Hum. Reprod. Advance Access originally published online on August 26, 2006
Human Reproduction 2007 22(1):215-220; doi:10.1093/humrep/del333
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Epilepsy and febrile seizures in children of treated and untreated subfertile couples
1 The Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, University of Aarhus, Aarhus, Denmark 2 Shanghai Institute of Planned Parenthood Research, Shanghai, China 3 Department of Neurology and Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark and 4 Department of Epidemiology, School of Public Health, University of California at Los Angeles, LA, USA
5 To whom correspondence should be addressed at: Department of Epidemiology, University of Aarhus, DK-8000 Aarhus C, Denmark. E-mail: ys{at}soci.au.dk
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Abstract |
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BACKGROUND: Only few studies have addressed the long-term neurological outcomes of children born by subfertile couples. We studied the risk of epilepsy and febrile seizures in children of treated and untreated subfertile couples. METHODS: The study included 83 194 live singletons born by mothers who took part in the Danish National Birth Cohort (DNBC). Information on time to pregnancy (TTP) and infertility treatment was reported by the mothers in computer-assisted telephone interviews. Data on epilepsy and febrile seizures were extracted from the Danish National Hospital Register. RESULTS: Overall, children of subfertile couples (TTP > 12 months) had a 51% higher risk of epilepsy [incidence rate ratio (IRR): 1.51; 95% confidence interval (95% CI): 1.17–1.94] compared with children of couples with a TTP of 0–5 months. The corresponding estimates were 1.71 (95% CI: 1.21–2.42) if the couples had received infertility treatment and 1.38 (95% CI: 1.00–1.89) if they conceived spontaneously. Children of subfertile couples did not have a higher risk of febrile seizures except for those who received hormonal treatment (HT) with or without intrauterine insemination (IRR = 1.37; 95% CI: 1.14–1.66). CONCLUSIONS: Children of subfertile couples had a slightly increased risk of epilepsy, and the risk tended to be higher for children of couples who received infertility treatment. Whether this reflects side effects of treatment or severity of subfecundity is not known.
Key words: artificial reproduction technology/epilepsy/febrile seizures/infertility
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Introduction |
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About 16% of couples in Europe have a waiting time of more than 12 months when trying to become pregnant, and infertility treatment is increasingly being used in many countries (Olsen et al., 1996
; Juul et al., 1999). Some studies indicate that subfertile couples have an increased risk of preterm birth, low birthweight, congenital malformation and perinatal death related to either subfertility itself or infertility treatment (Williams et al., 1991; Olivennes et al., 1993; Draper et al., 1999; Basso and Baird, 2003; Hansen et al., 2005; Thomson et al., 2005; De Geyter et al., 2006). A few studies also indicate an increased risk of long-term health hazard after assisted reproduction technologies (ART), including neuropsychiatric conditions such as cerebral palsy, mental retardation, behavioural problems and epilepsy (Stromberg et al., 2002; Kallen et al., 2005a), but not all studies support these findings (Sutcliffe et al., 2001; Olivennes et al., 2002; Stewart et al., 2002). These associations could also be related to subfecundity itself rather than side effects of treatment.
Epilepsy is a disorder characterized by recurrent unprovoked seizures (International League Against Epilepsy, 1993), and febrile seizures is a condition in childhood characterized by seizures occurring during an acute febrile episode but without evidence of intracranial infections or other defined causes (Concensus statement, 1981). The aetiology of these conditions is often unknown (Hauser et al., 1993), but environmental factors operating in prenatal life are causal candidates (Lilienfeld and Pasamanick, 1954; Rocca et al., 1987; Greenwood et al., 1998; Vestergaard et al., 2002; Sun et al., 2006).
In this study, we hypothesize that children born by subfertile couples have a higher risk of epilepsy and febrile seizures in childhood. We tried to separate the effects of infertility treatment from the underlying condition of subfecundity.
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Methods |
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Study population
The Danish National Birth Cohort (DNBC) is a pregnancy cohort that recruited about 100 000 women between 1 March 1996 and 1 November 2002 (Olsen, 2005
). The participants took part in four computer-assisted telephone interviews, twice during pregnancy and twice after delivery. In this study, we included live singletons born between October 1997 and June 2003 by mothers taking part in the first interview of DNBC. We excluded participants who did not provide informative time to pregnancy (TTP) data (n = 3539) and those who reported that they had received infertility treatment but not for the index pregnancy (n = 76), leaving 83 194 for the final analysis (Figure 1).
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Subfertility and infertility treatment
The information on TTP and infertility treatment was reported by the participants in the first interview that took place around 16th gestational week. Firstly, pregnant women were asked whether their pregnancy was planned, partly planned or unplanned. If the pregnancy was planned or partly planned, they were asked about TTP using the following answering categories: (i) did not try to become pregnant, (ii) became pregnant right away, (iii) 1–2 months, (iv) 3–5 months, (v) 6–12 months, (vi) >12 months, (vii) don’t know and (viii) do not want to answer. Pregnant women who reported that it took 6 months or longer to get pregnant were asked whether they received any infertility treatment before this pregnancy and, if relevant, the methods of infertility treatment including (i) ICSI; (ii) IVF; (iii) intrauterine insemination (IUI); (iv) surgery; (v) rinsing of Fallopian tubes; (vi) hormonal treatment (HT); (vii) other, please specify; (viii) don’t know and (ix) do not want to answer. Couples who reported infertility treatment were classified as treated subfertile couples independently of the reported TTP. The remaining couples were categorized into three groups according to their TTP: 0–5 months, 6–12 months and more than 12 months. The latter group was labelled ‘untreated subfertile couples’. Infertility treatments were categorized into three groups: IVF/ICSI, IUI/HT and others. The ‘others’ group included various treatments such as operation, rinsing of Fallopian tubes, acupuncture, herbal medicine and unknown treatment. Unplanned pregnancies were treated in the analyses as a separate group.
To evaluate whether IVF/ICSI treatments were correctly reported by participants in DNBC, we linked our study population with the Danish IVF register that holds information on IVF and ICSI treatments in Denmark since January 1994 (Andersen et al., 1999a). We had access to information from the IVF register for couples who received IVF/ICSI between 1994 and December 2000.
Epilepsy and febrile seizures
Information on epilepsy and febrile seizures was obtained from the Danish National Hospital Register (Andersen et al., 1999b) that, since 1995, has stored diagnostic codes for all persons treated as outpatients or inpatients in all Danish hospitals. The coding was based on the International Classification of Disease—10th Revision (ICD10). We classified children as having epilepsy when they were registered with codes G40-G41 beyond the first 28 days of life. We classified children with febrile seizures if they were registered with code R56.0 and were between 3 months and 5 years of age at the time of diagnosis and had no history of epilepsy.
Potential confounders
Information on cerebral palsy (ICD10: G80) and congenital malformation of children (ICD-10: Q00-Q99) was obtained from the Danish National Hospital Register (Andersen et al., 1999b). Information on parental age, gestational age and Apgar scores at 5 min was obtained from the Danish Medical Birth Registry (Knudsen and Olsen, 1998). We obtained information on parental history of epilepsy from the Danish National Hospital Register (ICD8: 345; ICD10: G40-G41). Information on maternal weight and height before pregnancy, maternal social status and smoking at the recruitment was obtained from DNBC’s first interview. Maternal social status was based on self-reported education and current job titles. Women with a higher education (4 years beyond secondary school education) or in management were classified as ‘high’ social status. Women with middle-range training and skilled workers were classified as ‘middle’ and unskilled workers and unemployed were classified as ‘low’.
Statistical analysis
The children were followed from the birth until they were diagnosed with epilepsy or febrile seizures, day of death or the end of study (31 December 2003), whichever came first. Onset age of epilepsy or febrile seizures was defined as the day when the children were first diagnosed with epilepsy or febrile seizures. We estimated incidence rate ratios (IRR) by Cox regression models in STATA 8.2.
We modelled the TTP and different treatments in one variable (TTP: 0–5 months, TTP: 6–12 months, untreated subfertile couples with a TTP more than 12 months, subfertile couples treated with IVF/ICSI, IUI/HT and other methods and unplanned pregnancy). The analyses were adjusted for parental age at the birth of the child, maternal social status, pre-pregnancy BMI, smoking status at the time of recruitment and parental history of epilepsy, calendar years, all as categorical variables. We used robust standard errors to adjust for dependency between those who provided more than one pregnancy in the cohort. We repeated the analyses among planned pregnancies, term births, primiparas and multiparas. We also modelled the association after taking the Apgar score, cerebral palsy and congenital malformation into consideration. Trend tests for associations between TTP and epilepsy or febrile seizures were done by treating TTP of ‘0–5 months’, ‘6–12 months’, ‘12+ months’ as an ordered variable coded as 1, 2, and 3, respectively. Children were excluded in the relevant analysis due to missing values on paternal age (n = 1288), BMI (n = 1354), 5-min Apgar scores (n = 994), social status (n = 310), smoking status (n = 31) and parity (n = 3).
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Results |
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In the cohort of 83 194 live born singletons, 497 were diagnosed with epilepsy and 3055 with febrile seizures. The median age of the children was 3.3 years old (range: 0–6.2). Table I summarizes the characteristics of their parents and neonatal outcomes according to parental fertility, treatment and planning of their pregnancies. Subfertile couples (both sexes) were older than couples with a TTP of 0–5 months. Treated couples were more often primiparas than other groups. The subfertile women (treated and untreated) had more often a pre-pregnancy BMI of 30 kg/m2 or more (obese).
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Overall, children of subfertile couples had an IRR for epilepsy of 1.51 (95% confidence interval (95% CI): 1.17–1.94) compared with children of couples with a TTP of 0–5 months. The corresponding estimates were 1.71 (95% CI: 1.21–2.42) if the couples had received infertility treatment and 1.38 (95% CI: 1.00–1.89) if they conceived spontaneously (Table II). The risk of epilepsy tended to increase with the duration of TTP albeit the test for trend was not statistically significant (P = 0.068). As compared with children of untreated subfertile couples, children of treated subfertile couples were associated with a higher, but not statistically significant, risk of epilepsy (IRR = 1.25, 95% CI: 0.81–1.91) (data not shown in the table). After restricting the cohort to children born at term, the estimates decreased slightly for children born by untreated subfertile couples and by IVF-treated couples but were slightly higher for those treated with IUI/HT. The effect of IUI/HT on epilepsy was found among multiparas only, but the numbers were small (Table II). Further adjustments for Apgar scores, cerebral palsy and congenital malformation decreased the IRR slightly for untreated subfertile couples (IRR = 1.28, 95% CI: 0.94–1.75, not significant) and treated subfertile couples (IRR = 1.61, 95% CI: 1.15–2.25) (data not shown in the table).
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We found no consistent association between subfertility and the risk of febrile seizures. However, children conceived after IUI/HT had a higher risk of febrile seizures (IRR = 1.37, 95% CI: 1.14–1.66) compared with children of couples with a TTP of 0–5 months (Table III).
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We found no change in the estimates of interest after restricting the analyses to couples who reported planned pregnancies (data not shown in the table).
We found that 552 pregnant women in the DNBC were registered in the IVF registry and gave birth to a live born singleton. In the questionnaire, 80.4% of them reported IVF/ICSI, 16.1% reported other types of infertility treatment such as IUI/HT and 3.4% did not report their infertility treatment (2.9% reported their TTP <6 months and were not asked about the treatment). Children conceived after IVF/ICSI according to the register had a higher risk of epilepsy (IRR = 3.54; 95% CI: 1.87–6.71) but not of febrile seizures (IRR = 1.12, 95% CI: 0.73–1.72) compared with children born of couples with a TTP of 0–5 months (data not shown in the table).
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Discussion |
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Children born by subfertile couples had an increased risk of epilepsy, especially if the parents had received infertility treatment. Subfertility was not associated with febrile seizures except in children conceived after HT, which may be a chance finding. Our results on IVF/ICSI births are consistent with the results of a Swedish register-based study, which indicates an increased risk of epilepsy after IVF (Kallen et al., 2005a
). However, the risk of epilepsy after IVF/ICSI in children born at term remained slightly elevated in our study although not statistically significant. The Swedish study did not find this association in children born at term. Our results on IVF/ICSI are supported by another Swedish study showing that children born after IVF treatment had an increased risk of neurological problems, especially cerebral palsy (Stromberg et al., 2002). Olivennes et al. (2002) reviewed the studies on the developmental outcomes after IVF and concluded that children conceived after IVF treatment have a normal behavioural development, but the reviewed studies had low statistical power. Our results indicate subfertility itself is associated with an increased risk of epilepsy, but an earlier study did not find an association between infertility and postneonatal non-febrile seizure (Nelson and Ellenberg, 1986). However, we found no data in the article on the characteristics of infertility in that study, including how they collected the information.
Health problems in singletons of subfertile couples may be because of the underlying conditions of subfertility, the procedures related to treatment and medication used to stimulate follicular development and ovulation (Lambert, 2003). Studies have shown that subfertile couples with or without ART have the increased risk of adverse obstetric outcomes including pre-eclampsia, placenta praevia, placental abruption and intrauterine growth retardation (Thomson et al., 2005; Kallen et al., 2005b).
We found an increased risk of epilepsy and febrile seizures after IUI/HT. This increased risk remained when we restricted our analyses to children born at term. The mechanisms for these associations are not clear, but studies show that pregnant women with ovarian stimulation but without IVF have increased risk of preterm birth, low birthweight, malformation, intracranial bleeding, respiratory distress syndrome and perinatal death (Olivennes et al., 1993; Kallen et al., 2002; Ombelet et al., 2006). Our study population was singletons, and some of these may be the results of spontaneous reduction of multiple pregnancies. A study shows that about 10% of the singletons born after IVF originated from a twin gestation, and singletons due to the spontaneous reduction of multiples pregnancies have a higher risk of adverse perinatal outcome compared with single gestation (Pinborg et al., 2005).
We used untreated infertile couples as reference in order not to overestimate the adverse effect of infertility treatment. We should be aware that subfertile couples receiving infertility treatment tend to be older, have more preterm births and smoke less than subfertile couples who conceived naturally. We cannot rule out that the higher risks for treated subfertility couples are related to the underlying subfecundity and not to infertility treatment. Treated subfertile couples have a longer TTP than subfertile couples who conceive spontaneously (Thomson et al., 2005), and treated couples may have a more severe form of infertility that could lead to confounding by indication.
Parental history of epilepsy is a potential confounder if it is related to subfecundity, which could be expected because male or female partners with epilepsy have reduced fertility (Nappi et al., 1994; Schupf and Ottman, 1994). In our study, fewer couples became pregnant within 5 months if one of the couples had epilepsy (62.3% if the mother had epilepsy versus 68.1% if the mother did not have epilepsy and 64.1% if the father had epilepsy versus 68.1% if the father did not have epilepsy). We traced all parental records in the Danish National Hospital Register to obtain a parental history of epilepsy, and this data source is not subject to recall bias but it is not complete because outpatients were not included in the Danish National Hospital Register before January 1995. Adjustment for parental history of epilepsy did not change the association between subfertility and the risk of epilepsy.
Fecundity is the probability of becoming pregnant within a given menstrual cycle of trying to become pregnant, and the TTP measure carries a substantial and unavoidable risk of misclassification. A proportion of normal fertile couples will have a long TTP just because of chance. Furthermore, the TTP will depend upon the couples understanding of when the chances of conception peak in the cycle and thus be able to time sexual intercourse to maximize the chances of conception.
The main limitation of this study is that the information on TTP and infertility treatments was self-reported and subject to misclassification. It is possible that the women reported infertility treatments that took place before the cycle leading to the conception, which would attenuate the associations we find for treatment. Furthermore, treated subfertile couples could be classified in the group with a TTP of 0–5 because the treated subfertile couples were recruited from those with a TTP 
6 months. Among 552 treated pregnant women registered in the IVF register, 13 (2.4%) reported a TTP of 0–5 months. This misclassification may tend to bias the results towards the null. The data also indicated some misclassification of treatment groups. Among 552 women registered in the IVF register, 16% reported that they had received other kinds of treatment (mainly IUI/HT) rather than IVF/ICSI. This misclassification would not affect the relative risk of overall treatment but may affect the relative risks in treatment specific strata.
Being born in an unplanned pregnancy was associated with an increased risk of epilepsy. The couples were older and had a higher proportion of a parity 3+ than that of fertile couples who planned their pregnancy. More were in the group of low social status and more smoked and had a history of epilepsy. Furthermore, 23% of couples who reported an unplanned pregnancy became pregnant despite using contraception.
We rely on data from the hospital discharge system for diagnoses of epilepsy and febrile seizures. The positive predictive value in the registry has been estimated to 81% (95% CI: 75–87) for epilepsy (Christensen et al., 2005) and 93% (95% CI: 89–96) for febrile seizures (Vestergaard et al., 2005). The completeness of registration on febrile seizures was 72% (95% CI: 66–76) (Vestergaard et al., 2005), but we have no data on the completeness of registration on epilepsy. An incomplete registration of epilepsy causes underestimation of the cumulative incidence of epilepsy, but rate ratios are affected only if the completeness of the registration is different for offspring of couples with different fertility status and treatments, which is unlikely.
If the associations between epilepsy and subfecundity and infertility treatment are causal, they have public health significance because subfecundity is common and infertility treatment is being used more and more. The treatment effects could, however, be confounded by the indication of treatment, and we need to know more about possible common causes for subfecundity and epilepsy.
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Acknowledgements |
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The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the DNBC. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the DNBC is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation.
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References |
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Submitted on April 3, 2006; resubmitted on June 9, 2006; resubmitted on July 7, 2006; accepted on July 11, 2006.
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