bmj open · bodil hammer bech (bh)5, and lars henning pedersen (lp)5,6 affiliations 1) department...

For peer review only

Apgar-Score in Children Prenatally Exposed to Antiepileptic

Drugs

Journal: BMJ Open

Manuscript ID: bmjopen-2014-007425

Article Type: Research

Date Submitted by the Author: 10-Dec-2014

Complete List of Authors: Christensen, jakob; Aarhus University Hospital, Neurology Pedersen, Henrik; Research Unit for General Practice, Department of Public Health Kjærsgaard, Maiken; Section for Biostatistics, Department of Public Health, Aarhus University Parner, Erik; Section for Biostatistics, Department of Public Health, Aarhus University Vestergaard, Mogens; Research Unit for General Practice, Department of

Public Health Sørensen, Merete; Aarhus University Hospital, Risskov, Regional Center for Child and Adolescent Psychiatry Olsen, Jørn; Aarhus University, Section for Epidemiology, Department of Public Health Bech, Bodil; Aarhus University, Section for Epidemiology, Department of Public Health Pedersen, Lars; Aarhus University, Section for Epidemiology, Department of Public Health

<b>Primary Subject Heading</b>:

Epidemiology

Secondary Subject Heading: Epidemiology, Neurology, Pharmacology and therapeutics, Reproductive medicine, Paediatrics

Keywords: EPIDEMIOLOGY, Epilepsy < NEUROLOGY, Maternal medicine < OBSTETRICS, Reproductive medicine < GYNAECOLOGY, PERINATOLOGY

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Apgar-Score in Children Prenatally Exposed to Antiepileptic Drugs

_________________________________________________________________________________

Title page


Jakob Christensen (JC)1, Henrik Pedersen (HP)

2, Maiken Ina Siegismund Kjaersgaardy (MK)

3, Erik

Thorlund Parner (EP)3, Mogens Vestergaard (MV)

2, Merete Juul Sørensen (MS)

4, Jørn Olsen (JO)

5,

Bodil Hammer Bech (BH)5, and Lars Henning Pedersen (LP)

5,6

Affiliations

1) Department of Neurology and Clinical Pharmacology, Institute of Clinical Medicine, Aarhus

University Hospital, Aarhus, Denmark

2) Research Unit for General Practice, Department of Public Health, Aarhus, Denmark

3) Section for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark

4) Regional Center for Child and Adolescent Psychiatry, Aarhus University Hospital, Risskov,

Aarhus, Denmark

5) Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark

6) Department of Obstetrics and Gynecology, Institute of Clinical Medicine, Aarhus University

Hospital, Aarhus, Denmark

Words (abstract): 216 (Max 300 words).

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Summary and Key Words

Objectives: It is unknown if prenatal exposure to AEDs increases the risk of low Apgar score in the

offspring.

Setting: Population based study using health registers in Denmark.

Participants: We identified all 677,021 singletons born in Denmark from 1997 to 2008 and linked

Apgar score from the Medical Birth Register with information on the women’s prescriptions for

AEDs during pregnancy from the Danish Register of Medicinal Product Statistics. Results were

adjusted for smoking and maternal age.

Results: Among 2,906 children exposed to AEDs, 55 (1.9%) were born with an Apgar score ≤ 7 as

compared with 8,797 (1.3%) children among 674,115 pregnancies unexposed to AEDs (adjusted

Relative Risk (aRR) = 1.41 (95% confidence interval (95% CI): 1.07 - 1.85). When analyses were

restricted to the 2,215 children born of mothers with epilepsy, the aRR of having a low Apgar score

associated with AED exposure was 1.34 (95% CI: 0.90 - 2.01). There were too few AED exposed

pregnancies of women without epilepsy to allow for adjusted estimates in that sub-cohort.

Conclusions: Prenatal exposure to antiepileptic drugs was associated with an increased risk of

being born with a low Apgar score, but the absolute risk of a low Apgar score was <2%.

Key words: Antiepileptic drugs, pregnancy, Apgar score, epilepsy, epidemiology

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Article summary - Strengths and limitations of this study

- The register study includes all singletons (N = 677,021) born in Denmark from 1997 to

2008.

- The Apgar score from the Medical Birth Register was linked with information on the

women’s prescriptions for AEDs during pregnancy from the Danish Register of Medicinal

Product Statistics.

- AED exposure was associated with a 41% increased risk of having a low Apgar score (≤ 7)

(adjusted Relative Risk (aRR) = 1.41 (95% CI: 1.07 - 1.85).

- The absolute risk following AED exposure in pregnancy was low (<2%).

- AED exposure was based on information from registers and residual confounding may

explain part of the increased risk.

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Background/rationale

The Apgar score evaluates the clinical state of newborn children in a broad sense based on five

physical signs (heart rate, respiratory effort, reflex irritability, muscle tone and colour) present

shortly after birth.1 A total score of 10 indicates that the baby is - at that time - in “its best possible

condition”. The scoring system is an accepted tool for assessing the vitality of newborn infants

worldwide,2, 3

and the Apgar score measured 5 min. after birth is a predictor of neonatal mortality

and several neurological outcomes.4-6

Offspring of women with epilepsy7 and offspring of women

using antiepileptic drugs in pregnancy have been found to have lower Apgar score compared to

offspring of women without epilepsy.7-9

However, low Apgar score is a rare outcome and

associations with AED exposure during pregnancy have been based on a very small number of

pregnancies and therefore have had low statistical precision.

Objectives

We studied the risk of low Apgar score in children prenatally exposed to antiepileptic drugs in a

large cohort of children accounting for confounding factors including epilepsy in the mothers.

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Methods

Study design

This is a population-based cohort study based on all singleton live-born children in Denmark from 1

February 1997 to 31 December 2008. The study used data from the Danish Civil Registration

System, the Danish Medical Birth Registry and the Danish Register of Medicinal Product Statistics.

Setting

Children born in Denmark between February 1997 and 31 December 2008 were identified from the

Danish Medical Birth Registry. Information from the Danish Medical Birth Register and the Danish

Register of Medicinal Product Statistics was linked through the Danish civil registration number

(CPR number) from the Danish Civil Registration System, a unique identification number given to

each citizen living in Denmark.

Participants and study size

All singletons (N = 677,021) born in Denmark from 1997 to 2008.

Variables, data sources and measurement

Medication exposure

The Danish Register of Medicinal Product Statistics holds information on all redeemed

prescriptions since 1 January 1996. Taking AEDs in Denmark require a prescription except for

drugs used in hospitals and they are not included in the register. We included information on all

redeemed prescriptions from 1 January 1996 to 31 December 2008. The exposure window was

defined as 30 days before the estimated day of conception to the day prior to birth. AED exposure

was defined as redemption of prescription for medicines with the Anatomical Therapeutic Codes

(ATC code) N03A (AEDs) and N05BA09 (Clobazam).

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Pregnancies exposed to monotherapy were defined as pregnancies where the mothers had redeemed

prescriptions for only one type of AED, while pregnancies exposed to polytherapy were defined as

pregnancies of mothers who had redeemed prescriptions for more than one type of AED in the

exposure window. For both monotherapy and polytherapy, the mothers may also have redeemed

prescriptions for other types of medicine during pregnancy. The estimated average daily dose of

AEDs was calculated from the total amount of AEDs redeemed during the time from 30 days before

pregnancy until birth divided by the number of days in the same time period. Based on the Defined

Daily Dose (DDD),10

the estimated daily AED dose was dichotomized into high (> 50% of DDD)

and low (≤ 50% of DDD).

Epilepsy and psychiatric disease

The Danish National Hospital Registry holds information on inpatients with epilepsy since 1977

and outpatients from 1995. We used this register to identify mothers diagnosed with epilepsy before

birth of the child (ICD8: 345 and ICD10: G40 and G41).

The Danish Psychiatric Central Research Register was used to identify parents diagnosed with

psychiatric disorders before birth of the child (ICD 8: 290-315 and ICD 10: F00.0-F99.9). We

specifically looked at mothers with substance abuse (ICD 8: 291, 294.3, 303, 304 and ICD 10: F10-

F19) and severe psychiatric disorders (ICD 8: 296.1-296.8, 298.1 and 295 and ICD 10: F30-F31 and

F20).

Pregnancy outcomes

The Danish Medical Birth Registry contains data on new-born children including information on

gestational age and Apgar score at birth (5 min.).

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Statistical methods

We estimated relative risk (RR) of low Apgar score using binomial regression with robust variance

estimation to allow for correlation between pregnancy outcomes within each woman. RRs of low

Apgar score (≤ 7) were adjusted for maternal age (divided into tertiles) and smoking (yes, no).

However, when analyzing individual drugs, there were too few exposed cases to allow for adjusted

estimates. This was also the case for women without epilepsy when we stratified on epilepsy

diagnosis in the mother.

We used multinomial logistic regression to calculate the odds ratio of being born with an Apgar

score ≤ 7 and the odds ratio of being born with an Apgar score 8 – 9, compared to being born with

an Apgar score of 10.

Statistical analyses were performed using Stata 13 (StataCorp, Texas, USA).

Bias

Sensitivity analyses

To minimize confounding by indication, we stratified the main analyses for mothers ever having a

diagnosis of epilepsy identified in the Danish National Hospital Register (i.e. from 1977). In further

analyses, we stratified for having a diagnosis of epilepsy during the five years before conception of

the index pregnancy.

In sensitivity analyses, we excluded women exposed to antipsychotics, antidepressants, and insulin

and insulin analogues (ATC codes: N05A, N06A and A10A).

We analyzed the risk after extending the exposure period from 30 before pregnancy to 180 days

before pregnancy, and we analyzed the risk after excluding, from the control group, women who

had been exposed to AED from 180 days before pregnancy to 30 days before pregnancy but not

during the index pregnancy.

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We restricted the cohort to include families with at least two full siblings and with at least one of

the siblings being born with a low Apgar score. The association with AED exposure in the paired

data was analyzed using conditional logistic regression.

Results

Participants and descriptive data

Out of the 677,021 singletons, 8,852 (1.3%) were born with Apgar score ≤ 7. Characteristics of

study participants are shown in Table 1.

Main results

After adjustment for confounders, children of women using AED during pregnancy (N = 2,906) had

an adjusted RR of 1.41 (95% CI: 1.07 - 1.85) of having a low Apgar at five minutes (≤ 7) when

compared to children of women who did not use AEDs during pregnancy (Table 2).

We also analyzed the adjusted odds ratio (aOR) of being born with an Apgar score ≤ 7 (aOR = 1.47

(95% CI: 1.10 – 1.94)) and the aOR of being born with an Apgar score 8 – 9 (aOR = 1.59 (95% CI:

1.49 – 1.81)) compared to being born with an Apgar score 10 (eTable 1).

When stratified on the mothers’ epilepsy diagnosis prior to birth, the unadjusted RR of having a low

Apgar score following AED exposure was increased by 34% in offspring of women with epilepsy

(RR= 1.34 (95% CI: 0.90 - 2.01)) (Table 3). There were too few cases to estimate the adjusted risk

in offspring of mothers without an epilepsy diagnosis, but the unadjusted estimate was 77%

increased (RR = 1.77 (95% CI: 1.09 - 2.88)) (Table 3).

We found that the crude RR were increased for all types of AED albeit the estimates reached

statistical significance only for use of carbamazepine, valproic acid and topiramate exposure

(eTable 2 and Figure 1).

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We analyzed the outcome after exposure to high and low dose of AEDs (monotherapy only). There

were 1,339 children exposed to high dose of AED among whom 19 (1.4%) had a low Apgar score,

and 1,164 children were exposed to low dose of whom 25 (2.2%) had a low Apgar score. The RR

associated with high AED drug dose was 1.10 (95% CI: 0.71 - 1.72) and aRR associated with low

AED dose was 1.68 (95% CI: 1.14 - 2.48) when compared to unexposed children.

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Other analyses

Sibling analyses

For sibling-pairs, discordant for low Apgar score and AED use (18 women with a total of 50 birth

outcomes), the odds ratio of being born with a low Apgar score for those with AED exposure was

1.21 (95% CI: 0.50 - 2.96).


After excluding 16,090 women exposed to antipsychotics, antidepressants, and insulin and insulin

analogues, the risk of low Apgar score associated with AED exposure was almost identical to the

results of the overall analysis (aRR: 1.46 (95% CI: 1.09 - 1.96)).

We excluded 1,343 women with severe mental disorders from the analysis which attenuated the

association with prenatal AED exposure to aRR: 1.34 (95% CI: 1.01 - 1.79).


before pregnancy which slightly attenuated the risk of low Apgar score associated with AED

exposure (RR: 1.29 (95% CI: 0.99 - 1.68)). After excluding, from the control group, 584

pregnancies exposed to AED from 180 days before pregnancy to 30 days before pregnancy, but not

during the index pregnancy; the estimate of a low Apgar score was almost identical to the overall

analysis (aRR: 1.41 (95% CI: 1.07 - 1.85)).

We stratified the main analyses for mothers having a diagnosis of epilepsy during the five years

before conception of the index pregnancy. The adjusted RR of low Apgar score was 1.22 (95% CI:

0.73- 2.05) for women diagnosed with epilepsy within five years of birth. For women without an

epilepsy diagnosis it was not possible to calculate adjusted RR of low Apgar, but the unadjusted RR

for low Apgar score was 1.92 (95% CI: 1.23 – 2.99) for women without an epilepsy diagnosis

within five years of birth.

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Discussion

Key results

AED exposure in pregnancy was associated with an elevated risk of being born with low Apgar

score (≤ 7), although the absolute risk was low (< 2%).

There are only few studies of Apgar score at birth following exposure to AEDs in pregnancy. A

multicenter study across 25 centers in the United States and United Kingdom of the

Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study found no difference in risk of

low 5 minutes Apgar score when comparing the risk in offspring of women who used

carbamazepine, lamotrigine, phenytoin and valproate8. A Finish register study found no risk of low

5 min. Apgar score associated with overall AED therapy in offspring of women with epilepsy7, but

a more than doubling of the risk associated with valproate exposure. We found increased risks of

low Apgar score at 5 min. following carbamazepine, valproic acid and topiramate exposure, but

number of exposed cases was low.

We also found that AED exposure in pregnancy was associated with an increased risk for the less

severe outcome (i.e. Apgar score 8 – 9). An Apgar score of 8 - 9 have also been associated with

adverse outcome in the affected children.6

Limitations

Even though we studied almost 3,000 exposed pregnancies, only 2% of children exposed to AEDs

were born with an Apgar score ≤ 7. Therefore, unadjusted, residual confounding may account for

some of the risk associated with AED exposure.

The Apgar score was registered at birth with some measurement error, and at that point of time, the

use of AEDs in pregnancy would have been known. However, we have no reason to believe that

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allocation of a specific Apgar score was influenced by the knowledge of the AED exposure during

pregnancy.

The study was based on redeemed prescriptions, and it is not known whether the women actually

took the medication, but compliance with AEDs are generally believed to be good - also when

estimated from register data11

We analyzed all singletons born in Denmark, and loss to follow-up is very unlikely.

Interpretation and generalisability

Low Apgar score at 5 min. has been associated with increased risk of subsequent death 12

, cancer13

,

epilepsy4, 6

or neurologic disability 12, 14

, and is thus an important outcome to consider when

evaluating the risks in pregnancy. However, the majority of surviving babies with low Apgar scores

grow up without disability which should also be taken into account when evaluating the risks of

AED treatment in pregnancy.

Conclusion

Prenatal exposure to antiepileptic drugs was associated with a 41% increased relative risk of low

Apgar score, but the absolute risk was low (<2 %), and may be partly be explained by confounding

by indication.

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Acknowledgements

Dr Christensen receives research support from the Danish Epilepsy Association.

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Author's contributions

All authors initiated the study, obtained funding, and designed the study. MK constructed the

population. HP analysed the data. JC wrote the first draft. All authors interpreted the results,

revised the manuscript, and approved the final version of the manuscript. All authors had access to

all of the data in the study and take responsibility for the integrity of the data and the accuracy of

the data analysis.

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Disclosure of Conflicts of Interest

Dr Christensen reported receiving honoraria for serving on the scientific advisory boards of UCB

Nordic and Eisai AB; receiving lecture honoraria from UCB Nordic and Eisai AB; and receiving

travel funding from UCB Nordic.

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Table 1 Characteristics of study participants

Characteristics Exposed to AED

N = 2,906

Not Exposed to AED

N = 674,115

(n) (%) (n) (%)

Smoking

Yes 780 (26.8) 125,863 (18.7)

No 1,981 (68.2) 527,907 (78.3)

Missing 145 (5.0) 20,345 (3.0)

Maternal age (years)

<21 83 (2.9) 17,991 (2.7)

21-25 476 (16.4) 102,276 (15.2)

26-30 1,044 (35.9) 257,147 (38.1)

31-35 895 (30.8) 214,628 (31.8)

>=36 408 (14.0) 82,072 (12.2)

Missing 0 (0.0) 1 (0.0)

Parity

0 1,367 (47.0) 288,334 (42.8)

>=1 1,538 (52.9) 385,402 (57.2)

Missing 1 (0.0) 379 (0.1)

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Cohabitation

Yes 2,222 (76.5) 553,987 (82.2)

No 670 (23.1) 114,150 (16.9)

Missing 14 (0.5) 5978 (0.9)

Income (%)

0-19 624 (21.5) 118,703 (17.6)

20-39 805 (27.7) 134,876 (20.0)

40-59 600 (20.6) 139,171 (20.6)

60-79 510 (17.5) 141,922 (21.1)

80-100 367 (12.6) 138,736 (20.6)

Maternal education

<10 years 411 (14.1) 57,956 (8.6)

10-12 years 1,066 (36.7) 197,633 (29.3)

>12 years 1,365 (47.0) 402,117 (59.7)

Missing 64 (2.2) 16,409 (2.4)

Drug abuse

Yes 106 (3.6) 2284 (0.3)

No 2,800 (96.4) 671,831 (99.7)

Missing 0 (0.0) 0 (0.0)

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Table 2 Apgar score (≤ 7) in AED exposed and unexposed children

AED

exposure

N (%) Apgar score

≤ 7

n (%)

Apgar score

> 7

n (%)

Relative Risk

Crude

(95 % CI)

Relative Risk

Adjusted*

(95% CI)

Yes 2,906 (100) 55 (1.9) 2,851 (98.1) 1.45 (1.12 - 1.88) 1.41 (1.07 - 1.85)

No 674,115 (100) 8,797 (1.3) 665,318 (98.7) 1.00 (reference) 1.00 (reference)

*Apgar score was adjusted for maternal age and smoking.

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Table 3 Relative risk for Apgar score (≤ 7) in exposed and unexposed children stratified on mother’s diagnosis of epilepsy

Epilepsy AED N (%) Apgar score ≤ 7

n (%)

Apgar score > 7

n (%)

Relative Risk

Crude (95% CI)

Relative Risk

Adjusted* (95% CI)

Yes Yes 2,215 (100) 39 (1.8) 2,176 (98.2) 1.38 (0.94 - 2.04) 1.34 (0.90 - 2.01)

No 5,261 (100) 67 (1.3) 5,194 (98.7) 1.00 (reference) 1.00 (reference)

No Yes 691 (100) 16 (2.3) 675 (97.7) 1.77 (1.09 - 2.88) NA (-)

No 668,854 (100) 8,730 (1.3) 660,124 (98.7) 1.00 (reference) NA (-)

*Apgar score was adjusted for smoking.

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Figure 1

Unadjusted relative risk of low Apgar score (≤ 7) by AED exposure during pregnancy

Unadjusted relative risk of low Apgar score (<=7)

0 1 2 3 4 5 6 7 8

Anti

epil

epti

c d

rug (

AE

D)

exp

osu

re i

n p

regn

ancy

Topiramate (n = 124)

Carbamazepine (n = 401)

Valproic acid (n = 444)

Clonazepam (n = 364)

Oxcarbazepine (n = 397)

Lamotrigine (n = 1134)

Any AED (n = 2949)

Unadjusted relative risk of low Apgar score (<= 7) (95%)

Refernce (unexposed children)

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Technology Assessment Subcommittee of the American Academy of Neurology and

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6. Sun Y, Vestergaard M, Pedersen CB, Christensen J, Olsen J. Apgar scores and long-term

risk of epilepsy. Epidemiology 2006;17(3):296-301.

7. Artama M, Gissler M, Malm H, Ritvanen A. Effects of maternal epilepsy and antiepileptic

drug use during pregnancy on perinatal health in offspring: nationwide, retrospective cohort

study in Finland. Drug Saf 2013;36(5):359-369.

8. Pennell PB, Klein AM, Browning N et al. Differential effects of antiepileptic drugs on

neonatal outcomes. Epilepsy Behav 2012;24(4):449-456.

9. Borthen I, Eide MG, Daltveit AK, Gilhus NE. Delivery outcome of women with epilepsy: a

population-based cohort study. BJOG 2010;117(12):1537-1543.

10. WHO ATC code. 2014. (http://www.whocc.no/atc_ddd_index/)

11. Olesen C, Sondergaard C, Thrane N, Nielsen GL, de Jong-van den Berg, Olsen J. Do

pregnant women report use of dispensed medications? Epidemiology 2001;12(5):497-501.

12. Ehrenstein V, Pedersen L, Grijota M, Nielsen GL, Rothman KJ, Sorensen HT. Association

of Apgar score at five minutes with long-term neurologic disability and cognitive function in

a prevalence study of Danish conscripts. BMC Pregnancy Childbirth 2009;9:14. doi:

10.1186/1471-2393-9-14.:14-19.

13. Li J, Cnattingus S, Gissler M et al. The 5-minute Apgar score as a predictor of childhood

cancer: a population-based cohort study in five million children. BMJ Open

2012;2(4):e001095.

14. Li J, Olsen J, Vestergaard M, Obel C. Low Apgar scores and risk of childhood attention

deficit hyperactivity disorder. J Pediatr 2011;158(5):775-779.

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eTable 1 Odds Ratio of being born with an Apgar score of ≤ 7 and an Apgar score of 8-9 compared with an Apgar score of 10 for exposed and

unexposed children

Agar Score

≤ 7 10

Crude OR

(95 % CI)

Adjusted OR*

(95 % CI)

AED Yes 55 ( %) 2,582 ( %) 1,51 (1.15 – 1.97) 1.47 (1.10 – 1.94)

No 8,797 ( %) 624,237 ( %) 1.00 (reference) 1.00 (reference)

Apgar Score

8 - 9 10

Crude OR

(95 % CI)

Adjusted OR*

(95 % CI)

AED Yes 269 ( %) 2,582 ( %) 1.58 (1.39 – 1.80) 1.59 (1.49 – 1.81)

No 41,081 (%) 624,237 ( %) 1.00 (reference) 1.00 (reference)

*adjusted for smoking and maternal age

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eTable 2 Unadjusted relative risk of low Apgar score (≤ 7) by AED exposure during pregnancy

*Estimates are only presented for AEDs with 5 or more exposed cases.

AED Apgar > 7

(%)

Apgar ≤ 7

(%)

Relative Risk*

(Crude)

(95 % CI)

Phenobarbital 106 (98.1) 2 (1.9)

Primidone 34 (100.0) 0 (0.0)

Phenytoin 13 (100.0) 0 (0.0)

Ethosuximide 10 (100.0) 0 (0.0)

Clonazepam 364 (98.1) 7 (1.9) 1.44 (0.70 - 3.00)

Carbamazepine 401 (97.6) 10 (2.4) 1.86 (1.01 - 3.42)

Oxcarbazepine 397 (98.5) 6 (1.5) 1.14 (0.51 - 2.52)

Valproic acid 444 (97.6) 11 (2.4) 1.85 (1.04 - 3.30)

Vigabatrin 50 (98.0) 1 (2.0)

Tiagabine 2 (66.7) 1 (33.3)

Lamotrigine 1,134 (98.5) 17 (1.5) 1.13 (0.71 - 1.81)

Topiramate 124 (96.1) 5 (3.9) 2.97 (1.26 - 7.01)

Gabapentin 89 (97.8) 2 (2.2)

Levetiracetam 71 (97.3) 2 (2.7)

Zonisamide 1 (100.0) 0 (0.0)

Pregabalin 17 (94.4) 1 (5.6)

Clobazam 115 (97.5) 3 (2.5)

Any AED 2,851 (98.1) 55 (1.9) 1.45 (1.12 - 1.88)

No AED 665,318 (98.7) 8,797 ( 1.3) 1.00 (reference)

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Drugs – a population based cohort study

Journal: BMJ Open

Manuscript ID: bmjopen-2014-007425.R1


Date Submitted by the Author: 12-May-2015




Epidemiology




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Title page


– a population based cohort study


2, Maiken Ina Siegismund Kjaersgaard (MK)

3, Erik



4, Jørn Olsen (JO)

5,


5,6

Affiliations

1) Department of Neurology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus,

Denmark




Aarhus, Denmark





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Objectives: It is unknown if prenatal exposure to AEDs increases the risk of low Apgar score in the

offspring.




AEDs during pregnancy from the Danish Register of Medicinal Product Statistics. We used the

Danish National Hospital Registry to identify mothers diagnosed with epilepsy before birth of the

child. Results were adjusted for smoking and maternal age.





associated with AED exposure was 1.34 (95% CI: 0.90 - 2.01) When assessing the individual

AEDs, we found increased, unadjusted RR for exposure to carbamazepine (RR = 1.86 (95% CI:

1.01 - 3.42), valproic acid (RR = 1.85 (95% CI: 1.04 - 3.30) and topiramate (RR = 2.97 (95% CI:

1.26 - 7.01)) when compared to unexposed children

Conclusions: Prenatal exposure to AEDs was associated with an increased risk of being born with a

low Apgar score, but the absolute risk of a low Apgar score was <2%. Risk associated with the

individual AEDs indicate that the increased risk is not a class effect, but that there may be particular

high risks of low Apgar score associated with certain AEDs.

Key words: Antiepileptic drugs, pregnancy, Apgar score, epilepsy, epidemiology, patient register.

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- The register study includes all singletons (N = 677,021) born in Denmark from 1997 to

2008.



Product Statistics.






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worldwide,2, 3




using antiepileptic drugs in pregnancy have been found to have lower Apgar score compared to

offspring of women without epilepsy.7-9

However, low Apgar score is a rare outcome and

associations with AED exposure during pregnancy have been based on a very small number of

pregnancies and therefore have had low statistical precision.

Objectives

We studied the risk of low Apgar score in children prenatally exposed to antiepileptic drugs in a

large cohort of children accounting for confounding factors including epilepsy in the mothers.

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Methods

Study design




Setting


Danish Medical Birth Registry. We used the Danish National Hospital Registry to identify mothers

diagnosed with epilepsy before birth of the child. Information from the Danish national health

registers was linked through the Danish civil registration number (CPR number) from the Danish

Civil Registration System. , The Danish civil registration number is a unique identification number

given to each citizen living in Denmark ensuring accurate linkage between registers.


All singletons (N = 677,021) born in Denmark from 1997 to 2008 among whom 2,906 were

exposed to AEDs and 674,115 were not exposed to AEDs.


Medication exposure






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Daily Dose (DDD),10




The Danish National Hospital Registry holds information on inpatients since 1977 and outpatients

from 1995. From 1977 to 1993 diagnostic information in the Danish National Hospital Register was

based on the International Classification of Diseases, 8th

revision (ICD 8), and from 1994 to 2008

on the International Classification of Diseases; 10th

revision (ICD 10). The 9th

revision of the

International Classification of Disease (ICD 9) has not been used in Denmark. We used this register

to identify mothers diagnosed with epilepsy before birth of the child (ICD8: 345 and ICD10: G40

and G41).





F20).

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Pregnancy outcomes


gestational age and Apgar score at birth (5 min.).

Statistical methods




However, when analyzing individual drugs, there were too few exposed cases to allow for adjusted

estimates. This was also the case for women without epilepsy when we stratified on epilepsy






Bias








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Results




Main results

After adjustment for confounders, children of women using AED during pregnancy (N = 2,906) had

an adjusted RR of 1.41 (95% CI: 1.07 - 1.85) of having a low Apgar at five minutes (≤ 7) when

compared to children of women who did not use AEDs during pregnancy (Table 2).

We also analyzed the adjusted odds ratio (aOR) of being born with an Apgar score ≤ 7 (aOR = 1.47








We found that the crude RRs were increased for all types of AED albeit the estimates reached

statistical significance only for use of carbamazepine, valproic acid and topiramate exposure (Table

4 and Figure 1). When we restricted the analyses to children exposed to monotherapy there was no

increased risk associated with lamotrigine exposure and only exposure to carbamazepine was

significantly increased compared to unexposed children (eTable 2 and eFigure 1). Due to a low

number of exposed cases with low Apgar score (<5), it was not possible to assess the risk associated

with topiramate and oxcarbazepine monotherapy exposure in pregnancy.

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and 1,164 children were exposed to low dose of AED among whom 25 (2.2%) had a low Apgar

score. The aRR associated with high AED drug dose was 1.10 (95% CI: 0.71 - 1.72) and the aRR

associated with low AED dose was 1.68 (95% CI: 1.14 - 2.48) when compared to unexposed

children (Comparison of aRR for high dose with low dose; P = 0.16).

We analyzed the outcome after exposure to monotherapy and polytherapy of AEDs. There were

2459 children exposed to AED monotherapy among whom 44 (1.79 %) had a low Apgar score, and

447 children were exposed to AED polytherapy of whom 11 (2.46 %) had a low Apgar score. The

aRR (adjusted for smoking and maternal age) associated with AED monotherapy was 1.36 (95%

CI: 1.01 - 1.85) and the aRR associated with AED polytherapy was 1.65 (95% CI: 0.87 - 3.14)

when compared to unexposed children (Comparison of aRR for monotherapy with polytherapy; P =

0.60).

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Other analyses

Sibling analyses



1.21 (95% CI: 0.50 - 2.96).












analysis (aRR: 1.41 (95% CI: 1.07 - 1.85)).







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Discussion

Key results







carbamazepine, lamotrigine, phenytoin and valproate8. A Finnish register study found no risk of

low 5 min. Apgar score associated with overall AED therapy in offspring of women with epilepsy7,

but a more than doubling of the risk associated with valproate exposure. We found increased risks

of low Apgar score at 5 min. following carbamazepine, valproic acid and topiramate exposure, but





Limitations


were born with an Apgar score ≤ 7, and in a large number of analyses it was not possible to adjust

the risk estimates for potential confounders. Therefore, unadjusted, residual confounding may

account for some of the risk associated with AED exposure.

Gestational age may confound the association between AED exposure in pregnancy and low Apgar

score. However, AED exposure in pregnancy was not associated with preterm birth in a recent

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study from Denmark,11

and prior to study onset it was decided to focus on two well established

confounders namely smoking in pregnancy and maternal age.12, 13

In addition, low gestational age

following AED exposure may lie on the causal pathway between AED exposure and low Apgar

score and therefore should not necessarily be adjusted for.14




pregnancy.



estimated from register data.15

The exposure window was based on the time point when the women

redeemed a prescription and not on when the women actually ingested the tablets; therefore,

misclassification of timing of the exposure may have occurred. We therefore did not analyze the

risk of low Apgar score by exposure trimester. Because the timing of exposure is not precise, it was

not possible to discriminate between sequential mono-therapy (i.e. switching from one AED to

another AED without overlap) and polytherapy (two AEDs taken concomitantly), and both groups

were included as polytherapy. The children exposed to polytherapy may thus in reality have been

exposed sequential monotherapy although switching between AEDs without overlap is probably not

common.

We were unable to identify difference between high dose and low dose of AED exposure in

pregnancy. Greater risk may be associated with high dose AEDs as has been identified for the risk

of congenital malformations following valproate exposure in pregnancy16, 17

. However, our estimate

of drug dose is based on reimbursement rate in pregnancy and thus is likely an imprecise measure

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of drug dose in pregnancy. Given the low number of exposed cases within the individual AEDs, it

was not possible to compare high dose with low dose within the individual AEDs.

We analyzed all singletons born in Denmark, and loss to follow-up is very unlikely in this study.



, cancer19

,

epilepsy4, 6






Conclusion

Prenatal exposure to antiepileptic drugs was associated with a 41% increased relative risk of low

Apgar score, but the absolute risk was low (<2 %), and may be partly be explained by confounding

by indication.

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Acknowledgements

Dr Christensen receives research support from the Danish Epilepsy Association.

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Author's contributions

All authors initiated the study, obtained funding, and designed the study. MK constructed the

population. HP analysed the data. JC wrote the first draft. All authors interpreted the results,

revised the manuscript, and approved the final version of the manuscript. All authors had access to

all of the data in the study and take responsibility for the integrity of the data and the accuracy of

the data analysis.

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Disclosure of Conflicts of Interest

Dr Christensen reported receiving honoraria for serving on the scientific advisory boards of UCB

Nordic and Eisai AB; receiving lecture honoraria from UCB Nordic and Eisai AB; and receiving

travel funding from UCB Nordic.

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Table 1 Characteristics of study participants (monotherapy and polytherapy combined).

Characteristics Exposed to AED

N = 2,906

Not Exposed to AED

N = 674,115

(n) (%) (n) (%)

Smoking

Yes 780 (26.8) 125,863 (18.7)

No 1,981 (68.2) 527,907 (78.3)

Missing 145 (5.0) 20,345 (3.0)


<21 83 (2.9) 17,991 (2.7)

21-25 476 (16.4) 102,276 (15.2)

26-30 1,044 (35.9) 257,147 (38.1)

31-35 895 (30.8) 214,628 (31.8)

>=36 408 (14.0) 82,072 (12.2)

Missing 0 (0.0) 1 (0.0)

Parity

0 1,367 (47.0) 288,334 (42.8)

>=1 1,538 (52.9) 385,402 (57.2)

Missing 1 (0.0) 379 (0.1)

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Cohabitation

Yes 2,222 (76.5) 553,987 (82.2)

No 670 (23.1) 114,150 (16.9)

Missing 14 (0.5) 5978 (0.9)

Income (%)

0-19 624 (21.5) 118,703 (17.6)

20-39 805 (27.7) 134,876 (20.0)

40-59 600 (20.6) 139,171 (20.6)

60-79 510 (17.5) 141,922 (21.1)

80-100 367 (12.6) 138,736 (20.6)

Missing 0 (0.0) 707 (0.1)

Maternal education

<10 years 411 (14.1) 57,956 (8.6)

10-12 years 1,066 (36.7) 197,633 (29.3)

>12 years 1,365 (47.0) 402,117 (59.7)

Missing 64 (2.2) 16,409 (2.4)

Substance abuse

Yes 106 (3.6) 2284 (0.3)

No 2,800 (96.4) 671,831 (99.7)

Missing 0 (0.0) 0 (0.0)

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Table 2 Apgar score (≤ 7) in AED exposed and unexposed children (monotherapy and polytherapy combined)

AED

exposure

N (%) Apgar score

≤ 7

n (%)

Apgar score

> 7

n (%)

Relative Risk

Crude

(95 % CI)

Relative Risk

Adjusted*

(95% CI)

Yes 2,906 (100) 55 (1.9) 2,851 (98.1) 1.45 (1.12 - 1.88) 1.41 (1.07 - 1.85)



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Table 3 Relative risk for low Apgar score (≤ 7) in AED exposed and unexposed children stratified on mother’s diagnosis of epilepsy (monotherapy and

polytherapy combined)


n (%)

Apgar score > 7

n (%)

Relative Risk

Crude (95% CI)

Relative Risk

Adjusted* (95% CI)

Yes Yes 2,215 (100) 39 (1.8) 2,176 (98.2) 1.38 (0.94 - 2.04) 1.34 (0.90 - 2.01)


No Yes 691 (100) 16 (2.3) 675 (97.7) 1.77 (1.09 - 2.88) NA (-)

No 668,854 (100) 8,730 (1.3) 660,124 (98.7) 1.00 (reference) NA (-)


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Table 4 Unadjusted relative risk of low Apgar score (≤ 7) by AED exposure during pregnancy

(monotherapy and polytherapy combined)


AED Apgar > 7

(%)

Apgar ≤ 7

(%)

Relative Risk*

(Crude)

(95 % CI)

Clonazepam 364 (98.1) 7 (1.9) 1.44 (0.70 - 3.00)

Carbamazepine 401 (97.6) 10 (2.4) 1.86 (1.01 - 3.42)

Oxcarbazepine 397 (98.5) 6 (1.5) 1.14 (0.51 - 2.52)

Valproic acid 444 (97.6) 11 (2.4) 1.85 (1.04 - 3.30)

Lamotrigine 1,134 (98.5) 17 (1.5) 1.13 (0.71 - 1.81)

Topiramate 124 (96.1) 5 (3.9) 2.97 (1.26 - 7.01)

Any AED 2,851 (98.1) 55 (1.9) 1.45 (1.12 - 1.88)

No AED 665,318 (98.7) 8,797 ( 1.3) 1.00 (reference)

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Figure 1 Unadjusted relative risk of low Apgar score (≤ 7) by AED exposure during pregnancy



0 1 2 3 4 5 6 7 8

Antiepileptic drug exposure in pregnancy

Any AED (2906)

Lamotrigine (1151)

Oxcarbazepine (403)

Clonazepam (371)

Valproic acid (455)

Carbamazepine (411)

Topiramate (129)


Reference line (children unexposed to antiepileptic drugs)

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References

Reference List

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16. Vajda FJ, O'Brien TJ, Graham JE, Lander CM, Eadie MJ. Dose dependence of fetal

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eTable 1 Odds Ratio of being born with an Apgar score of ≤ 7 and an Apgar score of 8-9 compared with an Apgar score of 10 for AED exposed and

unexposed children (monotherapy and polytherapy combined)

Agar Score

≤ 7 10

Crude OR

(95 % CI)

Adjusted OR*

(95 % CI)

AED Yes 55 ( %) 2,582 ( %) 1,51 (1.15 – 1.97) 1.47 (1.10 – 1.94)

No 8,797 ( %) 624,237 ( %) 1.00 (reference) 1.00 (reference)

Apgar Score

8 - 9 10

Crude OR

(95 % CI)

Adjusted OR*

(95 % CI)

AED Yes 269 ( %) 2,582 ( %) 1.58 (1.39 – 1.80) 1.59 (1.49 – 1.81)

No 41,081 (%) 624,237 ( %) 1.00 (reference) 1.00 (reference)


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eTable 2 Unadjusted relative risk of low Apgar score (≤ 7) by AED exposure during

pregnancy(monotherapy only)

*Estimates are only presented for AEDs with 5 or more exposed cases

.

AED Apgar > 7

(%)

Apgar ≤ 7

(%)

Relative Risk*

(Crude)

(95 % CI)

Clonazepam 255 (98.1) 5 (1.9) 1.47 (0.62 - 3.51)

Carbamazepine 335 (97.4) 9 (2.6) 2.00 (1.06 - 3.80)

Valproic acid 330 (97.9) 7 (2.1) 1.59 (0.77 - 3.29)

Lamotrigine 865 (98.9) 10 (1.1) 0.88 (0.47 - 1.62)

Any AED 2415 (98.2) 44 (1.8) 1.37 (1.02 – 1.84)

No AED 665,318 (98.7) 8,797 ( 1.3) 1.00 (reference)

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eFigure 1 Unadjusted relative risk of low Apgar score (≤ 7) by AED exposure during pregnancy

(monotherapy only)*



0 1 2 3 4 5 6 7 8

Antiepileptic drug exposure in pregnancy

Any AED (2459)

Lamotrigine (875)

Clonazepam (260)

Valproic acid (337)

Carbamazepine (344)



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Drugs – a population based cohort study

Journal: BMJ Open

Manuscript ID: bmjopen-2014-007425.R2


Date Submitted by the Author: 16-Jun-2015




Epidemiology




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Title page


– a population based cohort study


2, Maiken Ina Siegismund Kjaersgaard (MK)

3, Erik



4, Jørn Olsen (JO)

5,


5,6

Affiliations

1) Department of Neurology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus,

Denmark




Aarhus, Denmark




Corresponding author: Jakob Christensen (JC), Department of Neurology, Institute of Clinical

Medicine, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Aarhus, Denmark

Mobile: (+45) 60865899, E-mail: [email protected]

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Objectives: It is unknown if prenatal exposure to antiepileptic drugs (AEDs) increases the risk of

low Apgar score in the offspring.




AEDs during pregnancy from the Danish Register of Medicinal Product Statistics. We used the

Danish National Hospital Registry to identify mothers diagnosed with epilepsy before birth of the

child. Results were adjusted for smoking and maternal age.





associated with AED exposure was 1.34 (95% CI: 0.90 - 2.01) When assessing the individual

AEDs, we found increased, unadjusted RR for exposure to carbamazepine (RR = 1.86 (95% CI:

1.01 - 3.42), valproic acid (RR = 1.85 (95% CI: 1.04 - 3.30) and topiramate (RR = 2.97 (95% CI:

1.26 - 7.01)) when compared to unexposed children

Conclusions: Prenatal exposure to AEDs was associated with an increased risk of being born with a

low Apgar score, but the absolute risk of a low Apgar score was <2%. Risk associated with the

individual AEDs indicate that the increased risk is not a class effect, but that there may be particular

high risks of low Apgar score associated with certain AEDs.

Key words: Antiepileptic drugs, pregnancy, Apgar score, epilepsy, epidemiology, patient register.

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- The register study includes singletons with information on Apgar score (N = 677,021) born

in Denmark from 1997 to 2008.



Product Statistics.






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worldwide,2, 3




using AEDs in pregnancy have been found to have lower Apgar score compared to offspring of

women without epilepsy.7-9

However, low Apgar score is a rare outcome and associations with

AED exposure during pregnancy have been based on a very small number of pregnancies and

therefore have had low statistical precision.

Objectives

We studied the risk of low Apgar score in children prenatally exposed to AEDs in a large cohort of

children accounting for confounding factors including epilepsy in the mothers.

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Methods

Study design




Setting


Danish Medical Birth Registry. We used the Danish National Hospital Registry to identify mothers

diagnosed with epilepsy before birth of the child. Information from the Danish national health

registers was linked through the Danish civil registration number (CPR number) from the Danish

Civil Registration System. , The Danish civil registration number is a unique identification number

given to each citizen living in Denmark ensuring accurate linkage between registers.


We included all singletons (N = 693,838) born in Denmark from 1997 to 2008 excluding those with

missing information on Apgar score (n =16,817) leaving 677,021 for analyses. Among these

children 2,906 were exposed to AEDs and 674,115 were not exposed to AEDs.


Medication exposure





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Daily Dose (DDD),10




The Danish National Hospital Registry holds information on inpatients since 1977 and outpatients

from 1995. From 1977 to 1993 diagnostic information in the Danish National Hospital Register was

based on the International Classification of Diseases, 8th

revision (ICD 8), and from 1994 to 2008

on the International Classification of Diseases; 10th

revision (ICD 10). The 9th

revision of the

International Classification of Disease (ICD 9) has not been used in Denmark. We used this register

to identify mothers diagnosed with epilepsy before birth of the child (ICD8: 345 and ICD10: G40

and G41).




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F20).

Pregnancy outcomes


gestational age and Apgar score (0-10) at birth (5 min.).

Statistical methods




Singletons with missing information on smoking (n = 20,490), maternal age (n= 1), and gestational

age (n = 2,230) were excluded from analyses.

When analyzing individual drugs, there were too few exposed cases to allow for adjusted estimates.

This was also the case for offspring of women without epilepsy when we stratified on epilepsy






Bias


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Results




Main results

After adjustment for smoking and maternal age, children of women using AED during pregnancy

(N = 2,906) had an adjusted RR of 1.41 (95% CI: 1.07 - 1.85) of having a low Apgar at five minutes

(≤ 7) when compared to children of women who did not use AEDs during pregnancy (Table 2). We

also estimated the risk of low Apgar score with additional adjustment for gestational age and found

an almost unchanged aRR of 1.38 (95% CI: 1.05 – 1.82).

We analyzed the adjusted odds ratio (aOR) of being born with an Apgar score ≤ 7 (aOR = 1.47








We found that the crude RRs were increased for all types of AEDs albeit the estimates reached

statistical significance only for use of carbamazepine, valproic acid and topiramate exposure (Table

4 and Figure 1). When we restricted the analyses to children exposed to monotherapy there was no

increased risk associated with lamotrigine exposure and only exposure to carbamazepine was

significantly increased compared to unexposed children (eTable 2 and eFigure 1). Due to a low

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number of exposed cases with low Apgar score (<5), it was not possible to assess the risk associated

with topiramate and oxcarbazepine monotherapy exposure in pregnancy.



and 1,164 children were exposed to low dose of AED among whom 25 (2.2%) had a low Apgar

score. The unadjusted RR associated with high AED drug dose was 1.10 (95% CI: 0.71 - 1.72) and

the unadjusted RR associated with low AED dose was 1.68 (95% CI: 1.14 - 2.48) when compared

to unexposed children (Comparison of RR for high dose with low dose; P = 0.16).

We analyzed the outcome after exposure to monotherapy and polytherapy of AEDs. There were

2459 children exposed to AED monotherapy among whom 44 (1.79 %) had a low Apgar score, and

447 children were exposed to AED polytherapy of whom 11 (2.46 %) had a low Apgar score. The

aRR (adjusted for smoking and maternal age) associated with AED monotherapy was 1.36 (95%

CI: 1.01 - 1.85) and the aRR associated with AED polytherapy was 1.65 (95% CI: 0.87 - 3.14)

when compared to unexposed children (Comparison of aRR for monotherapy with polytherapy; P =

0.60).

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Other analyses

Sibling analyses



1.21 (95% CI: 0.50 - 2.96).












analysis (aRR: 1.41 (95% CI: 1.07 - 1.85)).







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Discussion

Key results







carbamazepine, lamotrigine, phenytoin and valproate8. A Finnish register study found no risk of

low 5 min. Apgar score associated with overall AED therapy in offspring of women with epilepsy7,

but a more than doubling of the risk associated with valproate exposure. We found increased risks

of low Apgar score at 5 min. following carbamazepine, valproic acid and topiramate exposure, but





Limitations


were born with an Apgar score ≤ 7, and in a large number of analyses it was not possible to adjust

the risk estimates for potential confounders. Therefore, unadjusted, residual confounding may

account for some of the risk associated with AED exposure.

Adjusting for gestational age had almost no effect on the association between AED exposure in

pregnancy and risk of low Apgar score in the offspring. AED exposure in pregnancy was not

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associated with preterm birth in a recent study from Denmark,11

and prior to study onset it was

decided to focus on two well established confounders namely smoking in pregnancy and maternal

age.12, 13

In addition, low gestational age following AED exposure may lie on the causal pathway

between AED exposure and low Apgar score and therefore should not necessarily be adjusted for.14




pregnancy.



estimated from register data.15

The exposure window was based on the time point when the women

redeemed a prescription and not on when the women actually ingested the tablets; therefore,

misclassification of timing of the exposure may have occurred. We therefore did not analyze the

risk of low Apgar score by exposure trimester. Because the timing of exposure is not precise, it was

not possible to discriminate between sequential mono-therapy (i.e. switching from one AED to

another AED without overlap) and polytherapy (two AEDs taken concomitantly), and both groups

were included as polytherapy. The children exposed to polytherapy may thus in reality have been

exposed sequential monotherapy although switching between AEDs without overlap is probably not

common.

We were unable to identify difference between high dose and low dose of AED exposure in

pregnancy. Greater risk may be associated with high dose AEDs as has been identified for the risk

of congenital malformations following valproate exposure in pregnancy16, 17

. However, our estimate

of drug dose is based on reimbursement rate in pregnancy and thus is likely an imprecise measure

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of drug dose in pregnancy. Given the low number of exposed cases within the individual AEDs, it

was not possible to compare high dose with low dose within the individual AEDs.

We analyzed all singletons born in Denmark, and loss to follow-up is very unlikely in this study.



, cancer19

,

epilepsy4, 6






Conclusion

Prenatal exposure to AEDs was associated with a 41% increased relative risk of low Apgar score,

but the absolute risk was low (<2 %), and may be partly be explained by confounding by indication.

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Table 1 Characteristics of study participants (monotherapy and polytherapy combined).

Characteristics Exposed to AED#

N = 2,906

Not Exposed to AED#

N = 674,115

(n) (%) (n) (%)

Smoking

Yes 780 (26.8) 125,863 (18.7)

No 1,981 (68.2) 527,907 (78.3)

Missing 145 (5.0) 20,345 (3.0)


<21 83 (2.9) 17,991 (2.7)

21-25 476 (16.4) 102,276 (15.2)

26-30 1,044 (35.9) 257,147 (38.1)

31-35 895 (30.8) 214,628 (31.8)

>=36 408 (14.0) 82,072 (12.2)

Missing 0 (0.0) 1 (0.0)

Parity

0 1,367 (47.0) 288,334 (42.8)

>=1 1,538 (52.9) 385,402 (57.2)

Missing 1 (0.0) 379 (0.1)

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Cohabitation

Yes 2,222 (76.5) 553,987 (82.2)

No 670 (23.1) 114,150 (16.9)

Missing 14 (0.5) 5978 (0.9)

Income (%)*

0-19 % 624 (21.5) 118,703 (17.6)

20-39 % 805 (27.7) 134,876 (20.0)

40-59 % 600 (20.6) 139,171 (20.6)

60-79 % 510 (17.5) 141,922 (21.1)

80-100 % 367 (12.6) 138,736 (20.6)

Missing 0 (0.0) 707 (0.1)

Maternal education

<10 years 411 (14.1) 57,956 (8.6)

10-12 years 1,066 (36.7) 197,633 (29.3)

>12 years 1,365 (47.0) 402,117 (59.7)

Missing 64 (2.2) 16,409 (2.4)

Substance abuse

Yes 106 (3.6) 2284 (0.3)

No 2,800 (96.4) 671,831 (99.7)

Missing 0 (0.0) 0 (0.0)

#Antiepileptic drug (AED).

*The annual income was divided into quintiles (0-19%, 20-39%, 40-59%, 60-79%, 80-100%).

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Table 2 Apgar score (≤ 7) in AED# exposed and unexposed children (monotherapy and polytherapy combined)

AED

exposure

N (%) Apgar score

≤ 7

n (%)

Apgar score

> 7

n (%)

Relative Risk

Crude

(95 % CI)

Relative Risk

Adjusted*

(95% CI)

Yes 2,906 (100) 55 (1.9) 2,851 (98.1) 1.45 (1.12 - 1.88) 1.41 (1.07 - 1.85)




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Table 3 Relative risk for low Apgar score (≤ 7) in AED# exposed and unexposed children stratified on mother’s diagnosis of epilepsy (monotherapy and

polytherapy combined)


n (%)

Apgar score > 7

n (%)

Relative Risk

Crude (95% CI)

Relative Risk

Adjusted* (95% CI)

Yes Yes 2,215 (100) 39 (1.8) 2,176 (98.2) 1.38 (0.94 - 2.04) 1.34 (0.90 - 2.01)


No Yes 691 (100) 16 (2.3) 675 (97.7) 1.77 (1.09 - 2.88) NA (-)

No 668,854 (100) 8,730 (1.3) 660,124 (98.7) 1.00 (reference) NA (-)



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Table 4 Unadjusted relative risk of low Apgar score (≤ 7) by AED# exposure during pregnancy




AED Apgar > 7

(%)

Apgar ≤ 7

(%)

Relative Risk*

(Crude)

(95 % CI)

Clonazepam 364 (98.1) 7 (1.9) 1.44 (0.70 - 3.00)

Carbamazepine 401 (97.6) 10 (2.4) 1.86 (1.01 - 3.42)

Oxcarbazepine 397 (98.5) 6 (1.5) 1.14 (0.51 - 2.52)

Valproic acid 444 (97.6) 11 (2.4) 1.85 (1.04 - 3.30)

Lamotrigine 1,134 (98.5) 17 (1.5) 1.13 (0.71 - 1.81)

Topiramate 124 (96.1) 5 (3.9) 2.97 (1.26 - 7.01)

Any AED 2,851 (98.1) 55 (1.9) 1.45 (1.12 - 1.88)

No AED 665,318 (98.7) 8,797 ( 1.3) 1.00 (reference)

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Contributorship statement

JC, HP, MK, EP, MV, MS, JO, BH, and LP initiated the study, obtained funding, and designed the

study. MK constructed the population. HP analysed the data. JC wrote the first draft. JC, HP, MK,

EP, MV, MS, JO, BH, and LP interpreted the results, revised the manuscript, and approved the final

version of the manuscript. JC, HP, MK, EP, MV, MS, JO, BH, and LP had access to all of the data

in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Competing interests

JC reported receiving honoraria for serving on the scientific advisory boards of UCB Nordic and

Eisai AB; receiving lecture honoraria from UCB Nordic and Eisai AB; and receiving travel funding

from UCB Nordic.

Funding

JC receives research support from the Danish Epilepsy Association.

Data sharing statement

There are two supplemental tables and one figure with data (eTable 1, eTable 2 and eFigure 1). No

additional data available.

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Figure 1 Unadjusted relative risk of low Apgar score (≤ 7) by antiepileptic drug (AED) exposure

during pregnancy (monotherapy and polytherapy combined)

References

Reference List

1. APGAR V. A proposal for a new method of evaluation of the newborn infant. Curr Res

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Health 2006;6:23.
















11. Kilic D, Pedersen H, Kjaersgaard MI et al. Birth outcomes after prenatal exposure to

antiepileptic drugs--a population-based study. Epilepsia 2014;55(11):1714-1721.

12. Cnattingius S. The epidemiology of smoking during pregnancy: smoking prevalence,

maternal characteristics, and pregnancy outcomes. Nicotine Tob Res 2004;6 Suppl 2:S125-

40.:S125-S140.

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13. Waldenstrom U, Aasheim V, Nilsen AB, Rasmussen S, Pettersson HJ, Schytt E. Adverse

pregnancy outcomes related to advanced maternal age compared with smoking and being

overweight. Obstet Gynecol 2014;123(1):104-112.

14. Rothman KJ. Modern epidemiology. Boston: Little, Brown, cop. 1986.



16. Vajda FJ, O'Brien TJ, Graham JE, Lander CM, Eadie MJ. Dose dependence of fetal

malformations associated with valproate. Neurology 2013;81(11):999-1003.

17. Vajda F, O'Brien T. Valproic acid use in pregnancy and congenital malformations. N Engl J

Med 2010;363(18):1771-1772.




10.1186/1471-2393-9-14.:14-19.



2012;2(4):e001095.



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Figure 1 Unadjusted relative risk of low Apgar score (≤ 7) by antiepileptic drug (AED) exposure during pregnancy (monotherapy and polytherapy combined)

133x100mm (300 x 300 DPI)

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eTable 1 Odds Ratio of being born with an Apgar score of ≤ 7 and an Apgar score of 8-9 compared with an Apgar score of 10 for AED# exposed and

unexposed children (monotherapy and polytherapy combined)

Agar Score€

≤ 7

n (%)

8,852 (1.3)

10

n (%)

626,819 (92,6)

Crude OR

(95 % CI)

Adjusted OR*

(95 % CI)

AED Yes 55 (1,9) 2,582 (88.9) 1,51 (1.15 – 1.97) 1.47 (1.10 – 1.94)

No 8,797 (1.3) 624,237 (92.6) 1.00 (reference) 1.00 (reference)

Apgar Score$

8 - 9

n (%)

41,350 (6.1)

10

n (%)

626,819 (92,6)

Crude OR

(95 % CI)

Adjusted OR*

(95 % CI)

AED Yes 269 (9.3) 2,582 (88.9) 1.58 (1.39 – 1.80) 1.59 (1.49 – 1.81)

No 41,081 (6.1) 624,237 (92.6) 1.00 (reference) 1.00 (reference)


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€ Excluding 41,350 (6.1%) with Apgar score 8-.9.

$ Excluding 8852 (1.3%) with Apgar score ≤ 7.

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eTable 2 Unadjusted relative risk of low Apgar score (≤ 7) by AED# exposure during pregnancy

(monotherapy only)

*Estimates are only presented for AEDs with 5 or more exposed cases


.

AED Apgar > 7

n (%)

667,733 (98.7)

Apgar ≤ 7

n (%)

8,841 (1.3)

Relative Risk*

(Crude)

(95 % CI)

Clonazepam 255 (98.1) 5 (1.9) 1.47 (0.62 - 3.51)

Carbamazepine 335 (97.4) 9 (2.6) 2.00 (1.06 - 3.80)

Valproic acid 330 (97.9) 7 (2.1) 1.59 (0.77 - 3.29)

Lamotrigine 865 (98.9) 10 (1.1) 0.88 (0.47 - 1.62)

Any AED 2415 (98.2) 44 (1.8) 1.37 (1.02 – 1.84)

No AED 665,318 (98.7) 8,797 ( 1.3) 1.00 (reference)

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eFigure 1 Unadjusted relative risk of low Apgar score (≤ 7) by AED# exposure during pregnancy

(monotherapy only)*




0 1 2 3 4 5 6 7 8

Antiepile

ptic d

rug e

xposure

in p

regnancy

Any AED (2459)

Lamotrigine (875)

Clonazepam (260)

Valproic acid (337)

Carbamazepine (344)



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1

STROBE Statement—checklist of items that should be included in reports of observational studies

Item

No Recommendation

Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract

(Page 1, a population based cohort study)

(b) Provide in the abstract an informative and balanced summary of what was done

and what was found

(Page 2, Abstract)

Introduction

Background/rationale 2 Explain the scientific background and rationale for the investigation being reported

(Page 4, Background/rationale)

Objectives 3 State specific objectives, including any prespecified hypotheses

(Page 4, Objectives)

Methods

Study design 4 Present key elements of study design early in the paper

(Page 5, Study design)

Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment,

exposure, follow-up, and data collection

(Page 5, Setting)

Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of

selection of participants. Describe methods of follow-up

(Page 5, Participants and study size)

Case-control study—Give the eligibility criteria, and the sources and methods of case

ascertainment and control selection. Give the rationale for the choice of cases and

controls

Cross-sectional study—Give the eligibility criteria, and the sources and methods of

selection of participants

(b) Cohort study—For matched studies, give matching criteria and number of

exposed and unexposed


Case-control study—For matched studies, give matching criteria and the number of

controls per case

Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect

modifiers. Give diagnostic criteria, if applicable

(Page 5-7, Variables, data sources and measurement)

Data sources/

measurement

8* For each variable of interest, give sources of data and details of methods of

assessment (measurement). Describe comparability of assessment methods if there is

more than one group

(Page 5-7, Variables, data sources and measurement)

Bias 9 Describe any efforts to address potential sources of bias

(Page 7, Bias)

Study size 10 Explain how the study size was arrived at


Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable,

describe which groupings were chosen and why

(Page 7, Statistical methods)

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Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding

(Page 7, Bias)

(b) Describe any methods used to examine subgroups and interactions

(Page 7, Bias)

(c) Explain how missing data were addressed

(Shown in Table 1, Singletons with missing values were excluded)

(d) Cohort study—If applicable, explain how loss to follow-up was addressed

(Missing values on potential confounders are shown in Table 1. Singletons with

missing values on Apgar score (n = 16,817), smoking (n = 20,490), maternal age

(n= 1), and missing values on Gestational age (n = 2,230) were excluded from

analyses).

Case-control study—If applicable, explain how matching of cases and controls was

addressed

Cross-sectional study—If applicable, describe analytical methods taking account of

sampling strategy

(e) Describe any sensitivity analyses

(Page 7, Sensitivity analyses described under Bias)

Continued on next page

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Results

Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible,

examined for eligibility, confirmed eligible, included in the study, completing follow-up, and

analysed

(Page 8 Participants and descriptive data)

(b) Give reasons for non-participation at each stage

(All patients were included)

(c) Consider use of a flow diagram

(Flow diagram not included)

Descriptive

data

14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information

on exposures and potential confounders

(Table 1)

(b) Indicate number of participants with missing data for each variable of interest

(Table 1).

(c) Cohort study—Summarise follow-up time (eg, average and total amount)

(Participants were included at birth, thus no follow up time)

Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time

(Main results, page 9)

Case-control study—Report numbers in each exposure category, or summary measures of

exposure

(NA)

Cross-sectional study—Report numbers of outcome events or summary measures

(NA)

Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their

precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and

why they were included

(Main results, page 9, Table 2)

(b) Report category boundaries when continuous variables were categorized

(Pregnancy outcomes, page 7)

(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful

time period

(Proportion of participants with low Apgar score (absolute risk) is presented in the

outcome tables).

Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity

analyses

(Page 10, Sibling analyses and sensitivity analyses)

Discussion

Key results 18 Summarise key results with reference to study objectives

(Page 12, Key Results).

Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision.

Discuss both direction and magnitude of any potential bias

(Page 12, Limitations)

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity

of analyses, results from similar studies, and other relevant evidence

(Page 14, Interpretation and generalizability)

Generalisability 21 Discuss the generalisability (external validity) of the study results

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(Page 14, Interpretation and generalizability)

Other information

Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable,

for the original study on which the present article is based

(Page 15, Funding)

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and

unexposed groups in cohort and cross-sectional studies.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and

published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely

available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at

http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is

available at www.strobe-statement.org.

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