 0.27 0.20 0.34
4.47 4.60 3.40 1.53
0.83*** 0.63** 0.63*** 0.52***
5.58 5.12 4.46 1.96
0.64 0.43 0.86 0.20
5.27 4.27 1.60 1.67 1.80 2.93 3.73 3.00 2.20 1.27
1.10*** 1.10* 0.51 ** 1.18* 0.41 0.46 0.46 0.38 1.32 1.16
6.42 4.81 1.96 2.38 1.92 3.00 3.85 3.19 2.96 1.88
0.86 0.49 0.20 0.70 0.39 0.00 0.46 0.49 1.18 1.07
55.87
9.45***
65.38
5.12
lable 3
Means and standard deviations for total scores and item scores for infants in the BZO group and the reference group at 10 months of age. *p ~ 0.05, **p ~ 0.01, ***p ~ 0.001
Reactions and responses ATNR imposed ATN R spontaneous Palmar grasp reflex Reaction to push against the shoulders when sitting Following of an object with the eyes and rotation of the head when sitting Optical placing reaction of the hands Parachute reaction of arms and hands in prone position Optical placing reaction of the feet Acoustic orientation Total score
1.00 1.00 0.67
0.00 0.00 0.49*
1.00 1.00 0.96
0.00 0.00 0.20
2.73
0.59
2.65
0.63
3.13 1.53
0.83** 0.74
3.69 1.88
0.47 0.43
1.53 1.67 1.93
0.74 0.49 0.26
1.88 1.85 1.85
0.43 0.46 0.37
15.20
3.34
16.77
2.44
had predominantly asymmetrical motility in their legs (score 4) compared with 2/26 in the reference group (8 %). Six of 15 infants in the BZD group (40 %) as compared with 24/26 in the reference group (92 %) had predominantly symmetrical motility or predominantly arbitrary movements (scores 5, 6).
Type ofvoluntary grasping: 1/15 infants in the BZD group (7 %) had a radial palmar grasp (score 2) and 7/15 (470/0) had a scissor grasp (score 3) compared with none in the reference group. None of the infants in the BZD group had a pincer grasp (score 6) compared with 6/26 infants in the reference group (23 %).
group. Six of 15 infants in the BZD group (40 %) lifted their head and thorax part of the time without supporting themselves and part of the time supporting themselves on open hands and extended arms (score 5) compared with 6/26 in the reference group (23 %). Five of 15 infants in the BZD group (33 %) supported themselves on their hands and extended arms exclusively (score 6, 7) compared with 20/26 in the reference group (77 %).
18 months ofage (Table 4)
Type ofvoluntary grasping: 3/16 children in the BZD group (19 %) had a radial palmar grasp (score 2) and 1/16 (6 %) had a scissor grasp (score 3) compared with none of the Co-ordination of upper extremities: 7/15 in- infants in the reference group. Five of 16 children in the BZD fants in the BZD group (47 %) had well-directed movements al- group (31 %) had a pincer grasp (score 6) compared with 22/26 though overshooting occurred repeatedly (score 1) compared children in the reference group (85 %). with 1/26 in the reference group (4 %). Eightof 15 infants in the Clinical neurologie examination (Table 5): The BZD group (53 %) had well-directed arm and hand movements BZD group had a consistently lower proportion of normal find(score 2) compared to 25/26 in the reference group (96 %). ings than the reference group. In practically all the items the differences were statistically significant. At 6 months of age 3 inPosture ofhead, trunk and arms in prone posi- fants were considered to have anormal development, at 10 tion: 4/15 infants in the BZD group (27 %) did not support months 8 infants, and at 18 months 9 infants. Five infants themselves on their elbows or hands (swimming position, showed deviations from normality in muscle tone and pattern of score 4) compared with none of the infants in the reference movements on all three follow-up occasions. Füur of these 5
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64
Fetal Benzodiazepine Exposure
Neuropediatrics 23 (1992)
Table 4
BZO group n = 16 Mean
Reference group n = 26 Mean SO
SO
Posture and motility Spontaneous posture of the arms Spontaneous posture of the legs Spontaneous motility of the arms Spontaneous motility of the legs Spontaneous motility of the legs in vertical position Goal-directed motility of arms and hands Type of voluntary grasping Co-ordination of upper extremities Posture of head, trunk and arms in prone position Locomotion in prone position Rolling over from supine to prone position Rolling back from prone to supine position Spontaneous head-Iifting in supine position Sitting up Ouration of sitting Posture of the trunk during sitting Standing up Walking Total score
4.00 4.00 4.38 4.00
0.00 0.00 0.50 0.00
4.00 4.00 5.00 4.00
0.00 0.00 0.00 0.00
5.56 5.25 4.50 1.94
0.73 0.86 1.51 *** 0.25
5.62 5.42 5.81 2.00
0.57 0.70 0.49 0.00
6.31 4.75 2.00 2.88 2.00 3.00 4.00 3.38 3.88 3.75
0.70 0.58 0.00 0.34 0.00 0.00 0.00 0.50 0.34 0.77
6.69 4.85 2.00 3.00 2.00 3.00 4.00 3.62 3.96 3.96
0.47 0.37 0.00 0.00 0.00 0.00 0.00 0.50 0.20 0.20
72.92
2.08
69.56
5.03**
Reactions and responses ATN R im posed ATN R spontaneous Palmar grasp reflex Reaction to push against the shoulders when sitting Following of an object with the eyes and rotation of the head when sitting Optical placing reaction of the hands Parachute reaction of arms and hands in prone position Optical placing reaction of the feet Acoustic orientation Total score
Table 5
Findings at the clinical examination at 6, 10 and 18 months of age. *p ~ 0.05, **p ~ 0.01, ***p ~ 0.001, BZD group vs reference group
1.00 1.00 1.00
0.00 0.00 0.00
1.00 1.00 1.00
0.00 0.00 0.00
3.00
0.00
3.00
0.00
3.94 2.00
0.25 0.00
3.88 2.00
0.33 0.00
2.00 2.00 2.00
0.00 0.00 0.00
2.00 1.77 1.96
0.00 0.51 0.20
17.94
0.25
17.62
0.64
BZO group 6 months n = 14
18 months n = 16
18 months n = 26
Muscle tone Normal Hypotonus Hypertonus
10* 2 3
10* 3 3
14 1 0
25 1 0
25 1 0
0 0 14
0 0 15
10** 5 1
0 0 15
0 3 23
26 0 0
10 4
11* 4
12* 4
15 0
26 0
26 0
15 0 0
26 0 0
25 1 0
4*** 3 7
Walking pattern Normal Immature No walking
Tremor No Present
Movements Normal Siow Stereotype
6*** 5 3
also showed intention tremor in their hands. A squint was found in 2 children in the BZD group. No child had a severe impairment of vision or hearing.
9** 4 2
9*** 5 2
Discussion
To our knowledge, no prospective, longitudinal study of the pattern of growth and neurodevelopment in children born to mothers who used BZD in therapeutic doses throughout pregnancy has previously been reported.
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Means and standard deviations for total scores and item scores for children in the BZO group and the reference group at 18 months of age. **p ~ 0.01, ***p ~ 0.001
65
Neuropediatrics 23 (1992)
Deviant neurodevelopmental and clinical symptoms and signs were common in the BZD children during their first 18 months of life. The most prominent finding was the significant delay in fine motor function found at all ages. At lower ages, difficulties in reaching out to grasp with poorly controlled arm- and hand-motility were common and, at 18 months, an immature pincer grasp was a frequent finding. At 6 months, a delayed sitting balance and a delay in leg control was obvious. The low muscle tone, often found in the newborn period (24), slowly improved and eventually changed to mild hypertonicity in the legs, but the hypotonicity in the arms remained. In these children independent walking was delayed and they displayed an immature broad gait with abducted arms and flexed elbows. Adverse effects on the fetus and the developing child as a result of the maternal use of BZD in pregnancy have been disputed and are difficult to demonstrate. One of the reasons for this is that BZD is often used in combination with other psychoactive substances (35). By selectively including mothers who used BZD as the single psychotropic drug without the simultaneous use of street drugs or the abuse of alcohol, it was possible to control some of these confounding factors. The neurodevelopmental evaluation of the BZD group could not be performed in a blind manner. However, the assessment was considered to have been performed objectively because the items used, according to Touwen (37), indicated a gradual and protracted developmental course, and the manual for assessment was clear and instructive. In addition, our results were supported by a parallel psychometric test using the Griffiths' Mental Developmental Scales, where the psychologist was unaware of- the group to which the specific child belonged (40). Like ours, this study revealed an impaired fine motor function. All the mothers in the BZD group were longterm, regular users of BZD and had been diagnosed as having a psychiatric disorder. It is well-known that maternal depression causes an important adverse effect on the development of children (6). The vast majority of the mothers in our BZD group were not depressed, however, but suffered from an anxiety disorder. They showed emotional instability, excessive concern, overindulgence and anxiety about their children. Psychic illhealth in mothers may cause a disturbed maternal-childinteraction (32) with the risk of a failure-to-thrive situation (21). The BZD children's growth profile, however, argues against maternal deprivation. The children caught up their low birth-weight and reached a near normal level at 10 months of age. There were no large differences in the social situation between the mothers in the BZD group and the reference group, contrasting to mothers using street drugs or abusing alcohol who live in more disorganized families and poor social environments (30, 39). Children of alcoholic mothers - with or without signs of the fetal alcohol syndrome - have been reported as showing the permanent stunting of postnatal growth (22). Decreased fetal head growth has been associated with fetal exposure to many psychotropic agents such as alcohol, anticonvulsants, heroin and cocaine (2, 28, 30, 39). Small head size in young infants has been reported as being a predictor of poor developmental outcome (12) and may be an indicator of the high-risk status of all drug-exposed infants (3), including those exposed to BZD.
L. Laegreid et al
The presence of several clustered minor anOffialies is considered to be a clue to altered embryonic development (29). In our experience, children excessively exposed to BZD in utero, have a pattern of craniofacial anomalies (23), which was also found in 5 of our 17 BZD children exposed to therapeutic doses of BZD. This finding indicates that BZDs have a teratogenic effect, and this is in agreement with the accepted occurrence of dysmorphic features seen in children after prenatal exposure to alcohol (4) and anticonvulsant drugs (14, 16). Lindahl and Michelson (26) found an association between prenatal insults in form of minor congenital anomalies and neurodevelopmental disturbances. Dissociated gross motor development with an advanced fine motor function and normal general development can be considered to be a constitutional problem (27). The deviant gross motor findings in our BZD-exposed children were transient and parallel to a persistent delay in fine motor functions. Transient abnormal gross motor development during the first 18 months of life combined with delayed fine motor functions have been reported in preterms (10) and high-risk infants (9). The perinatal compromising events found in our BZD group were, however, never of the severe type that has been connected with a poor developmental outcome (43). Both the perinatal complications and the deviating neuro-behavior in the newborn period were thought to be explained by the intoxication and withdrawal symptoms of BZD (24). The gross motor skill in preterm infants matures according to their conceptional age, while the fine motor one is retarded (31) and is considered to be delayed sensorimotor development (34). The more primitive goaldirected motility of arms and hands is thought to be mediated by non-cortical structures, i. e. the basal ganglia, brainstem and cerebellum (7), where the highest concentrations of BZD receptors are found in the newborn (15). In his studies of eye-hand co-ordination in healthy infants, Hoßten (17) found that the capacity to catch a moving object develops at a postnatal age of just 18 weeks. The vast majority of the BZD-exposed infants still had a flexion posture in their arms with no goal-directed motility of arms and hands at 6 months of age. The pincer grasp, i. e. the final type of grasping, is considered to be a typical motor-cortical and corticospinal function, thus requiring the more mature devel
