18
The Effect ofBenzodiazepines on the Fetus and the Newborn* By Liv Laegreid, Gudrun Hagberg and Anita Lundberg Department of Pediatrics 11, Gothenburg University, Gothenburg, Sweden
The effect of the maternal use of benzodiazepines (BZD) on the fetus and the newborn infant has been studied in a representative series of 17 newborn infants (BZD group). The pregnancy and the perinatal period were characterized by 20 items. On the 2nd day of life, a neurologic investigation was performed and .comprised a total of 38 items, subgrouped into items of reflexes/ reactions, tonus, and other symptoms and signs. An optimum finding for each item was selected. The results were compared with a group of 21 newborns fetally exposed to psychotropic drugs other than BZD (drug group) and a reference group of 29 newborns with no known fetal exposure to drugs. Infants in the BZD group had a lower birth weight for birth length, as compared to hoth the drug group and the reference group. Significant differences in frequency of pre- and perinatal complications and in neuro-behavior between the BZD group and the reference group were found in all groups of items. We conclude that the use of BZD during pregnancy is associated with impaired intrauterine growth and an increased frequency of pre- and perinatal events. It affects the newborn infant neurologically mainly in the form of intoxication and withdrawal symptoms.
Keywords Benzodiazepine use - Pregnancy - Perinatal period - Intrauterine growth retardation - Neuro-behavior
Introduction In recent decades an ever-increasing emphasis has been placed on the child's right to an optimum environment in order to achieve optimum physical and mental development. This right must obviously include the unborn child. Pregnant women are encouraged to live a healthy life including the avoidance of smoking, alcohol and unnecessary medication. Until recently, research on the deleterious effects of drugs during pregnancy has concentrated on the use of narcotics and abuse of al-
This paper is part I of a prospective longitudinal study on children whose mothers have used BZD in prescribed doses throughout pregnancy. The purpose was to study the potential impact of BZD on the newborn by recording preand perinatal events and to evaluate neonatal neurologic conditions in groups of infants with and without fetal exposure to BZD.
Material and methods The data were taken from the following 3 groups of infants with different fetal exposure to psychotropic drugs: I Maternal use of BZD (BZD group); 11 Maternal use of psychotropic drugs other than BZD, i. e. antidepressants, neuroleptics or antiepileptics (drug group) and 111 No known maternal use of psychotropic drugs (reference group). The doctors at the general maternity outpatient unit and the obstetricians at the 2 delivery departments in Gothenburg were asked to inform pregnant mothers using psychotropic drugs about the study and, if they were willing to participate, to referthem to one of us (LL). The studywas started in May 1984 and finished in August 1986. Because no mothers using BZD were r~ferred during the first year from these sources, all the psychiatrists in the city of Gothenburg were also asked to take part. Referred mothers were interviewed 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 of street drugs (i. e. cocaine, heroin, marijuana, amphetamines) or abuse of alcohol were included. In this way 41 mothers were ascertained. At the interview, 20 mothers stated that they consumed BZD. Three used BZD in combination with other psychotropic drugs and one delivered a boy with a Zellweger syndrome, these 4 were excluded from the study. One of the
Received September 11, 1990; accepted September 25, 1990 Neuropediatrics 23 (1992) 18-23 © Hippokrates Verlag Stuttgart
* Supported by grants from the Swedish Medical Research Council (grant No. K90-27P-8465-03A), First of May Flower Annual Campaign for Childrens Health and "Expressen" Prenatal Research Foundation.
Downloaded by: University of British Columbia. Copyrighted material.
Abstract
cohol (14, 27, 34). Benzodiazepines (BZD) constitute the most commonly used psychotropic substances, accounting for 88 % of all the hypnotics/sedatives prescribed in Sweden (3), and are frequently used in pregnancy (4, 11). The suspicion has been voiced that these drugs when used during pregnancy may have teratogenic or other prejudicial properties which affect the future development and behavior of the child (19, 20).
Neuropediatrics 23 (1992)
mothers had twins. TheBZD 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 1 mother lorazepam (5-15 mg daily). Twenty-one mothers stated that they consumed psychotropic drugs other than BZD and their children comprised the drug group. The reference group comprised 29 children born to 29 mothers. These mothers had been randomly selected from 3 maternal welfare centers in Gothenburg as controls in a study, conducted in order to estimate the frequency of women using psychoactive drugs during pregnancy (33) and to evaluate the development of their children. The mothers included had no recorded psychiatrie disease and were all found to be negative for metabolites of BZD, marijuana, morphine, heroin, amphetamines, alcohol, phenobarbitone, meprobamate, codeine, propoxyphene, salicylic acid and nicotine when their urine sampIes were screened in early pregnancy. All the obstetric and neonatal records from the 3 infant groups were carefully reviewed and 8 maternal items and 12 child items were chosen to characterize the pregnancy and the perinatal period (Table 1). Maternal disorder was used in case of chronic disease other than psychiatrie and protracted illness (e. g. severe hyperemesis). Threatened abortion was used in case of uterine bleeding, treatment for premature labor or cerclage. Preeclamptic signs was considered mild when systolic blood pressure was 2 140 or diastolic 2 90 together with proteinuria and severe when systolic blood pressure was 2 160 and diastolic 2 90, both at least on two occasions. Intrauterine
Table 1 Pre- and perinatal period. Deviations from the optimum in individual items according to group of infants.
Item
Maternal Maternal age < 18 or > 30 years Spontaneous abortions Legal abortions Pregnancy number > 4 Maternal disorder (exel. psychiatrie) Threatened abortion Pre-eclamptie signs Placental infaretion Child Labor 24 hours Rupture of membranes > 12 hours Intrauterine asphyxia Presentation other than erown Instrumental delivery No respiration established first min Resuscitation (Apgar ~ 6) Respiratory disturbanee Hemoglobinemia Infeetion work out Hyperbilirubinemia Hypoglycemia
Reference group n = 29 n %
BZD group n = 17a n % 8 3 8 4
50 19 50 25
9 5 11 3
43 24 52 14
9 3 8 2
31 10 28 7
2 1 0 3
13 6 0 19
4 6 2 1
19 29 10 5
4 5 1 0
14 17 3 0
0
0
0
0
0
0
2 6 0 10
12 35 0 59
4 9 0 9
19 43 0 43
3 5 1 8
10 17
1 2 2 1 4 0 0
6 12 12 6 24 0 0
2 2 2 0 2 1 0
10 10 10 0 10 5 0
0 2 1 0 2 1 0
a In maternal items n = 16 beeause of one twin birth
3 28 0 7
3 0 7 3 0
19
asphyxia was considered when fetal heart rate during labor was less than 100 or above 160 beats per minute and/or dip 2 or silent pattern was registered. Respiratory disturbance was considered when there was need of extra oxygen, or cyanotic speIls, grunting, cyanosis or respiratory distress syndrome were present. Hemoglobinemia was defined as Hb less than 140 or above 230 g/l or EVF less than 40 % or above 70 %. Hyperbilirubinemia as tot. bil. > 170 J,lmol/l (BW ~ 1500 g), > 255 J,lmol/l (BW ~ 2500 g), > 340 J,lmol/l (BW > 2500 g) or blood exchange and hypoglycemia as blood sugar < 1.7 mmol/l. Physical growth at birth was measured in standard deviation (SD) scores from the mean of Swedish growth charts (17, 21). All these data had been recorded by persons unaware of this study. The neurologie examination was in all the infants performed by one of us (LL). It was made with the child in a quiet awake or active awake state (Prechtl states 3 and 4) (28). It was not possible to meet the criteria on open eyes in all cases because of frequent drowsiness in the groups exposed to psychotropic drugs. Two newborns, one in the drug group and one in the reference group, were not examined due to unforeseen circumstances and were drop-outs. The neurologie examination thus comprised 65 infants, of whom 60 were examined on the second day after birth and 5 on the third (2 from the BZD group, 2 from the drug group and 1 from the reference group). The neonates were assessed by a standardized quantification of reflexes and spontaneous motor behavior largely based on the Manual of Prechtl and Beitema (28). To further evaluate depression and excitability of the CNS the quality of the following reflexes were judged according to a scoring system by Capute (5): positive support reflex, Moro reflex, assymetric tonic neck reflex (ATNR), symmetrical tonic neck reflex (STNR) in supine position, STNR in prone position and Galant reflex. Head raising in prone position was scored according to Dubowitz (9). Symptoms and signs other than reflexes/reactions and tonus were, with minor modifications, further studied according to a neonatal abstinence scoring system proposed by Finnegan et al (11 ). The examination comprised a total of 38 neurologie and behavioral items (Table 2) grouped into 3 subgroups: reflexes/ reactions (n = 12); tonus (n = 5); and other symptoms and signs (n = 21). It was not possible to perform the evaluation blind in all infants, as the mothers in the BZD group and the drug group were weIl known from the interviews prior to partus. Infants in the reference group were, however, blindly evaluated as part of another study (33). All the mothers in the BZD group were on BZD medication at the time of the examination. In order to avoid unnecessary anxiety in the mothers and to sustain a good contact for the future, we did not perform any biochemical BZD-tests in the newborns. The optimality concept by Prechtl was adopted (29). An optimum finding, according to Touwen (32), was selected for each item. The number of items deviating from the optimum was calculated for each individual and was defined as the deviating score. Differences in deviating scores between the3 groups of children were tested for significance using the nonparametrie Kruskal-Wallis one-way analysis of variance test and between 2 groups with the Mann- Whitney U test (31). Differences in the proportion of deviating findings within individual items between groups of infants were tested for significance using Fisher's exact test for fourfold tables. A p-value ~ 0.05 was considered statistically significant.
Downloaded by: University of British Columbia. Copyrighted material.
The Bffect ofBenzodiazepines on the Fetus and the Newborn
Neuropediatrics 23 (1992)
Liv Laegreid et al
Table 2
Neurologie examination. Deviations from the optimum in individual items aeeording to group of infants. Referenee group n = 28
n
Item
Reflexesjreactions Pos. support reflex absentj vigorous 11 Moro reflex absentjvigorous 7 ATN R exaggerated 9 STN R supine exaggerated 4 STNR prone exaggerated 4 Galant reflex absentjexaggerated 3 No abdominal skin reflex 10 No palmar grasp reflex 1 No plantar grasp reflex 1 No withdrawal reaetion 2 No rooting reflex 1 No optieal blink reflex 12 Tonus Prone-supine asymmetry Side asymmetry No head lifting in prone position Prolonged head lifting in prone pos. No reeoil of fore-arms
** p
The Effect ofBenzodiazepines on the Fetus and the Newborn* By Liv Laegreid, Gudrun Hagberg and Anita Lundberg Department of Pediatrics 11, Gothenburg University, Gothenburg, Sweden
The effect of the maternal use of benzodiazepines (BZD) on the fetus and the newborn infant has been studied in a representative series of 17 newborn infants (BZD group). The pregnancy and the perinatal period were characterized by 20 items. On the 2nd day of life, a neurologic investigation was performed and .comprised a total of 38 items, subgrouped into items of reflexes/ reactions, tonus, and other symptoms and signs. An optimum finding for each item was selected. The results were compared with a group of 21 newborns fetally exposed to psychotropic drugs other than BZD (drug group) and a reference group of 29 newborns with no known fetal exposure to drugs. Infants in the BZD group had a lower birth weight for birth length, as compared to hoth the drug group and the reference group. Significant differences in frequency of pre- and perinatal complications and in neuro-behavior between the BZD group and the reference group were found in all groups of items. We conclude that the use of BZD during pregnancy is associated with impaired intrauterine growth and an increased frequency of pre- and perinatal events. It affects the newborn infant neurologically mainly in the form of intoxication and withdrawal symptoms.
Keywords Benzodiazepine use - Pregnancy - Perinatal period - Intrauterine growth retardation - Neuro-behavior
Introduction In recent decades an ever-increasing emphasis has been placed on the child's right to an optimum environment in order to achieve optimum physical and mental development. This right must obviously include the unborn child. Pregnant women are encouraged to live a healthy life including the avoidance of smoking, alcohol and unnecessary medication. Until recently, research on the deleterious effects of drugs during pregnancy has concentrated on the use of narcotics and abuse of al-
This paper is part I of a prospective longitudinal study on children whose mothers have used BZD in prescribed doses throughout pregnancy. The purpose was to study the potential impact of BZD on the newborn by recording preand perinatal events and to evaluate neonatal neurologic conditions in groups of infants with and without fetal exposure to BZD.
Material and methods The data were taken from the following 3 groups of infants with different fetal exposure to psychotropic drugs: I Maternal use of BZD (BZD group); 11 Maternal use of psychotropic drugs other than BZD, i. e. antidepressants, neuroleptics or antiepileptics (drug group) and 111 No known maternal use of psychotropic drugs (reference group). The doctors at the general maternity outpatient unit and the obstetricians at the 2 delivery departments in Gothenburg were asked to inform pregnant mothers using psychotropic drugs about the study and, if they were willing to participate, to referthem to one of us (LL). The studywas started in May 1984 and finished in August 1986. Because no mothers using BZD were r~ferred during the first year from these sources, all the psychiatrists in the city of Gothenburg were also asked to take part. Referred mothers were interviewed 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 of street drugs (i. e. cocaine, heroin, marijuana, amphetamines) or abuse of alcohol were included. In this way 41 mothers were ascertained. At the interview, 20 mothers stated that they consumed BZD. Three used BZD in combination with other psychotropic drugs and one delivered a boy with a Zellweger syndrome, these 4 were excluded from the study. One of the
Received September 11, 1990; accepted September 25, 1990 Neuropediatrics 23 (1992) 18-23 © Hippokrates Verlag Stuttgart
* Supported by grants from the Swedish Medical Research Council (grant No. K90-27P-8465-03A), First of May Flower Annual Campaign for Childrens Health and "Expressen" Prenatal Research Foundation.
Downloaded by: University of British Columbia. Copyrighted material.
Abstract
cohol (14, 27, 34). Benzodiazepines (BZD) constitute the most commonly used psychotropic substances, accounting for 88 % of all the hypnotics/sedatives prescribed in Sweden (3), and are frequently used in pregnancy (4, 11). The suspicion has been voiced that these drugs when used during pregnancy may have teratogenic or other prejudicial properties which affect the future development and behavior of the child (19, 20).
Neuropediatrics 23 (1992)
mothers had twins. TheBZD 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 1 mother lorazepam (5-15 mg daily). Twenty-one mothers stated that they consumed psychotropic drugs other than BZD and their children comprised the drug group. The reference group comprised 29 children born to 29 mothers. These mothers had been randomly selected from 3 maternal welfare centers in Gothenburg as controls in a study, conducted in order to estimate the frequency of women using psychoactive drugs during pregnancy (33) and to evaluate the development of their children. The mothers included had no recorded psychiatrie disease and were all found to be negative for metabolites of BZD, marijuana, morphine, heroin, amphetamines, alcohol, phenobarbitone, meprobamate, codeine, propoxyphene, salicylic acid and nicotine when their urine sampIes were screened in early pregnancy. All the obstetric and neonatal records from the 3 infant groups were carefully reviewed and 8 maternal items and 12 child items were chosen to characterize the pregnancy and the perinatal period (Table 1). Maternal disorder was used in case of chronic disease other than psychiatrie and protracted illness (e. g. severe hyperemesis). Threatened abortion was used in case of uterine bleeding, treatment for premature labor or cerclage. Preeclamptic signs was considered mild when systolic blood pressure was 2 140 or diastolic 2 90 together with proteinuria and severe when systolic blood pressure was 2 160 and diastolic 2 90, both at least on two occasions. Intrauterine
Table 1 Pre- and perinatal period. Deviations from the optimum in individual items according to group of infants.
Item
Maternal Maternal age < 18 or > 30 years Spontaneous abortions Legal abortions Pregnancy number > 4 Maternal disorder (exel. psychiatrie) Threatened abortion Pre-eclamptie signs Placental infaretion Child Labor 24 hours Rupture of membranes > 12 hours Intrauterine asphyxia Presentation other than erown Instrumental delivery No respiration established first min Resuscitation (Apgar ~ 6) Respiratory disturbanee Hemoglobinemia Infeetion work out Hyperbilirubinemia Hypoglycemia
Reference group n = 29 n %
BZD group n = 17a n % 8 3 8 4
50 19 50 25
9 5 11 3
43 24 52 14
9 3 8 2
31 10 28 7
2 1 0 3
13 6 0 19
4 6 2 1
19 29 10 5
4 5 1 0
14 17 3 0
0
0
0
0
0
0
2 6 0 10
12 35 0 59
4 9 0 9
19 43 0 43
3 5 1 8
10 17
1 2 2 1 4 0 0
6 12 12 6 24 0 0
2 2 2 0 2 1 0
10 10 10 0 10 5 0
0 2 1 0 2 1 0
a In maternal items n = 16 beeause of one twin birth
3 28 0 7
3 0 7 3 0
19
asphyxia was considered when fetal heart rate during labor was less than 100 or above 160 beats per minute and/or dip 2 or silent pattern was registered. Respiratory disturbance was considered when there was need of extra oxygen, or cyanotic speIls, grunting, cyanosis or respiratory distress syndrome were present. Hemoglobinemia was defined as Hb less than 140 or above 230 g/l or EVF less than 40 % or above 70 %. Hyperbilirubinemia as tot. bil. > 170 J,lmol/l (BW ~ 1500 g), > 255 J,lmol/l (BW ~ 2500 g), > 340 J,lmol/l (BW > 2500 g) or blood exchange and hypoglycemia as blood sugar < 1.7 mmol/l. Physical growth at birth was measured in standard deviation (SD) scores from the mean of Swedish growth charts (17, 21). All these data had been recorded by persons unaware of this study. The neurologie examination was in all the infants performed by one of us (LL). It was made with the child in a quiet awake or active awake state (Prechtl states 3 and 4) (28). It was not possible to meet the criteria on open eyes in all cases because of frequent drowsiness in the groups exposed to psychotropic drugs. Two newborns, one in the drug group and one in the reference group, were not examined due to unforeseen circumstances and were drop-outs. The neurologie examination thus comprised 65 infants, of whom 60 were examined on the second day after birth and 5 on the third (2 from the BZD group, 2 from the drug group and 1 from the reference group). The neonates were assessed by a standardized quantification of reflexes and spontaneous motor behavior largely based on the Manual of Prechtl and Beitema (28). To further evaluate depression and excitability of the CNS the quality of the following reflexes were judged according to a scoring system by Capute (5): positive support reflex, Moro reflex, assymetric tonic neck reflex (ATNR), symmetrical tonic neck reflex (STNR) in supine position, STNR in prone position and Galant reflex. Head raising in prone position was scored according to Dubowitz (9). Symptoms and signs other than reflexes/reactions and tonus were, with minor modifications, further studied according to a neonatal abstinence scoring system proposed by Finnegan et al (11 ). The examination comprised a total of 38 neurologie and behavioral items (Table 2) grouped into 3 subgroups: reflexes/ reactions (n = 12); tonus (n = 5); and other symptoms and signs (n = 21). It was not possible to perform the evaluation blind in all infants, as the mothers in the BZD group and the drug group were weIl known from the interviews prior to partus. Infants in the reference group were, however, blindly evaluated as part of another study (33). All the mothers in the BZD group were on BZD medication at the time of the examination. In order to avoid unnecessary anxiety in the mothers and to sustain a good contact for the future, we did not perform any biochemical BZD-tests in the newborns. The optimality concept by Prechtl was adopted (29). An optimum finding, according to Touwen (32), was selected for each item. The number of items deviating from the optimum was calculated for each individual and was defined as the deviating score. Differences in deviating scores between the3 groups of children were tested for significance using the nonparametrie Kruskal-Wallis one-way analysis of variance test and between 2 groups with the Mann- Whitney U test (31). Differences in the proportion of deviating findings within individual items between groups of infants were tested for significance using Fisher's exact test for fourfold tables. A p-value ~ 0.05 was considered statistically significant.
Downloaded by: University of British Columbia. Copyrighted material.
The Bffect ofBenzodiazepines on the Fetus and the Newborn
Neuropediatrics 23 (1992)
Liv Laegreid et al
Table 2
Neurologie examination. Deviations from the optimum in individual items aeeording to group of infants. Referenee group n = 28
n
Item
Reflexesjreactions Pos. support reflex absentj vigorous 11 Moro reflex absentjvigorous 7 ATN R exaggerated 9 STN R supine exaggerated 4 STNR prone exaggerated 4 Galant reflex absentjexaggerated 3 No abdominal skin reflex 10 No palmar grasp reflex 1 No plantar grasp reflex 1 No withdrawal reaetion 2 No rooting reflex 1 No optieal blink reflex 12 Tonus Prone-supine asymmetry Side asymmetry No head lifting in prone position Prolonged head lifting in prone pos. No reeoil of fore-arms
** p
