Risk of major congenital malformations in the offsprings of women with epilepsy is not related to family history

1. Introduction 

Epilepsy is a common neurological disorder that affects about 50 million people in the world. The risk of major congenital malformation (MCM) is a matter of concern to all women with epilepsy (WWE). Pregnancy in WWE is associated with a two to three fold increase in the risk of fetal malformations (Barrett and Richens, 2003, Tomson and Battino, 2008). The excess risk of MCM in offsprings of WWE can be potentially attributed to a genetic predisposition related to maternal epilepsy, the harmful effects of seizures during pregnancy, or the teratogenic effect of antiepileptic drug (AED). Metabolic derangements and vitamin deficiency induced by AEDs could also be the additional mechanisms for malformations. Data from pregnancy registries indicate that antenatal exposure to AEDs is associated with excess risk of malformations (Thomas et al., 2001, Morrow et al., 2006, Vajda et al., 2007). Typically teratogenic agents demonstrate a dose–response curve in which the risk of malformations increases considerably beyond a certain threshold value (Morrow et al., 2006). A genetic predisposition to malformations may also be operating as only less than ten percent of infants exposed to AEDs in utero develop malformations. Earlier studies had suggested that some of the minor dysmorphic features observed in the offsprings of WWE could have a genetic basis (Gaily et al., 1988). Studies that focused on genetic liability to malformation when mother has epilepsy have been few in the past, although a causal relationship had been raised in some of the earlier papers (Meadow, 1970). Genetic association between epilepsy and malformation had been discussed in relation to cleft lip or palate (Starreveld-Zimmerman et al., 1974). It has been shown that there is increased risk of malformations when the father had epilepsy just as when the mother had epilepsy (Dieterich et al., 1980, Koch et al., 1982). In a subsequent paper, Koch et al. (1992) postulated that a special genetic background that predisposes to epilepsy also renders the fetus more vulnerable to major and minor anomalies. Recent observations from registries of pregnancy and epilepsy indicate that there could be variation in the frequency of malformations between geographic areas. Excess risk of cleft lip and palate associated with lamotrigine was observed in North America (Holmes et al., 2008), but was not confirmed in the United Kingdom (Morrow et al., 2006). Nevertheless, there are other studies that negate any genetic liability to MCM attributable to maternal epilepsy. A meta-analysis of 1443 pregnancies in WWE using AEDs during pregnancy, 400 WWE not using AEDs during pregnancy and 2492 non-epileptic healthy control women showed that epilepsy per se did not increase risk of fetal malformations (Fried et al., 2004). Another review of published literature on epilepsy and cleft disorders in the offsprings failed to demonstrate any familial aggregation of cleft disorders in epilepsy (Hecht and Annegers, 1990). The Rochester population study observed that children of mothers with epilepsy, unexposed to AEDs did not have increased risk of malformations (Annegers et al., 1978). It is possible that a complex interaction between genetic factors and certain AEDs could also account for the excess risk of MCM. Our objective in this study was to ascertain whether there is increased family history for MCM in the first and second degree relatives of WWE and to ascertain the risk of MCM in the offspring, when the mother had family history of MCM.

3. Results 

Between April 1998 and April 2006, we obtained detailed pedigree of 614 probands. Probands had consanguinity with spouse in 41 cases which were excluded. Pedigree details of remaining 573 probands were used for this study, which encompassed 11,777 family members. The control sample consisted of 550 spouses (pedigree details of 23 spouses were not available) and 10,832 family members. The mean age of probands was 25.9 and that of the controls was 31.4. Hindus constituted 62% of the sample followed by Christians (24%) and Muslims (14%). The ethnic, religious, and socioeconomic characteristics of the controls were similar to that of the probands. Out of the 202 families whose economic status was recorded, family income was less than Rs. 2000 per month (USD <50) for 77% of the probands. The education level of probands (and spouse) in percentage were as follows: illiterate 0.7 (nil), 1–4 classes 2.6 (0.7), 5–10 classes 37.3 (19), 12th class 22.9 (6.6), university degree 27.7 (8.7), professional degree 8.2 (5.8). A higher proportion of probands had university education (p value=0.02) when compared to controls. More than half (55.5%) of the WWE had LRE and others had juvenile myoclonic epilepsy (22.7%) or other types of generalized epilepsies (21.6%). WWE with unclassified epileptic syndromes were not included in this analysis. Family history of epilepsy, where at least one of the first or second degree relatives had epilepsy, was significantly higher for probands (14%) when compared to controls (2%).

Family history was positive for MCM for 27 probands (4.7%) and 22 (4%) controls. There were 84 persons with history of MCM among 11,777 family members of the probands (0.71%) and 64 persons with history of MCM among the 10,832 family members of the control group (0.59%) (see Table 1). The history MCM was higher in the first degree relatives (1.18% for probands and 0.9% for the controls) when compared to second degree relatives (0.57% for probands and 0.47% for controls), but the differences were not statistically significant. The odds ratio (95% confidence intervals) for positive family history of MCM for the probands as a group was 1.21 (95% CI 0.87–1.68). The corresponding figures for the first degree relatives were 1.31 (95% CI 0.78–2.19) and for the second degree relatives were 1.21 (95% CI 0.80–1.86). There was no excess risk of history of MCM in the first or second degree relatives of the probands when compared to controls.

Table 1. History of congenital malformations in the first and second degree relatives of probands with epilepsy and controls.

		Probands			Control			p
		N	CM	%	N	CM	%
	First degree relatives	2,717	32	1.18	2,992	27	0.90	0.37
	Second degree relatives	9,060	52	0.57	7,840	37	0.47	0.42
	Total	11,777	84	0.71	10,832	64	0.59	0.29

CM=history of congenital malformation.

There was no significant difference in the frequency of MCM between those with generalized epilepsy and those with localization related epilepsy or between JME and other types of generalized epilepsies (Table 2).

Table 2. History of congenital malformations in the first and second degree relatives of probands according to the type of maternal epilepsy.

		N	Yes	%	Odds ratio	95%CI
	First degree relatives
	LRE	1447	17	1.17
	All GE	1139	14	1.23	1.05a	0.51–2.13
	JME	606	7	1.16
	GE other types	533	7	1.31	1.14b	0.40–3.27
	Second degree relatives
	LRE	4751	28	0.59
	All GE	3887	22	0.57	0.96a	0.55–1.68
	JME	2036	12	0.59
	GE other types	1851	10	0.54	0.92b	0.39–2.13

GE=generalized epilepsy, JME=juvenile myoclonic epilepsy, LRE=localization related epilepsy, CI=confidence interval.

a Comparing all GE with LRE. b Comparing GE other types with JME.

Out of 573 probands, 516 had conceived and pregnancy outcome was known for 426 (22 had spontaneous abortion, 1 had induced abortion for social reasons, 6 had intrauterine death, 30 pregnancies were lost to follow up and 31 live born infants were not presented for malformation screening). There were 51 WWE without AED exposure during pregnancy. Monotherapy was used in 68%, two AEDs in 25.5% and three AEDs in 6.5% WWE. The AEDs used were carbamazepine 206 (40.2%), phenobaribitone 135 (26.4%), valproate 139 (27.1%), phenytoin 103 (20.1%), clobazam 34 (6.6%), clonazepam 20 (3.9%), lamotrigine 12 (2.3%), oxcarbazepine 8 (1.6%), primidone 4 (0.8%) and topiramate 2 (0.4%). There was no preferential use or avoidance of any particular AEDs in this cohort. Seizures were well controlled in most patients.

Forty-four offsprings (10.3%) had MCM confirmed after birth. The MCMs noted were cardiac malformations (21), neural tube defects and other CNS malformations (6), cleft palate (5), skeletal malformations (4), hernia (2), renal malformations (5) and liver cyst (1). The MCM rate between individual AEDs was not statistically significant. Two of the 44 (4.5%) only had a maternal first degree relative with history of MCM (8% of those with positive family history). The odds ratio for MCM (0.74) when the maternal (proband) family history was positive was not significant (95% CI 0.19–3.26). Family history was available for only 409 spouses (out of the 426 with known pregnancy outcome). Paternal family history was not available for one infant with MCM. None of the 43 infants with MCM had a paternal first degree relative with history of MCM while 14 (3.8%) children without MCM had a paternal first degree relative with history of MCM (see Table 3). These proportions were not statistically significant (p=0.21).

Table 3. Major congenital malformations (MCMs) in the offsprings and history of MCM in maternal and paternal first degree relatives.

		MCM in offspring
		Yes	No
	Maternal first degree relatives with MCM*	2	23
	Maternal first degree relatives without MCM	42	359
	Paternal first degree relatives with MCM#	0	14
	Paternal first degree relatives without MCM	43a	395

a Paternal pedigree details were not available for one offspring with MCM. * Odds ratio 0.74, 95% confidence interval 0.19–3.26 or p=0.51. # p=0.21.

4. Discussion 

Persons with epilepsy and their relatives are concerned whether maternal epilepsy per se would increase the risk of malformations in the offsprings. Since genetic traits and predispositions may differ according to ethnic variations, it is important to estimate familial tendencies for individual geographic and ethnic groups. Precise population data on MCM are not readily available in developing countries. We examined this issue by looking for any familial clustering of MCMs in WWE. We also prospectively looked for any significant association between family history of MCM and occurrence of MCM in the offsprings. Pregnancy registry provided us with a large cohort of well worked up WWE who were followed up prospectively from pre-conception period through pregnancy and delivery until the children were six years of age. The availability of detailed pedigree data in the setting of this registry provided us the unique opportunity to obtain a sizable number of families with epilepsy and comparator groups matched for socioeconomic status, education and religious background. Only a small number (5.8%) of subjects were lost to follow up. We compared WWE and their spouses (controls) for positive family history of MCM in the first and second degree relatives. Spouses were convenient controls as they matched the probands in terms of ethnic characteristics, socio economic background and religion. Spouses and their families were well motivated to provide reliable pedigree details. Our results indicate that there is no increased frequency of MCM in the first or second degree relatives of WWE when compared to controls (Table 1) and the risk of MCM in the offsprings although high (10.3%) was not related to family history of MCM (Table 3).

The MCM rates for the first degree relatives of WWE were higher than those for the second degree relatives; nevertheless, the differences were not statistically significant. A similar trend was observed for the control group also. This pattern of possible under reporting in the second degree relatives is an inherent limitation of pedigree analysis but is unlikely to influence the results as it applies to probands and controls.

This is the first report on family history of MCM in WWE of Asian Indian origin. Our results are comparable to the findings in population of Caucasian origin in Rochester, MN, USA, where the rate of MCM in relatives of patients with epilepsy and that of their spouses was ascertained (Annegers and Hauser, 1982). Similar findings had been reported by other groups in USA. Some of the earlier reports point towards possible genetic basis for the occurrence of MCM in the offsprings of WWE. Congenital anomalies in offsprings of WWE were reported in the era prior to the availability of modern AEDs. These anomalies were regarded as stigmata of developmental disturbances related to the disease (Dansky et al., 1977, Janz, 1982). There are other studies that had suggested a possible association between maternal epilepsy and facial clefts in the offsprings. The familial clustering of epilepsy observed in the first and second degree relatives of probands with cleft palate had suggested a potential link between epilepsy and MCM (Dronamraju, 1970). Subsequent population based case–control study from Atlanta, USA (Abrishamchian et al., 1994) and from Israel (Gadoth et al., 1987) had supported this hypothesis. Nevertheless, the medical records linked population study in Rochester did not confirm any association between epilepsy and MCM particularly cleft palate (Annegers et al., 1974, Fraser et al., 1978, Annegers and Hauser, 1982). A study conducted in Denmark had shown that the risk ratio for facial cleft was higher (4.7) when the mother was taking AEDs, lower when not taking AEDs (2.7) and not increased when the offspring was born before the mother had manifested epilepsy (Friis et al., 1986). This pattern also indicates that MCM is related to environmental exposure rather than to any genetic predisposition for MCM. In our series, family history of MCMs did not differ according to the type of maternal epilepsy (Table 2). The first part of our data indicates that there is no familial clustering of MCM in WWE when compared to the controls and that the family history MCM was similar for both GE and LRE.

In the second part of this prospective study we had compared the family history of MCM and risk of MCM in the offsprings. We observed that there was no association between history of MCM in maternal or paternal first degree relatives and occurrence of MCM in the infants of WWE. The higher prevalence of MCM observed for the offsprings (10.3%) when compared to first degree relatives of proband or controls could be due to several factors. In this prospective study, all subjects were enrolled in the registry before the fetal outcome was known (either in preconception stage or in the first trimester, before the first antenatal ultrasonography). All offsprings were intensely investigated with clinical examination, echocardiogram and ultrasonogram while MCM in the family members was ascertained by only history obtained from the proband or spouse. The family history is likely to be an under-report, particularly for MCM related to internal organs. There can also be recall bias related to the higher concern regarding MCM in offsprings of WWE. AEDs are well known teratogens and exposure to AEDs in utero is an important risk factor MCM. There was no significant association between MCM in the offspring and maternal epilepsy syndrome. Use of any particular AED was not significantly associated with MCM.

Our data revealed that there is no familial clustering of MCM for WWE (when compared to controls) or there was no significant difference in family history of MCM between GE and LRE type of epilepsy syndromes. Over ten percent offsprings of WWE had MCM. The risk of MCM in the offspring did not have any significant association to family history of MCM. The risk of MCMs would probably be due to exposure to AEDs during pregnancy and other environmental factors. Our data forms a useful base to counsel the WWE in this part of the world that epilepsy per se is unlikely to increase the risk of MCMs in the offspring.

The strength of this study is the availability of high quality pedigree data on the probands and controls, ascertainment of MCM in the offspring by prospective evaluation of a large cohort of offsprings over ten year period. There are several limitations for this study. We have not corroborated the history of MCMs with the medical records of the affected members, nor have we characterized their precise malformations. The facilities available in the pregnancy registry did not permit us to go further in this direction. As the pedigree data were collected by history, there is a possibility of under reporting, particularly of internal malformations, which nevertheless is likely to occur for the cases and controls. We had attempted to minimize the recall bias by verifying the data directly from the proband, spouse and relatives through leisurely interview. Our observations from this pedigree analysis indicate that epilepsy per se or a positive family history for MCM does not increase the risk of MCM in the offspring.