development of the central nervous system ( cns ) is a complex process , which requires integration of many cellular processes including neural stem cell proliferation , migration , and neuronal differentiation .
the major neuronal migration occurs in humans between the 12th and the 24th weeks of gestation and results in the formation of the cortical plate .
however , the cortex continues to develop , and late migrations from the germinal matrix into the cerebral cortex continue until five months postnatally .
classification of neuronal migration disorders is based on morphological criteria and includes schizenccphaly , porencephaly , lissencephaly , argyria , macrogyria , pachygyria , microgyria , and micropolygyria .
pathogenesis of these malformations is multifactorial and includes genetic factors and environmental agents . in recent years
few epidemiological studies have addressed the impact of prenatal exposures , although several maternal factors such as use of ethanol or drugs , viral infections , maternal diabetes , and untreated phenylketonuria can potentially influence the neuronal migration .
the aim of this population - based study was to describe perinatal characteristics in infants diagnosed with neuronal migration disorders aiming at identifying potential risk factors .
the infants included in the study were identified as those hospitalized with a diagnosis related to a neuronal migration abnormality and confirmed by a computer tomography ( ct ) or magnetic resonance imaging ( mri ) .
all swedish residents are assigned a unique 12-digit national registration number , which is used for official population - based registers .
this number makes it possible to identify individuals and collect certain information within registers and also to link information between different registers .
the inpatient register is held by the national board of health and welfare , and it records information concerning hospitalizations , including date of admission and discharge and primary and secondary diagnoses together with the national registration number . from 1987 and
the swedish medical birth register was established in 1973 and includes data on more than 99% of all births in sweden .
a standardized set of medical records is used by all antenatal care clinics and delivery units and at the examination of the newborn infant . selected information from the records is computerized and forwarded to the register , which is held by the national board of health and welfare . for all births , medical information on maternal demographic data , the reproductive history , maternal smoking habits ,
the registration starts at the first visit to the antenatal clinic and is completed when the mother and newborn infant are discharged from the hospital .
the records , which include copies of referrals for radiologic examinations , were used to identify the children who had been examined with ct or mri and to validate the diagnosis of a neuronal migration disorder .
information concerning factors that might influence neuronal migration disorders was obtained through the swedish medical birth register . for the mothers we obtained information about age , body mass index at first antenatal visit ( bmi , calculated as maternal weight in kilograms at first visit to the antenatal clinic / maternal height times height ) , chronic diseases prior to index pregnancy , reproductive history ( parity , years of infertility ) , and smoking in early pregnancy .
bmi was classified according to who definition as underweight < 18.5  kg / m , normal weight 18.5  kg / m and < 25  kg / m , overweight 25  kg / m and < 30  kg / m , and obesity 30  kg / m .
smoking was classified as no smoking , smoking 19 cigarettes / day , and > 10 cigarettes per day .
we also obtained information on maternal diseases during pregnancy and mode of delivery ( noninstrumental and instrumental vaginal delivery and emergency and elective cesarean section ) .
as chronic diseases we included kidney failure , celiac disease , epilepsy , ulcerative colitis , diabetes mellitus , asthma , and systemic lupus erythematosus . the information was retrieved by the international classification of diseases as icd-9 or icd-10 codes , and all icd-9 codes were manually transformed into icd-10 codes .
for the infants we obtained information on sex , gestational age at birth , birth weight and birth length , and the apgar scores at one and five minutes .
small for gestational age ( sga ) was defined as birth weight more than 2 standard deviations ( sds ) below the mean birth weight for gestational age and sex according to a swedish birth weight curve .
appropriate for gestational age ( aga ) was defined as a birth weight between 2  sd and + 2  sd and large for gestational age ( lga ) as a birth weight more than 2  sd above the mean .
all infants born alive from 1980 through 1999 and diagnosed with a neuronal migration disorder according to mri or ct scan sometime during this period were eligible for inclusion in the study .
a total of 820 infants had been hospitalized with a diagnosis such as congenital myopathies and malformations of the cns that could be related to a neuronal migration disorder ( icd 9 : 359.1 - 359.24 , 742.1 - 24 , 759.23 , and icd 10 : q 040.0 - 89.9 , g 71.2 ) .
we requested information on performed ct or mri scans by a letter sent to all paediatric and radiological clinics in the country , and about half of the 47 clinics responded to our request . in 120 of the patients ,
the diagnosis of neuronal migration was confirmed by the local radiologist in 17 subjects , 9 boys and 8 girls , all of whom were included in the study . as the study was purely descriptive , no formal testing was possible . for certain characteristics ( maternal age , bmi , gestational age at birth , and birth weight ) ,
the mother 's median age was 29 years , and most women were born in sweden ( table 1 ) .
one of the mothers was underweight with a bmi below 19 at the start of pregnancy , and none was obese .
the mean bmi of the mothers at first antenatal visit was 21.3 ( range 17.628.5 ) .
one woman suffered from chronic multifocal osteomyelitis and necrosis and another was involved in a motorbike accident .
maternal care for ( suspected ) damage to the fetus by radiation was reported in one case .
nine male infants and eight female infants were born after mean 39.3 gestational weeks and with a mean birth weight of 3327 grams .
all children were born as singletons and were aga , and all had a full apgar score .
most infants were classified to have an undefined migrational disorder , a disturbed migration of the immature brain or a migrational disorder of unknown type .
congenital malformations of the spleen or the heart , potter 's syndrome , and facial asymmetry were reported , including malformation of the eye and lens , microphthalmus , and cleft palate .
two infants had skin problems at birth , and one infant suffered from obstruction of the intestine by gallstones or meconium ( table 2 ) .
all infants were born at term and of ordinary birth weight to healthy mothers with normal or subnormal bmi and after normal pregnancies .
most of the infants had a concomitant malformation , and two infants were diagnosed with congenital rubella infections .
the use of modern techniques of brain imaging , especially mri , has dramatically improved the ability to detect these neurological disorders while the child is still alive . over 25 syndromes related to disturbances of neuronal migration
. the incidence of disturbances of the neuronal migration is not known , but is increasing in the pediatric population probably due to the use of mri techniques for brain imaging .
epidemiological studies and experimental data have demonstrated the importance of nutritional factors in fetal brain development and the deleterious effects of nutritional deficits [ 911 ] .
bmi was recorded for 12 of the women in the study , and more than half of them had subnormal or near subnormal bmi at start of pregnancy . since
1992 maternal bmi has been recorded in sweden at the first antenatal visit , and an increase from 23 to 24 in mean bmi was noted between 1992 and 2002 .
one can speculate whether the generally lower bmi among these 12 mothers of infants with neuronal migration disorder , as compared to the general pregnant population might have influenced the fetal brain development .
however , it was not possible to calculate the adjusted association between maternal bmi and risk of neuronal migrations disorder in this small descriptive study .
the impact of maternal bmi at start of pregnancy and/or weight gain during pregnancy on the fetal brain development and neuronal migration needs to be evaluated in a larger study .
it is well known that maternal diseases during pregnancy , such as diabetes and nontreated phenylketonuria , and conditions where the placental blood flow is reduced , such as preeclampsia , could interfere with the fetal brain development [ 1 , 9 , 13 , 14 ] .
even a less severe maternal hypothyroidism during the first half of gestation might affect the fetal neurodevelopment and neuronal migration .
few studies have addressed the impact on maternal health on specific migration disorders . in our study
however , conditions related to an abnormal pregnancy and conditions which all can cause suboptimal growth conditions for the fetus were reported in four women .
neuronal migration disorders have been described in humans and/or in animal models following in utero exposures to infections .
some viruses , such as herpes simples , cytomegalovirus ( cmv ) , or hiv , are potentially capable to persist in a latent form within the central nervous system .
several studies have described the teratogenic effect of cmv infection and the relation to neuronal migration disorders [ 1618 ] .
adverse impacts of maternal infections due to rubella , group b streptococcus , cytomegalovirus , toxoplasmosis , and chorioamnionitis in the fetal brain are known .
however , two children were reported with rubella syndrome at birth , which is more than expected .
the percentage of susceptible pregnant women with rubella was gradually reduced from 12% in 1975 to just below 2% in 1994 .
rubella syndrome is very uncommon , and between 1975 and 1985 , only a mean of two cases per year were recorded in sweden . since 1985 , no child with the rubella syndrome has been registered .
it can be speculated that rubella had an impact on the neuronal migration in two cases in this study .
it is well known that maternal smoking increases the risk of intrauterine growth restriction and affects the fetal brain by inducing intrauterine hypoxia or by acting directly on the developing brain [ 2123 ] .
smoking habits among women have changed over time in sweden . during the 1960s as many as 25%
of the women smoked , this was reduced to 14% in 2004 . in this study 23% of
the women smoked , which was more than in the general pregnant population during this time period .
the detection of cases was difficult mainly because of our strict criteria for eligibility , which included a ct or mri scan confirming the diagnosis . in 120 of all hospitalized children ,
a ct or mri scan of the brain was preformed , and only 17 of them were confirmed with a neuronal migration disorder . despite several reminders , only 50% of all hospitals in sweden responded to our request to send in ct and mri scans .
none of the hospitals actively rejected participation in the study . the cause of this dropout is not known but was evenly distributed between level i , ii , and iii hospitals over the country .
it can be speculated that journals from the study period were not easily found , and the time for searching these journals was regarded as too expensive for the hospitals .
the study refers to a time of great medical advances , and the use of ct and mri scan is more widely used today .
the cases were identified through the national patient register , and the responding hospitals were evenly spread over the country .
considering the increasing use of ct and mri scans , a study performed in more recent years might detect more children with neuronal migration disorder .
this descriptive study indicates that there might be an impact of low or subnormal maternal bmi before and during pregnancy , maternal infection , such as rubella , and maternal smoking on fetal brain development , including neuronal migration .
the roles of maternal bmi and congenital infections should be tested in future analytical studies .
 the development of the central nervous system is complex and includes dorsal and ventral induction , neuronal proliferation , and neuronal migration , organization , and myelination . 
 migration occurs in humans in early fetal life . 
 pathogenesis of malformations of the central nervous system includes both genetic and environmental factors . 
 few epidemiological studies have addressed the impact of prenatal exposures . 
 all infants born alive and included in the swedish medical birth register 19801999 were included in the study . by linkage to the patient register , 
 820 children with a diagnosis related to a neuronal migration abnormality were identified . through copies of referrals for computer tomography or magnetic resonance imaging of the brain , the diagnosis was confirmed in 17 children . 
 median age of the mothers was 29 years . at the start of pregnancy , four out of 17 women smoked . 
 almost half of the women had a body mass index that is low or in the lower range of average . 
 all infants were born at term with normal birth weights . 
 thirteen infants had one or more concomitant diseases or malformations . 
 two infants were born with rubella syndrome . the impact of low maternal body mass index and congenital infections on neuronal migration disorders in infants should be addressed in future studies . 