 |
|
 |
|
 |
 |
|
 |
 |
 |
 |
 |
 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PEDIATRICS Vol. 107 No. 1 January 2001, pp. 123-129
,
From the * Department of Pediatrics, Beatrix Children's
Hospital, University Hospital Groningen, Pathology and Laboratory
Medicine, University Hospital Groningen, § Department of Medical
Physiology Section Developmental Neurology, University of Groningen,
Department of Special Education, University of Groningen, Groningen,
The Netherlands.
 |
ABSTRACT |
|---|
Top
Abstract
Results
Discussion
References
|
|---|
Objective. To assess the cognitive abilities in school-aged children who have been exposed to coumarins in utero.
Background. Coumarin derivatives are an effective option for anticoagulant therapy in pregnant women. However, case reports describe anomalies of the fetal central nervous system after in utero exposure to coumarins. It is unclear whether prenatal exposure has an effect on cognitive functioning later in childhood.
Methods. The exposed cohort consisted of 291 children from mothers who were prospectively registered because of coumarin treatment during pregnancy. The nonexposed cohort included 253 age-matched peers. An IQ was estimated using subtests of the Weschler Intelligence Scale for Children-Revised. Educational achievement was examined with tests for reading, spelling, and arithmetic. In addition, schoolteachers were asked to judge performance on language and arithmetic. The observers were not aware of the exposure status of the child.
Results. No differences in mean IQ were found between the
exposed and nonexposed cohort (mean difference: 
1.1; 95% confidence
interval [CI]: 3.2-1.1), but an IQ score below 80 was found in 11 children in the exposed compared with 3 children in the nonexposed
cohort (odds ratio [OR] = 3.1; CI: 0.8-11.6). Regarding the tests
for educational achievement, exposed children as a group performed as
well as nonexposed controls. Exposed boys, in comparison with nonexposed boys, showed a higher frequency of poor performance on
reading (OR = 2.9; CI: 1.1-7.4) and spelling (OR = 2.5; CI: 1.0-6.0).
Conclusion. Cognitive functioning in coumarin-exposed children does not differ from nonexposed controls, but a minority of children seem to be prone to the potential negative effects of coumarins during pregnancy. Key words: IQ, educational achievement, long-term effect, anticoagulants.
Anticoagulation during pregnancy is required for the
treatment of acute thromboembolism and as a prophylactic measure in
high-risk situations to avoid the development of venous or arterial
thromboembolic complications.1 The prescription of
anticoagulants during pregnancy must be carefully considered because of
adverse effects on both mother and child. Heparins have the potential
for causing adverse effects in the mother whereas coumarins may cause
birth defects. In patients with artificial heart valves, the efficacy
of heparin for the prevention of systemic embolism has not been
established and coumarins are an effective option in these
patients.2 Several centers, particularly in Europe, use a
protocol that prescribes heparin during the first trimester of
gestation and from the 36th week until birth, and prescribes coumarins
during the second and third trimester.3,4 Because of
concern about the teratogenic effects of coumarin derivatives, other
centers, especially in the United States, prefer heparin throughout
pregnancy.5,6
Fetal exposure to coumarin derivatives (acenocoumarol, phenprocoumon
and coumadin/warfarin) during the first trimester, especially between 6 and 9 weeks of gestation, has been associated with skeletal deformities
known as warfarin embryopathy.7-9 Exposure at any time
during pregnancy may cause malformations of the fetal central nervous
system.10 Case reports describe optic atrophy, Dandy
Walker malformation, agenesis of the corpus callosum, hydrocephalus,
and mental retardation.11,12 These serious anomalies are
usually diagnosed shortly after birth. It is unclear whether less
severe abnormalities or (minor) dysfunctions become manifest later in
childhood. Only 3 small follow-up studies have investigated long-term
outcome in children who are exposed to coumarins in utero. These
studies report controversial results regarding late sequelae on the
central nervous system.13-15
In the Netherlands, oral anticoagulant therapy in outpatients is
monitored by regional anticoagulation clinics that prospectively register pregnant women who are being treated with coumarin
derivatives. Based on this registry, we performed a large cohort
study to assess late effects in children exposed to coumarins in utero.
The aim of the current analysis is to determine whether prenatal
exposure to coumarin derivatives has adverse effects on intellectual
and educational abilities at school age (8-14 years old).
Participants
Two groups are included in the study: a cohort of children who
were exposed in utero to coumarin derivatives and a cohort of
nonexposed control children. The coumarin-exposed children were the
offspring of mothers registered during pregnancy by Dutch anticoagulation clinics. Inclusion criteria for this cohort were: consent for registration, prescription of coumarin derivatives during
pregnancy, and childbirth between January 1, 1982 and December 31, 1990. Eligible registered women were approached by the anticoagulation clinics, either directly or after consultation with the family's general practitioner. Nonexposed control children, matched for age,
sex, and demographic region (postal code) were approached by regional
vaccination centers. Children with chromosomal defects, including Down
syndrome, were excluded from the study.
The study protocol was approved by the Medical Ethics Committee of the
University Hospital Groningen and all participants gave written
informed consent.
Pregnancy Guideline
The guideline16 of Dutch anticoagulation clinics
regarding anticoagulant therapy during pregnancy recommended to avoid
the prescription of coumarins between 6 and 9 weeks of gestation.
Anticoagulation with heparin was advised in the first trimester of
pregnancy (until approximately the 14th week). During the second and
third trimester, coumarin derivatives were regarded as the drugs of
first choice for long-term anticoagulation; the short-acting derivative
acenocoumarol was preferred. The guideline recommended to substitute
heparin for coumarins from the 36th week onward.
Data Collection
After enrollment, the children had a full physical examination,
including an age-adequate neurologic assessment and anthropometric measurements. To assess cognitive development, we investigated general
intelligence and educational achievement. Cognition was investigated on
a separate day to avoid fatigue and demotivation. The observer
collecting the data was not aware of the exposure status of the child.
Information about pregnancy and delivery, and about interval
complications and educational level of the child, were obtained by
questionnaire. Paternal occupation, classified according to Sixma and
Ultee,17 and maternal education were regarded as measures
of socioeconomic status.
For the exposed cohort, information about indication, period, coumarin
derivative, and prescribed dosage during pregnancy was collected from
the initial registration form together with medical records from
anticoagulation clinics and gynecologists.
Intellectual Ability
Intellectual ability was assessed with the Wechsler Intelligence
Scale for Children-Revised (WISC-R).18 Because of time
constraints, a short version of the WISC-R, consisting of 2 verbal and
2 performance subtests, was used. We chose Vocabulary, Similarities,
Picture Completion, and Object Assembly because they correlate most
highly on verbal understanding and perceptual organization in 2 and 3 factor analyses of a Dutch reference population.19
Regression formulae derived from the Dutch norm data were used to
estimate an IQ. An IQ score below 2 standard deviations of the mean IQ
score of our nonexposed control group (ie, below 80) was defined as low
intelligence.
Educational Achievement
Educational abilities were assessed by short standardized Dutch
tests for reading,20 spelling,21 and
arithmetic.22 Only children Because teachers judge the achievement of children over a longer period
of time, we asked teachers of primary schoolchildren to complete a
school performance index (SPI). The SPI is a questionnaire that
evaluates a child's performance on 7 school subjects; rating is done
in terms of quartile scores comparing the child with classmates. The 7 subjects were combined in 2 clusters: an arithmetic cluster describing
written and mental arithmetic and a language cluster describing
technical reading, reading comprehension, written usage, oral usage,
and spelling.
Statistical Analysis
To control for potential confounding, multiple linear regression
analyses were performed to assess differences between the exposed and
nonexposed cohort regarding IQ and educational achievement. We compared
the frequency of low intelligence and poor performance in the exposed
and nonexposed cohort by means of multiple logistic regression
analysis.
Nonparametric tests (Mann-Whitney U test) were used to
assess differences between the exposed and nonexposed cohort on the 2 clusters of the SPI. The frequency of children scoring in the lowest
quartile of the various school subjects were compared with the help of
multiple logistic regression analysis to adjust for confounding
variables.
Covariates in both the linear and logistic regression models were the
confounders: gestational age, sex, age, paternal education, and
socioeconomic status (maternal education and paternal occupation). In
the analysis of low intelligence, the number of covariates was
restricted to sex, age, and maternal education because of a limited
number of cases. Cognitive outcome was related to coumarin exposure
classified according to period of gestation, mean daily dosage, and
cumulative dosage during pregnancy. The statistical analyses were
conducted at the 5% significance level using the Statistical
Package for the Social Sciences (SPSS, Chicago,
IL).23
Study Population
For the exposed cohort, 451 pregnancies registered by Dutch
anticoagulation clinics were considered for inclusion. Fifty-five women
could not be traced because of incomplete personal data and in 14 cases
the general practitioner discouraged contact with the family. From the
remaining 382 registered mothers, 307 children participated in the
study (response rate: 80%). For the nonexposed cohort, 266 children
were enrolled in the study. Assessment of cognitive development was
conducted in 544 children (291 exposed and 253 nonexposed). Twenty-one
children who participated in the physical examination refused to
cooperate in the cognitive assessment and for 8 children the assessment
of cognition could not be realized during the planned investigation
period. There were no significant differences between the group of
children participating in the cognitive assessment (n = 544) and the complete study population (n = 573)
regarding age, school failure, level of education, and socioeconomic
status. SPI by teachers was completed and returned for 354 children
attending primary school: 191 exposed and 163 nonexposed children
(response rate: 91%).
Characteristics of the children participating in the cognitive
assessment are presented in Table 1.
Gestational age was significantly lower in the exposed cohort, probably
attributable to a higher percentage of labor induction in this cohort
(31%) compared with the nonexposed cohort (13%); risk ratio (RR) = 2.4 (95% confidence interval [CI] 1.7-3.5). Other obstetrical
conditions such as toxemia, pregnancy diabetes, maternal infections,
and asphyxia did not differ between the exposed and nonexposed cohort. The frequency of interval complications of the child, eg, head trauma,
epilepsy, infectious diseases, and long-lasting high fever, was
comparable between both cohorts.
TABLE 1
PARTICIPANTS AND METHODS
11.5 years old were tested
because of standardization of the available tests. For each child
chronologic age was expressed in didactic months (ie, the number of
months the child attended (or could have attended) a school according
to his age). The results of the tests for reading, spelling, and
arithmetic were also expressed in didactic months (test-age). The
child's chronologic age in didactic months subtracted from the
test-age, was used as an indication of the child's educational
performance. Children scoring in the lowest decile were regarded as
poor performers. We used our nonexposed control group to define cutoff
values for the deciles.
RESULTS
Top
Abstract
Results
Discussion
References
Characteristics of Study
Population
Exposure to Coumarin Derivatives (n = 291)
Indications for the prescription of coumarins during pregnancy were treatment (n = 60) and prophylaxis (n = 199) of thromboembolic events, hereditary thrombophilia (n = 10), artificial heart valves (n = 8), and incidental causes like antiphospholipid antibody syndrome, trauma, and surgery (n = 9); for 5 cases the indication could not be traced.
Specific data about the stage of pregnancy at which coumarin exposure occurred could be identified in 266 (91%) children. At the time of conception, 27 mothers were treated with coumarins, whereas 4 used heparin. Conforming to the pregnancy guideline, coumarins were replaced by heparin before the 6th week in 12 of the 27 women. In 13 mothers, heparin was introduced in or after the 6th week, whereas in 2 women coumarin was not replaced by heparin during the first trimester of gestation. In addition, 2 mothers started with coumarin therapy during the first trimester, in the 5th and 8th week respectively, while 8 women started at the end of the first trimester (in the 11th or 12th week). The remaining 229 children were only exposed during the second or third trimester of pregnancy. Of these children, 73 mothers received heparin therapy in the first trimester of gestation.
The duration of in utero exposure to coumarins ranged from 1 to 36 weeks (mean: 16 weeks). The mean length of coumarin therapy was 11 weeks in acute thromboembolism, 18 weeks for prophylaxis of thromboembolism, 20 weeks for hereditary thrombophilia, and 25 weeks for artificial heart valves. In 229 pregnancies, the short-acting coumarin derivative acenocoumarol was prescribed, while 29 mothers used phenprocoumon. Six women switched coumarin derivative during pregnancy and for 2 cases the prescribed derivative was unknown. Data concerning coumarin dosage during pregnancy could be retrieved in 155 (53%) cases; the mean daily dosage was 3.2 ± 1.2 mg (range: 0.65-7.9 mg).
Intellectual Ability
Figure 1 shows the distribution of the IQ of the exposed and nonexposed children. The mean IQ score of the exposed cohort did not differ from that of the nonexposed cohort (Table 2); there was no relation between cumulative dosage of in utero exposure to coumarins and IQ (Fig 2). An IQ score <80 (low intelligence) was found in 11 (4%) children of the exposed cohort; of these children, 3 had an IQ score <70 (range: 65.0-69.2). In the nonexposed cohort, 3 (1%) children had an IQ score <80, all ranging between 70 and 80. Using logistic regression analysis, the odds ratio (OR) for low intelligence in the exposed children was 3.1 (CI: 0.8-11.6). The 11 children with low intelligence were only exposed during the second or third trimester of pregnancy, with a mean duration of 17 weeks (range: 9-22 weeks). Nine of these mothers used acenocoumarol during pregnancy, 1 used phenprocoumon, and in 1 case the derivative could not be traced. In 10 of the 11 children with low intelligence, data on daily dosage were not available. The daily dosage for the mother using phenprocoumon was 3.09 mg.
|
|
|
Educational Achievement
The tests for reading, spelling, and arithmetic showed no differences in educational skills between the exposed and nonexposed children (Table 3). In general, boys performed less well in the reading and spelling tests in comparison to girls. A poor performance (lowest decile) on reading and spelling was found more often in exposed boys compared with nonexposed boys (Table 4). With logistic regression analysis we found an interaction between exposure and male sex for poor performance on reading; ORinteraction = 5.7 (CI: 1.1-31.0). Reading and spelling problems were not related to trimester of exposure or mean daily dosage during pregnancy.
|
|
The arithmetic cluster of the SPI (teacher ratings) showed no significant differences between the exposed and nonexposed cohort (Table 5). On the language cluster, exposed children were rated lower in comparison to classmates than nonexposed children. Logistic regression analysis of the separate language and arithmetic tasks showed that the frequency of children scoring in the lowest quartile did not differ between exposed and nonexposed children.
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Results
Discussion
References
|
|---|
This study, which compares 291 coumarin-exposed and 253 nonexposed children, is the first large cohort study to date assessing long-term cognitive outcome after exposure to coumarins in utero. It shows that the cognitive abilities of exposed children between the ages of 8 to 14 years do not, as a group, differ from the abilities of age-matched nonexposed control children.
Only a few small studies have investigated long-term outcome after prenatal exposure to coumarin derivatives. Wong et al14 performed a follow-up study of 29 children who were exposed prenatally to warfarin. They examined the children at a mean age of 5 years (range: 0.5-11.3 years) and found 2 children with an IQ score between 70 and 90. Another study, which examined 22 warfarin-exposed and 19 nonexposed children, found no differences in physical and mental development at the age of 4 years (range: 1.9-5.6 years).13 In both studies, the majority of children were young (<6 years old) and their mental development was examined with the Griffiths scale, which is a general developmental scale. With increasing age, a child's cognitive abilities grow and deviations can be investigated more reliably. Olthof et al15 assessed the intelligence and educational achievement of 21 coumarin-exposed and 17 control children between 8 and 10 years old. No significant differences between the 2 groups were found. However, in the exposed group 1 child could not be tested because of psychomotor retardation, 3 (14%) children had a low intelligence (IQ <80), and 1 child with a normal IQ score was not able to read, calculate, and write. The authors concluded that the number of children in the study was too small to draw conclusions about a definite effect of prenatal coumarin exposure.
The mean IQ in our study population (n = 544) did not differ between exposed and nonexposed children. We found a higher percentage of low intelligence (IQ score <80) in the exposed cohort (OR = 3.1; CI: 0.8-11.6), but this difference was not significant. From the 573 children who underwent a physical examination, 29 children (16 exposed and 13 nonexposed) did not participate in the assessment of cognitive abilities. One nonexposed (8%) and 4 exposed (25%) children who were not tested attended a school for special education. There are 2 types of special schools in the Netherlands: schools for children with (specific) learning disabilities (LD) and educational problems, and schools for children who are mildly mentally retarded (MMR). A major difference between the 2 school types is that the lower IQs are overrepresented in schools for MMR children, whereas normal IQs prevail in the schools for LD children.24 Two exposed children in our study who did not participate in the cognitive assessment attend a school for MMR children. The other 2 exposed children and the nonexposed child attend a school for LD children. To correct for a possible selection bias, we performed a second analysis in which the children at a school for MMR were pooled with the low intelligence children in our assessment. With logistic regression analysis we found a nearly fourfold (OR = 3.8; CI: 1.1-14.0) increased risk for low intelligence in coumarin-exposed children. In absolute terms, this implies an excess risk for low intelligence in 3 out of 100 coumarin-exposed children.
In literature, anomalies after exposure to coumarins in utero have primarily been described in case studies reported shortly after birth.7-12 Our study population consisted of school-aged children who, with the exception of 2 children, were considered to be normal at birth. One child had been diagnosed neonatally as having warfarin embryopathy, while another child showed symptoms after birth that retrospectively suggested warfarin embryopathy. At follow-up, both children had normal IQs (98 and 101) and performed well at school. In our study, all children with an IQ score below 80 (n = 11) had been exposed to coumarins during the second or third trimester of pregnancy. Four of these children also displayed minor neurologic dysfunctions, including associated movements and dysfunction in fine manipulative abilities. Furthermore, there was no increased incidence of dysmorphic features in the 11 children with an IQ score <80. Unfortunately, data concerning the dosage of coumarins were not available in 10 of the 11 children with a low IQ. So, we refrain from statements about the prevention of developmental delay by dosage restriction.
To assess cognition, we investigated general intelligence and educational abilities. Intellectual ability, measured by the WISC-R, expresses a mastery of higher-order cognitive components, whereas educational abilities like arithmetic are more dependent on lower-order nonstrategic processes. In the present design of the study, we put much effort to include a large population of coumarin-exposed children. Because of time constraints, it was only possible to perform a short version of the WISC-R and short standardized tests of educational abilities. The combination of subtests of the WISC-R was chosen because Dutch research showed this combination gives the best estimation of the total IQ.24 In addition, the tests of educational abilities are used on a large scale in elementary education to evaluate educational achievement.
Our assessment of educational achievement shows that the coumarin-exposed children, as a group, do not differ in educational skills from the nonexposed children. In reading and spelling tests, boys performed at a lower level than girls. This is a well-known phenomenon in literature.25 A poor performance on reading and spelling was found more often in the coumarin-exposed boys compared with the nonexposed boys (ORreading = 2.9; CI: 1.1-7.4) and (ORspelling = 2.5; CI: 1.0-6.0). In addition, the SPI showed a lower mean score on the language cluster in the exposed group. On the SPI, boys in general and exposed boys in particular had the lowest scores. Because rating is done in terms of quartile scores, the SPI does not define learning problems (eg, the lowest decile in a class). The result of both assessments indicate that coumarin-exposed boys have more difficulties with reading and spelling compared with nonexposed boys. The percentage of children attending schools for special education (eg, schools for learning difficulties in children with normal intelligence) was not different between the exposed and nonexposed cohort. Therefore, the reading and spelling problems are mild. The finding that boys are more prone to an exogenous factor, such as coumarin, is in concordance with the commonly reported greater vulnerability of males.26,27
Coumarin derivatives are vitamin K antagonists; they inhibit the vitamin K recycling in the cell. In the nervous system, vitamin K stimulates the activity of at least 2 microsomal enzymes in the sphingolipid pathway.28,29 Sphingolipids (eg, sulfatide) are important structural components of myelin,30 but they also serve as second messengers in intracellular signal transduction pathways.31 Sundaram showed that warfarin administration resulted in a significant reduction of sulfatides in mice brains through inhibition of the activity of galactocerebroside sulfotransferase.32 Another hypothesis about the effect of coumarins on the developing nervous system regards a recently discovered vitamin K-dependent protein, Gas6.33 This growth factor is thought to play an important role in cell migration, axonal pathfinding, cell survival, and neural cell-type determination. Gas6 and its receptor were found to be widely distributed throughout the central nervous system.34 Because the development of the nervous system of the human embryo is dependent on a highly coordinated repertoire of cell division, differentiation, and migration, inhibition of a regulatory growth factor such as Gas6, might cause disorganization of the central nervous system during development.
In this large cohort study, only 20 children were exposed during part of the suggested teratogenic period of 6 to 9 weeks of gestation. Therefore, we cannot confirm or refute the incidence of warfarin embryopathy given in literature. Of the 229 children exposed during part of the second or third trimester, 11 showed a developmental delay (4% of the cohort). Although some children showed to be prone to the potential negative effects of coumarin exposure, cognitive functioning of coumarin-exposed children as a group was not affected. In daily clinical practice, the risks for the child have to be weighed against the risks of the pregnant mother who need anticoagulation. For an evidence-based decision about anticoagulant therapy with either heparin or coumarins during pregnancy, a study regarding the long-term effect for the child of heparin use during pregnancy is urgently required. As we found, an IQ <80 in 11 out of 291 exposed children compared with 3 out of 253 controls, we believe that the risk for developmental delay is no reason not to prescribe coumarins to women when maternal disease necessitates prescription during pregnancy.
| |
ACKNOWLEDGMENTS |
|---|
This study was supported by a grant from the Dutch Heart Association (94.148) and the Praeventiefonds (002824340).
We thank the families and children who participated in the study and the Dutch Federation of Thrombosis Services, the various anticoagulation clinics, and the regional vaccination administrations for their help in approaching eligible participants. Furthermore, we thank M. Siekmans-Koopmann for her administrative assistance and the different hospitals for providing study accommodation. Last but not least, we would like to thank Professor H. S. A. Heymans, Professor F. R. Rosendaal, and L. M. Geven-Boere for their support and critical comments.
| |
FOOTNOTES |
|---|
Received for publication Dec 17, 1999; accepted Jul 14, 2000.
Reprint requests to (P.J.J.S.) Department of Pediatrics, Beatrix Children's Hospital, University Hospital Groningen, Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: p.j.j.sauer{at}bkk.azg.nl
| |
ABBREVIATIONS |
|---|
WISC-R, Wechsler Intelligence Scale for Children-Revised; SPI, school performance index; RR, risk ratio; CI, confidence interval; OR, odds ratio; LD, learning disabilities; MMR, mildy mentally retarded.
| |
REFERENCES |
|---|
|
Top
Abstract
Results
Discussion
References
|
|---|
This article has been cited by other articles:
 |
|
 |
|
  S. M. Bates, I. A. Greer, I. Pabinger, S. Sofaer, and J. Hirsh Venous Thromboembolism, Thrombophilia, Antithrombotic Therapy, and Pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 844S - 886S. [Abstract] [Full Text] [PDF]
|
|
Read all P3Rs
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
||
|
||
Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2001 American Academy of Pediatrics. All rights reserved. |
||
|
||
