Short-term results of patients with neural tube defects followed-up in the Konya region, Turkey

O R I G I N A L A R T I C L E

Short-term results of patients with neural tube defects

followed-up in the Konya region, Turkey

Alaaddin Yorulmaz

| Murat Konak

1_{Department of Pediatrics, Selçuk University,} Selçuklu Medical Faculty, Konya, Turkey 2_{Division of Neonatology, Selçuk University,} Selçuklu Medical Faculty, Konya, Turkey Correspondence

Murat Konak, Division of Neonatology, Selçuk University, Selçuklu Medical Faculty, Konya, Turkey.

Email: muratkonak@selcuk.edu.tr

Background:Additional congenital anomalies have often been found in patients with neural tube defect (NTD). We aimed to find out the clinical features, short term prognosis, treatment approaches, and systemic anomalies of NTD patients in the Konya region.

Method: A total of 186 newborn babies with NTD were retrospectively included in the study and all were assessed in detail for congenital anomalies and clinical features.

Results: When the application month of the patients was examined, it was seen that the most frequent month was July. Of 186 babies, 101(54.3%) had meningo-myelocele, 53 (28.5%) had meningocele, 13 (7.0%) had encephalocele, 16 (8.6%) had spina bifida occulta, and 4 (2.1%) had anencephaly. Of these patients, 97 (52.2%) were male and 89 (47.8%) were female. Hydrocephalus was an almost constant finding and was found in 140 (75.3%) patients. 51 (27.4%) patients had congenital heart disease (CHD). The most common CHD was atrial septal defect 22.3%. Orthopedic anomaly was detected in 51 (27.4%) patients, nephrological anomaly was found in 47 (25.3%) of the cases, congenital hypothyroidism was diagnosed in 14 (7.5%) patients with NTD. The mortality rate of patients diagnosed with NTD was 7.5%. The rates of premature delivery and consanguinity between parents were higher in patients with NTD.

Conclusions:Our results indicate that at least one congenital anomaly is also pre-sent in about two-thirds of newborn babies with NTD, and these anomalies signifi-cantly increase their morbidity and mortality. All newborn babies with NTD should be screened for additional congenital anomalies and evaluated with more organized, multidisciplinary methods.

K E Y W O R D S

congenital anomalies, congenital hypothyroidism, folic acid, hydrocephalus, neural tube defect

1 | I N T R O D U C T I O N

Neural tube defect (NTD) constitutes the most important ratio of congenital central nervous system malformations and develops due to non-closure of the neural tube between the third and fourth weeks of intrauterine period (Altas¸ et al., 2012; Greene & Copp, 2014). Its prevalence in the world varies between 0.57 and 13.87% (Nikkilä, Rydhström, &

Källén, 2006). Although the incidence in Turkey varies from 3 to 5.8 per 1000 by region, it is considered to be 3 per 1000 on average (Tunçbilek, 2004). The closure of the neural tube starts from the cervical region and continues through a continuous process toward the cranial and caudal area (ACOG, 2017).

Various NTD occur according to the region where the closure of the neural tube is affected. The neural tube closure

DOI: 10.1002/bdr2.1462

problem in the skull results in anencephaly, whereas the clo-sure problem in the caudal region results in myelomeningo-cele or spina bifida. NTDs include a heterogeneous group of spinal abnormalities with incomplete fusion of the midline mesenchymal, bony, and neural structures as common feature. If closure is not completed, the neuroepithelium remains exposed to the environment and consequently subject to degeneration and neuronal deficit. In spina bifida aperta, the overlying skin is deficient and neural tissue and/or meninges are exposed to the environment. The lesion may be covered by a membrane and an underlying cystic mass may protrude as spina bifida cystica. Myeloceles and myelomeningoceles are the two commonest forms of spina bifida aperta, and appear to result from disturbed neurulation. The neural tissues may be contained within a meninges-covered sac that pro-trudes through the open vertebrae (myelomeningocele; spina bifida cystica) or exposed directly to the amniotic fluid (mye-locele) (Naidich et al., 1996).

Severe forms of NTDs can result in death in the intra-uterine period or immediately after birth. Mild forms that are compatible with life cause serious morbidity in the neonatal and/or later periods. These patients have lifelong neurologi-cal, orthopedic, gastrointestinal and urological problems (Januschek et al., 2016). The medical expenses of NTD patients cause a serious financial burden and a cost of approximately $1.4 million is required for a case over a period of 20 years (Akar, Cavdar, & Arcasoy, 1988).

The etiology of NTD is multifactorial, and there are sev-eral factors in the etiology including drug exposure, geo-graphical and ethnic differences, chromosomal anomalies, single gene disorders, and positive family history (ACOG, 2017). With the support of maternal folic acid, formation of a significant ratio of NTD such as 15.5–58% can be pre-vented (Castillo-Lancellotti, Tur, & Uauy, 2013). NTD can be recognized by ultrasonographic imaging in intrauterine period. Because these patients require multidisciplinary follow-up and treatment, they should be referred to the top centers having third stage neonatal unit and neurosurgery unit in the intrauterine period.

In this study, we aimed to investigate the clinical fea-tures, short term prognosis, treatment approaches, and sys-temic anomalies of NTD patients followed in our newborn center and discuss them in the light of the literature.

2 | M A T E R I A L S A N D M E T H O D S

In this study, 186 newborn infants who were hospitalized with the diagnosis of NTD in Selcuk University Medical Faculty Neonatal Intensive Care Unit between April 2010 and May 2018 were retrospectively reviewed. Medical records of patients were obtained from patient files and com-puter electronic data. Perinatal information (gender, type of delivery, gestation week, birth weight) of the patient, socio-demographic characteristics of the mother (age, level of

education, number of pregnancies, regular doctor control, history of miscarriage or stillbirth, questioning of systemic disease), status of affinity between parents, NTD type, local-ization, operation time, accompanying additional anomalies, presence of hydrocephalus, ventriculo-peritoneal (VP) shunt requirement, and data for shunt infection were determined, examined, and recorded.

The diagnosis of NTD was based on physical examination and radiological findings. Radiological imaging and patholog-ical evaluation were used to determine the type and localiza-tion of NTD. Cardiological evalualocaliza-tion was performed. Radiological imaging was used to investigate urogenital anomalies, orthopedic deformities, and gastrointistinal anoma-lies. TSH level above 10 mIU/L while low level of fT4 was accepted as hypothyroid (Léger et al., 2014).

Local ethics committee approval was obtained for this study (2018/292).

2.1 | Statistical analysis

Statistical evaluation was performed using SPSS 21.0 (Statistical Program in Social Sciences) computer program. Data were expressed as number, percentage, mean, and stan-dard error of the mean. The comparisons between the groups were performed by the Mann–Whitney-U test for the signifi-cance test of the difference between the two means. Categor-ical data were compared by “chi-square” test. p values below 0.05 were considered statistically significant.

3 | R E S U L T S

In our study, 186 patients diagnosed with NTD were evalu-ated. Male/female ratio was 1.09. 55 (29.6%) patients were born with normal spontal vaginal route and 131 (70.4%) patients were born with C/S. Of these cases, 27.4% had pre-mature birth and 72.6% had pre-mature birth. Demographic char-acteristics of the patients are given in Table 1.

The mean age of the mothers was 27.85 ± 6.00 (17–42) years. Age of 8 (4.3%) of the mothers of the cases was <18 years while the age of 29 of them (15.9%) was >35 years. Four (2.2%) of the mothers were over 40 years old. There was no statistically significant difference between the age of mothers and NTD (p=0.275). There was no statis-tically significant difference between mothers' education level and NTD type (p=0.192). When the consanguinity between parents was examined, it was found that there was consanguinity between 26 (14.0%) couples. There was no statistically significant difference between NTD and consan-guinity (p=0.375). Previous history of childbearing with NTD of themselves or their close relatives were evaluated. One of the mothers previously had pregnancy with NTD. Four families (2.15%) had a history of having children with NTD in their close relatives. When the use of folic acid in the mothers was questioned, it was learned that 78 (41.93%)

of them used folic acid supplements recommended by the family physician or gynecologist even irregularly. When evaluated in terms of the febrile disease in pregnancy, 42 (22.58%) of the mothers had febrile disease in the prena-tal period. In terms of use of medicine in the first 3 months of pregnancy, 38.17% (n: 71) used medicine (Antibiotics, antiemetics, and analgesics). In our study, four (2.15%) mothers had a history of antiepileptic drug (Valproic acid) use. Four mothers had gestational diabetes, and three mothers had Type 1 diabetes. In addition, it was detected that four mothers had morbid obesity, and three mothers had preeclampsia. The number of mothers who had smoked in the first 3 months was 8 (4.30%). There was no alcohol use during pregnancy. There was no history of contact with radi-ation known in the mothers.

Of the cases with NTD, 101 (54.3%) had meningomyelo-cele, 53 (28.5%) had meningomeningomyelo-cele, 13 (7.0%) had encephalo-cele, 16 (8.6%) had spina bifida occulta, and 4 (2.1%) had anencephaly (Table 2). There was no statistically significant difference between NTD and gender (p=0.542). When the NTD were examined according to the sac localization, the

most common location was lumbar region (40.4%). All patients with encephalocele were with occipital location. Encephalocele was located in the occipital region in 11 patients (84.6%) and in frontoethmoidal and parietal regions in one patient per each (7.7%).

When the application month of the patients was exam-ined, it was seen that the most frequent month was July. This was followed by April and June.

All patients underwent detailed neurological examina-tion. Brain CT scan or Brain and spinal MRI was taken in all patients. When neurological complications of NTD were examined, hydrocephalus was an almost constant finding and was found in 140 patients (75.3%). The neurological findings of the patients according to the results of magnetic resonance imaging are shown in Table 3. VP shunt was applied in the same session or different session due to hydro-cephaly in 112 (65.9%) cases. When the timing of the opera-tion was evaluated, it was found as 5.45 ± 6.42 days for NTD and 12.5 ± 7.87 days for hydrocephalus. NTD improvement operation was performed in the first 72 hr in 47.3% of the cases. Shunt revisions were performed in 27 (14.51%) patients during follow-up periods. Shunt menin-gitis developed after VP shunt operation in 69 patients (37.1%). The second most common neurological complica-tion was Chiari malformacomplica-tion. Chiari II malformacomplica-tions were detected in 61 (32.8%) of the cases, and Chiari I malforma-tions were detected in 18 (9.7%) of the cases. Corpus callo-sum anomaly was present in 72 patients (38.7%). There was no statistically significant difference between NTD type and neurological anomaly (p=0.147).

Echocardiography was performed in 148 (79.6%) patients. 51 (27.4%) patients had congenital heart disease (CHD). The most common CHD was atrial septal defect (ASD) (22.3%) (Table 4). There was no statistically signifi-cant difference between NTD type and congenital heart dis-ease (p=0.290). There was no significant difference in terms of gender and CHD (p=0.756).

Orthopedic anomaly was detected in 51 (27.4%) patients with NTD. Among the orthopedic deformities observed dur-ing admission, pes equinovarus (17.2%; n: 32) was the most common one. It was detected that 17 patients (9.1%) had

TABLE 1 Demographic characteristics of the patients

N Percentage (%) Gender Male 97 52.2 Female 89 47.8 Gestational age <32 weeks 15 8.0 32–37 weeks 36 19.4 >37 weeks 135 72.6 Birth weight (gram)

<2,500 50 26.9 2,500–4,000 129 69.4 >4,000 7 3.8 Maternal age <18 8 4.3 18–30 109 58.6 30–35 40 21.5 >35 29 15.6

Mother's education level

Primary school 67 36.03 Secondary school 74 39.79 High school 40 21.50 University 3 1.61 Illiterate 2 1.07 Mortality 14 7.5 Mean ±SD (min–maks) Gestational age(week) 36.92 ± 2.94 (25–41) Maternal age(year) 27.85 ± 6.00 (17–42) Birth weight (gram) 2,875.46 ± 661.46 (960–4,690) Operation time

NTD correction (days) 5.45 ± 6.42 (2–17) V-P shunt for hydrocephalus (day) 12.5 ± 7.87 (2–24)

TABLE 2 NTD types and localization

NTD type N Percentage (%) Anencephaly 4 2.1 Encephalocele 13 7,0 Meningocele 53 28.5 Meningomyelocele 101 54.3 Spina bifida 15 8.1 Localization Lombar 73 39.2 Lombosacral 45 24.6 Thoracolumbar 34 18.6 Sacral 17 9.3

scoliosis and nine (4.8%) had developmental dysplasia of the hip. Orthopedic anomalies observed in our patients are shown in Table 5. There was a statistically significant differ-ence between the presdiffer-ence of orthopedic anomaly and NTD type (p=0.045). It was detected that orthopedic anomalies were more common in meningomyelocele patients.

When urinary system anomalies were examined, nephro-logical anomaly was found in 47 (25.3%) of the cases. Neu-rogenic bladder was detected most frequently with 24 patients (12.9%). This was followed by hydronephrosis

with 19 patients (10.2%). Other urinary tract anomalies are shown in Table 6. There was no statistically significant dif-ference between urinary tract anomaly and NTD type (p=0.351).

When endocrinologic anomalies were examined, con-genital hypothyroidism was diagnosed in 14 (7.5%) patients. In addition, diabetes insipidus was diagnosed in two patients, and inappropriate ADH and adrenal insufficiency in one patient for each.

For the anomalies in other systems, 5 (2.7%) patients had cleft lip and palate anomalies, 4 (2.2%) patients had unde-scended testes, 3 (1.6%) patients had inguinal hernia, and 3 (1.6%) patients had bilateral choanal atresia. The anoma-lies of the other systems are shown in Table 7.

Meckel-Gruber syndrome was diagnosed in two patients with encephalitis, two patients had trisomy 18, and one patient had trisomy 13. One patient with meningomyelocele for each was diagnosed with Goldenher syndrome, Fraser syndrome, Joubert syndrome and VATER syndrome. Two patients were diagnosed with immunodeficiency.

Of the NTD cases, 21 (11.3%) had meningitis, 17 (9.1%) had sepsis, 10 (5.3%) had wound infection and 4 (2.2%) had opening in wound area. Bacteria were isolated in BOS cul-ture in 7 of 21 newborns who were diagnosed with

TABLE 4 Types of congenital heart disease in patients with NTD CHD N Percentage (%)

Normal 97 65.5

Atrial septal defect 33 22.3 Ventricular septal defect 11 7.4 Patent ductus arteriosus 5 3.4 Pulmonary hypertension 4 2.7 Tetralogy of fallot 2 1.4 Dextrocardia 1 0.7 Total venous return anomaly 1 0.7 Situs solitus levocardi 1 0.7 Pulmonary valve insufficiency 1 0.7 Mitral valve prolapse 1 0.7 Tricuspid atresia 1 0.7 Tricuspid valve insufficiency 1 0.7

TABLE 5 Orthopedic anomalies in patients with NTD

Orthopedic anomalies N % Pes equinovarus 32 17.2

Scoliosis 17 9.1

Developmental hip dysplasia 9 4.8

Pes cavus 4 2.2

Lumbar kyphosis 4 2.2 Sacral (caudal) regression 3 1.6 Vetrebra anomaly 3 1.6 Hand and foot finger deformity 3 1.6 Chest costal deformity 3 1.6 Pectus carinatus 2 1.1 Syndactyly 2 1.1 Polydactyly 2 1.1 Limb anomaly 1 0.5 Foot contracture 1 0.5 Achondroplasia 1 0.5

TABLE 3 The neurological findings of the patients according to the results of magnetic resonance imaging

Neurological anomalies N Percentage (%) Hydrocephalus 140 75.3 Chiari malformation 79 42.5 Chiari malformation I 18 9.7 Chiari malformation II 61 32.8 Corpus callosum 72 38.7 Total agenesis 37 19.9 Partial agenesis 11 5.9 Dysgenesis 24 12.9 Colpocephaly 15 8.1 Syringohidromyelia 16 8.6 Dandy Walker variant 9 4.8 Tethered cord 8 4.3 Absence of septum pellucidum 6 3.2 Brain hypoplasia 5 2.7 Interhemispheric cyst 5 2.7 Polymicrogyria 4 2.1 Arachnoid cyst 3 1.6 Neuroenteric cyst 3 1.6 Cerebellum hypoplasia 2 1.1 Heterotopic gray matter (periventricular) 2 1.1 Cavum vergae variation 2 1.1 Mega cisterna magma 2 1.1 Posterior fossa cyst 1 0.5 Immature white matter 1 0.5

TABLE 6 Urinary system anomalies in patients with NTD

Urinary anomalies N Percentage (%) Neurogenic bladder 24 12.9

Hydronephrosis 19 10.21 Renal agenesis 5 2.7 Horseshoe kidney 2 1.1 Multicystic dysplastic kidney 2 1.1 Nephrolithiasis 2 1.1 Ureteropelvic stenosis 2 1.1 Polycystic kidney 2 1.1 Cortical cyst 1 0.5

meningitis. Three patients had Pseudomonas aeruginosa, two patients had Klebsiella pneumoniae and one patient for each had Acinetobacter baumannii and Enterobacter cloa-cae. The mortality rate of patients diagnosed with NTD was 7.5%. Four patients with anencephaly, two patients with encephalocele, who were diagnosed with Meckel-Gruber syndrome and one with meningomyelocele who were diag-nosed with VATER syndrome died. Three newborns died due to sepsis, two newborns died due to pneumonia, one newborn died due to being premature, one newborn died due to meningitis.

4 | D I S C U S S I O N

The term NTD defines the closure problems of the neural tube during the embryogenesis (Greene & Copp, 2014). The neural tube is formed by folding of the neuroepithelial cell layer 3–4 weeks after fertilization (ACOG, 2017). NTD is one of the most common congenital anomalies in neonates (Altas¸ et al., 2012).

The development of the neural tube is a multi-step pro-cess that is strictly controlled by genes and influenced by environmental factors (Volcik et al., 2002). It was shown that many factors, such as mother's malnutrition, obesity, diabetes mellitus, hypertension, and environmental pollut-ants, may cause failure of neural tube closure. In various comprehensive studies, it was found that NTD has a differ-ent incidence according to the geographical region and the socioeconomic status of the parents (Canfield, Annegers, Brender, Cooper, & Greenberg, 1996). In general, maternal age is thought to cause a minimal increase in the risk of NTD. In a limited number of studies examining the relation-ship between the risk of NTD and maternal age, it was found to be associated with a very young or over 40-year-old

pregnancy (Unusan, 2004). In a large-scale study conducted in Poland, it was reported that young mother's age causes a minimal increase in NTD risk (Materna-Kiryluk et al., 2009). Our study was consistent with this information in the literature.

Another known risk factor in the development of NTD is folic acid deficiency (Czeizel & Dudás, 1992). In developed countries, the incidence of NTD decreased to 1/1000 with folic acid supplementation especially after 1960. However, NTD is still a serious problem in developing countries (Perry, Albright, & Adelson, 2002). With folic acid supple-mentation, 79% decrease for spina bifida and 57% decrease for anencephaly can be achieved for the risk of developing NTD (ACOG, 2017). The United States enriched wheat flour with folic acid, resulting in a 19% decrease in all NTD rates (Honein, Paulozzi, Mathews, Erickson, & Wong, 2001). It was reported that the rate of NTD decreases by 70% with the use of 0.4 mg folic acid supplementation beginning from the periconseptional period (Czeizel & Dudás, 1992). A normal adult diet can meet only half of this requirement. For this reason, folic acid supplementation dur-ing antenatal period is very important in preventdur-ing the development of NTD. In our study, the fact that no mother received regular folic acid support during pregnancy, and during pregnancy suggests that folic acid support should be applied to cereal products in our country. In a study con-ducted in 2004 on women aged over 18 years in our country, it was observed that prevention of birth defects with folic acid was known by only 13% of the participants, and most of them were university graduates (Unusan, 2004). It was observed that none of the women in our study had used pre-conceptional folic acid, and postconceptally started folic acid and multivitamin preparations were not used as recom-mended. This situation suggests that the level of awareness of the society is insufficient and that more information should be provided.

Tunçbilek (2004) stated that the low maternal education, advanced maternal age or living in the east or north of Tur-key was a risk factor for NTD. Farley, Hambidge, and Daley (2002) reported that poor maternal education level may be an important indicator for having a child with NTD. In a study conducted by Mandıracıo
glu, Ulman, Lüleci, and Ulman (2004) in _lzmir, it was found that the education level of mothers with NTD was significantly lower than the con-trol group. Similarly in our study, when the educational level of mothers was evaluated, 67 mothers (36.03%) were pri-mary school graduate, 74 mothers (39.79%) were secondary school graduate, 40 mothers (21.50%) were high school graduate, and 3 mothers (1.61%) were university graduate, 2 mothers (1.07%) were illiterate. Although the importance of maternal education in the development of NTD was emphasized in many publications, in a study by Rouhani et al. in which mother education was accepted as a strong socioeconomic indicator in Spain, when all women were

TABLE 7 Anomalies related to other systems in patients with NTD Other anomalies N Percentage (%) Cleft lip and palate anomaly 5 2.7

Undescended testis 4 2.2 Inguinal hernia 3 1.6 Bilateral coanal atresia 3 1.6 Ttracheomalacia 2 1.1 Laryngomalacia 2 1.1 Esophageal atresia 2 1.1 Colon atresia 1 0.5 Anal atresia 1 0.5 Nasal agenesis 1 0.5 Lung hypoplasia 1 0.5 Omphalocele 1 0.5 Hirschsprung's disease 1 0.5 Microglossia 1 0.5 Low ear 1 0.5

allowed to reach folic acid rich foods, they stated that socio-economic level was not a significant risk in the development of NTD (Rouhani et al., 2007). They indicated the impor-tance of folate-rich diet, imporimpor-tance of providing folic acid supplementation by the state and providing adequate training to women with low socioeconomic status about the impor-tance of folate-containing foods.

Advanced maternal age poses a high risk for fetal loss, premature birth, low birth weight, various congenital anoma-lies, and infant mortality. Although studies on the effect of maternal age on NTD development have a small risk factor, it was pointed out that maternal age above 40 years and below 18 years leads to an increase in the development of NTD and in the probability of spina bifida compared to anencephaly in NTD types (Au, Ashley-Koch, & Northrup, 2010).

However, Mandıracıo
glu et al. (2004) did not find any significant difference between the age of the mothers having babies with NTD, and they found that mothers were in the younger age group in both groups. Also, in our study, age of 8 (4.3%) of the mothers of the cases was <18 years while the age of 29 of them (15.9%) was >35 years. Four (2.2%) of the mothers were over 40 years old.

Consanguineous marriages significantly affect the mor-tality and morbidity, and consanguineous marriages are com-mon in Turkey (25%). The risk of having NTD in the siblings, second-degree, and third-degree relatives of the individuals with NTD increased by 3.2, 0.5, and 0.17%, respectively. The risk in the presence of two siblings with NTD is up to 10% (Toriello, Higgins, & Opitz, 1983). In our study, it was detected that there was consanguinity between 14% of the cases.

In the formation of NTD, especially teratogenic factors encountered in the neural tube formation period were ques-tioned. Smoking, use of alcohol, febrile diseases during pregnancy and drugs used during pregnancy were empha-sized. It was shown that these teratogens will be toxic to the developing embryo, for example, the cadmium within the cigarette causes anencephaly, and nicotine induces embry-onic apoptosis in mice, antiepileptic drugs used in pregnancy (valproic acid, carbamazepine) and folic acid antagonists (methotrexate, aminopterin, and trimethoprim) were deter-mined to cause NTD. In the United States, an increased risk of NTD was observed in women who smoked 25 or more cigarettes per day (Suarez et al., 2011). In women who do not smoke, it was detected that the risk of developing NTD was found to increase because of the fact that their partners smoke (Suarez et al., 2011). In addition, no consistent evi-dence was found between cigarette consumption and con-genital anomalies in a study investigating the relationship between smoking, alcohol, and coffee consumption with congenital defects (McDonald, Armstrong, & Sloan, 1992). There are conflicting results regarding the relationship between smoking and NTD. In our study, the number of

mothers who had smoked in the first 3 months was 8 (4.30%). No association between alcohol use and NTD was found. However, studies showed that alcohol consump-tion in animal models leads to NTD and many other anoma-lies depending on the week and amount of alcohol consumption. In our study, there was no mother consuming alcohol.

Within the maternal chronic diseases, diabetes mellitus is the most studied one for the association with NTD. In a comprehensive study including England, Wales, and North-ern Ireland, nervous system anomalies in the babies of women with diabetes, especially NTD, were reported to increase by 4.2 times (Macintosh et al., 2006). It is reported that the risk of NTD increases due to genetic variants that play a role in glucose balance (Lupo et al., 2012). The effect of protein kinase C, which plays an active role in apoptosis, on the development of diabetes-induced NTD was also reported by Jorde, Fineman, and Martin (1984). In our study, it was detected that four mothers had gestational diabetes and three mothers had Type 1 diabetes.

Also, trisomy 13, trisomy 18, some chromosomal tions and duplications, genetic syndromes and micro dele-tions such as deletion of 22q11.2 are associated with NTD (ACOG, 2017). Increased maternal age primarily accom-panies chromosomal abnormalities. Gedikbas¸ı et al. reported that the possibility of coexisting karyotype abnormalities is low for isolated vertebral anomalies and therefore they do not require karyotype analysis (Gedikbas¸ı et al., 2002). In our study, trisomy 18 was found in two patients.

Another parameter we examined in our study varied according to months in the frequency of NTD. It was observed that there was a significant increase in July, June, and April compared to the other months. This was thought to be due to changes in the nutritional pattern during the periconceptional period.

Studies on NTD reported that the female gender was dominant. Himmetoglu et al. (1996) found the male/female ratio to be 0.56. In a study by Jorde et al. (1984)) the male/ female ratio was found as 0.67. In a study conducted on 694 cases by Whiteman, Murphy, Hey, O'donnell, and Gold-acre (2000), they found that the female/male ratio was more than two times. In our study, male/female ratio was found to be 1.09, and male gender was mildly dominant.

Delivery by cesarean section is the type of delivery that should be preferred to prevent the rupture of the sac and to prevent neurological symptoms due to tethered cord syn-drome (Hill & Beattie, 1994). The rate of cesarean delivery in the literature varies between 69–80% (Bülbül et al., 2010). In our study, cesarean delivery rate was found to be 70.4% in accordance with the literature.

In a study by Mohammad et al. (2010), they found spina bifida as the most common type of NTD. Second and third type was anencephaly and encephalocele, respectively. Accord-ing to the latest data from the International Birth Defects

Monitoring Systems (ICBDMS), spina bifida is the most fre-quent, anencephaly is the second most frequent and encephalo-cele is the third most common type of NTD in many countries of the world. In our study, spina bifida was the most common type of NTD. Encephalocele and anencephaly were detected as the second and third most common types, respectively, and it was thought that higher rate of encephalocele than anencephaly could be caused by NTD cases who were referred to our hospi-tal from surrounding centers for operations.

When looked at the location of NTD, it is most commonly seen in the lumbar region in the literature (Back & Plawner, 2012). In our study, it was observed that it was 39.2% in the lumbar region, 24.6% in the lumbosacral region and 18.6% in the thoracolumbar region in accordance with the literature. It was determined that early mortality and morbidity rates decreased in the babies with NTD in the early period. In the literature, 70–91% of newborns diagnosed for meningomyelo-cele were operated in the first 72 hr (Bülbül et al., 2010; Rodrigues, Krebs, Matushita, & de Carvalho, 2016). Bulbul et al found that duration of hospitalization and central nervous system (CNS) infection rate was significantly lower in babies undergone operations due to meningomyelocele in the first 3 days (Bülbül et al., 2010). Rodrigues et al. found that the risk of SSS infection was 5.72 times less in babies undergone operations in the first 48 hr (Rodrigues et al., 2016). There-fore, it is recommended that the operation for the improve-ment of NTD should be performed within the first 72 hr. It was observed that 47.3% of our patients were operated in the first 72 hr and this rate was lower compared to the literature.

With the early detection of fetal problems and the devel-opment of prenatal diagnostic methods, intrauterine fetal sur-gery has recently come into question. This invasive procedure is easy due to the rapid recovery of the wounds in intrauterine conditions, the absence of scarring, the neces-sary feeding and oxygenation provide by the umbilical cord and the poor development of the immune system in the fetus. Clinical and experimental studies showed that, it is possible to block Chiari 2 as well as prevent neurological damage if the neural plate closes on or before the 140th day of preg-nancy in the uterus (Adzick et al., 2011).

Neural crest cells play an important role in the develop-ment of mesodermal organs such as heart, urinary system, and skeleton. Therefore, the normal development of the spinal cord and these organs may be impaired after any migration defect that may occur in these cells. In general, the heart develops from neural crest cells and mesoderm originating from the dor-sal part of the neural tube. The group of cells originating from the ventral portion of the neural tube is transformed into car-diac myocytes by migrating into the developing heart (Ali, Farooqui, & Sohal, 2003). These cells are called ventral migra-tion cells (VENT, ventrally emigrating neural tube). In experi-mental studies VENT cells were shown to be in the ventricle and atrial wall, interventricular and interatrial septum. The rea-son why septal defects such as ASD and VSD are common in

patients with NTD may be disorders associated with VENT cells in the early embryonic period (Ali et al., 2003).

In other systems of infants with NTD (genitourinary, skel-etal, and skin), at least one major malformation may be pre-sent. Previous studies showed that 5 to 10% of patients with NTD have congenital heart disease (Jacobs & Hohn, 1992). In our study, it was detected that 27.4% of patients with NTD had CHD. The most common CHD was ASD. The frequency of congenital heart disease in patients with meningomyelocele ranges from 0.76 to 37%. The most common congenital heart diseases in these patients are ASD and VSD (Baradaran, Ahmadi, Nejat, El Khashab, & Mahdavi, 2008). The high rate of CHD in our study was attributed to the referral of patients from the surrounding provinces to our center.

Hydrocephalus is the most common congenital anomaly associated with NTD. In cases with open spina bifida, the rate of hydrocephalus is reported to be over 80–96% in stud-ies (Erss¸ahin, Mutluer, Kocaman, & Demirtass¸, 1998). Tala-monti, D'Aliberti, and Collice (2007) myelomeningocele reported that 78% of a series of 220 patients were treated due to hydrocephalus. Also, colposephaly was found in 8.1% of the patients. In our study, the incidence of hydro-cephalus was detected as 75.3%. Most of the spina bifida patients with ventriculomegaly need VP shunt placement in the first year (ACOG, 2017). In our study, VP shunt was applied to 112 (65.9%) cases due to hydrocephalus. Shunt revision is required in 2/3 of VP shunt implantation cases, and neurological development should be closely monitored (ACOG, 2017). In our series, shunt revisions were required in 14.5% of the cases during follow-up periods. The second most common cranial anomaly is Chiari Malformation (CM). Previous studies showed that CM occurs in approxi-mately 75% of children with meningomyelocele. CM was reported to be clinically significant in 85% of these children who need to VP shunt (Januschek et al., 2016). In our series, we detected in 42.5% of cases.

Chiari 2 malformations which is almost every time asso-ciated with hyrocephalus and spinal dysraphism is character-ized by protrusion of cerebellar vermis, medulla, and fourth ventricle foramen magnum to the upper cervical spinal chan-nel and as a result of a drop in hydrodynamic pressure the lateral ventricle. Reduction of ventricular pressure and reduction or absence of ventricular tension may not provide mesenchymal and endochondral ossification. Due to the col-lapse of the primitive ventricular structure, the third ventricle cannot expand sufficiently, both of the thalamus are close to each other. The glial cells, which must be driven out by the induction of the ventricular structure, may not be directed to the cortex due to a decrease in pressure and induction and so heterotopes occur (Meuli & Moehrlen, 2013). Adzick et al. (2011) found that as compared with postnatal surgery, prena-tal surgery for myelomeningocele reduced the need for shunting and improved motor outcomes at 30 months but was associated with maternal and fetal risks.

Total or partial agenesis of the corpus callosum in myelo-meningocele patients is a common finding. Just, Schwarz, Ludwig, Ermert, and Thelen (1990)) found corpus callosum partial agenesis in 56% of patients. In our study, we found a rate of 38.7%. In 33% of patients with myelomeningocele, epileptogenesis and polymicrogyria which cause mental retar-dation were observed (Chassoux et al., 2008). Polymicrogyria was observed in four patients in our study. The absence of septum pellucidum is often a reported abnormality in patients with myelomeningocele and corpus callosum abnormalities (Just et al., 1990; Miller, Widjaja, Blaser, Dennis, & Raybaud, 2008). There were six patients with partial agenesis of the cor-pus callosum and without the septum pellucidum in our study. Another detected abnormality, syringohydromyelia, is present in approximately 30–75% of children with NTD. It is usually asymptomatic in most cases (Iskandar, McLaughlin, & Oakes, 2000). In our study, the incidence of syringohydromyelia was 8.6%, which was lower than in the literature.

The incidence of scoliosis and talipes equinovarus reported in the literature varies from 30–50%, mostly found in the latent form of spinal dysraphism (Ulsenheimer et al., 2004). In our study, Pes echinovarus was the most common neuro-orthopedic syndrome in 32 (17.2%) cases. It was observed that 17 (9.1%) patients had scoliosis and nine cases had developmental hip dysplasia.

Most patients with NTD have impaired bowel and bladder functions, regardless of lesion level (ACOG, 2017). Chronic kidney disease develops in 30–40% of children diagnosed with NTD (ACOG, 2017). In these patients, renal dysfunction may cause an increase in mortality. In order to preserve the upper urinary system function, early follow-up and treatment of neurogenic bladder should be initiated (ACOG, 2017). Therefore, urinary systems of all NTD cases should be evaluated by ultrasonography. Twenty-four of our patients (12.9%) had neurogenic bladder, 19 (10.2%) had hydronephrosis, and close follow-up of these patients was planned.

The prevalence of congenital hypothyroidism ranges from 1:2,000–4,000 worldwide and mutations in different genes are responsible for one part (LaFranchi & Huang, 2016). In a study by Reddy et al. (2010) they found the inci-dence of NTD as 41% in infants with congenital hypothy-roidism. In our study, the incidence of hypothyroidism was found to be 7.5% and this increase can be associated with genetic factors.

In the literature, Hunt (1997) reported annual mortality rate as 3% during their 30-year follow-up. Oakeshott, Hunt, Whitaker, and Kerry (2007) thought that the mortality was due to the spinal level in their 40 years of follow-up and reported that the deaths were due to unexpected complica-tions out of hospital. In 20-year follow up of Bowman, Mohan, Ito, Seibly, and McLone (2009), they reported that the survey was 75% and deaths were due to shunt dysfunc-tion. The mortality rate was 6.5% in our study. The most fre-quent cause of death was observed as infection.

5 | C O N C L U S I O N

In Turkey, the rate of child birth with NTD is still high. Pre-ventable etiologic risk factors of NTD should be known, and families who are considering having children should be made more conscious about this issue. In particular, families with NTD children or relatives should be investigated starting from the preconceptional period and should be closely monitored. Complications in patients with NTD should be well-known. This study suggests that patients with NTD should be evalu-ated with more organized, multidisciplinary methods.

D I S C L O S U R E S T A T E M E N T

The authors have no conflicts of interest to declare.

O R C I D

Murat Konak https://orcid.org/0000-0001-8728-4541

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How to cite this article: Yorulmaz A, Konak M. Short-term results of patients with neural tube defects followed-up in the Konya region, Turkey. Birth Defects Research. 2019;111:261–269.https://doi.org/ 10.1002/bdr2.1462