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PERICONCEPTIONAL RISK FACTORS OF SPINA BIFIDA AMONG EGYPTIAN
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POPULATION: A CASE-CONTROL STUDY
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
Moutaz Elsherbini, MD(1)*. ([email protected])
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
Wafaa Ramadan, MD(1). ([email protected])
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
Rasha Elkomy,MD(1). ([email protected])
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
Omneya Helal,MD(2)*. ([email protected])
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
Dina Latif Hatem,MD(1).([email protected])
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
Hassan Gaafar, MD(2). ([email protected])
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(1) Lecturer of Obstetrics and Gynecology, Kasr Alaini, Faculty of Medicine, Cairo
University, Egypt
(2) Assistant professor of Obstetrics and Gynecology, Kasr Alaini, Faculty of Medicine,
Cairo University, Egypt
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Corresponding Author:
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Hassan Mostafa Gaafar
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4-Gamal salem St ,Dokki, Cairo
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Tel: 01224022330
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E-mail: [email protected]
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Periconceptional risk factors of spina bifida among Egyptian population:
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a case-control study
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Abstract
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Objective: To study the preconceptual & early conceptional risk factors that may
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predispose to the development of spina bifida (SB) malformation among Egyptian
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population.
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Methodology: The study involved 197 pregnant women undergoing fetal anatomy
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scan; 97 women proved to have fetal SB and 100 women with normal fetuses as a
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control group. The control group was recruited randomly in the same period from
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patients undergoing anatomical scan. Risk factors that might lead to SB were
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investigated including maternal age, gravidity, parity, residence, history of diabetes
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mellitus or drug intake, smoking, infections, exposure to X-ray, history of congenital
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anomalies in other offspring, parental consanguinity, positive family history, folate
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supplementations.
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Results: SB affected the lumbo-sacral region in the majority of cases (89.7%). It was
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associated with hydrocephalus in 66 cases (68%), polyhydramnios in 12 cases (12.4%).
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The SB group showed significantly higher parity (p = 0.005), more frequent history of
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drug intake (p < 0.001), higher frequency of infection with CMV (p = 0.004) and HSV (p
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= 0.013) and less proportion of folate supplementation (p < 0.001).
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Conclusion: The rate of spina bifida in the tested group was 5 per 1000. Risk factors
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were lack of folate supplementation & history of antiepileptic drugs intake. This
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association raises the hypothesis that the disturbed folate/homocysteine metabolism
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is the underlying mechanism for SB development.
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Keywords: Spina bifida, 3D ultrasound, Hydrocephalus, Consanguinity
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Introduction:
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Spina bifida (SB) is a serious neural tube birth defect that approximately
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affects 35/100000 live births
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dysraphisms as it represents about 90% of all spinal defects
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from failure of proper fusion in the spinal regions of the neural tube
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during early embryogenesis (within the first 28 days following conception)
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(3)
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Neural tube defect (NTD) incidence varies significantly across time and
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among different geographic areas within the same time with the highest
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incidences among Irish, Indian, Mexican and Northern China populations
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(3-5)
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however it might decrease due to maternal folic acid supplementation
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together with the prenatal diagnosis and termination of affected
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pregnancies (7,8).
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Babies with SB are compatible with life but handicapped with increased
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morbidity and mortality risks throughout their lives. They usually suffer
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from mental retardation, motor and sensory dysfunction of lower limbs
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and inability to control the anal and urethral sphincters (9).
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Many surgical procedures are usually required to close the vertebrae,
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stabilize the joints and drain the associated hydrocephalus but without
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complete restoration of normal life and consequently, when parents faced
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with diagnosis of SB prenatally, nearly ¾ of them decide to induce
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abortion (10).
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Like other NTD, SB appears to have a multifactorial etiology, with the
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environmental factors, lifestyle; social and cultural habits interacting with
(1)
. It is the most common form of spinal
(2)
. SB results
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. In Europe and North America, SB birth prevalence is 0.3-0.6/1000
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(6)
,
(11)
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the genetic susceptibilities to determine the risk of development
.
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Particularly, maternal nutrition has been recognized as an important
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predisposing factor
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recommended daily dose of 400 μg, preconceptually and in the first
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trimester was found to reduce the risk of NTD development
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consequently, US and Canada in 1998 started folic acid fortification of
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enriched cereal grains (13).
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The risk increases to 3% with one previous NTD-affected pregnancy and to
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10% with two previous NTD-affected pregnancies. Other risk factors
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include the maternal use of antiepileptic drugs (e.g., valproic acid) or folic
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acid antagonists (e.g., methotrexate), preconceptual maternal diabetes
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and obesity and maternal exposure to high temperature in early
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pregnancy (e.g., fever, hot tubs and saunas)
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recognizable risk factors in 90% of cases (16).
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NTDs are the easiest congenital anomalies to diagnose prenatally
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Traditionally, elevated maternal serum α-fetoprotein (α-FP) followed by
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sonographic scanning were the diagnostic tools (18). More recently, Routine
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antenatal fetal anatomy scan using 2D & 3D is an efficient screening tool
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of SB (detection rate up to 95-100%) (19).
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The aim of this work is to study the preconceptual and early conceptional
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risk factors that may predispose to the development of SB malformation
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among Egyptian population.
(11)
. Maternal folic acid supplementation, with
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4
(12)
and
(14,15)
. However, there are no
(17)
.
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Subjects and Methods:
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In the current study, 18653 pregnant women were scanned in the
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ultrasound department in Kasr-El-Aini University hospital (Cairo University,
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Egypt) from the period of June 2011 to June 2014 after being approved by
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the hospital ethics research committee. All of them were referred from the
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obstetric outpatient clinic for routine obstetric ultrasound or for suspected
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anomalies recorded at any trimester of pregnancy.
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Ultrasound was done by two expert operators with the use of high
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resolution ultrasound unit with 3-5 MHz transabdominal transducers
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(General electric voluson Pro-V 730). Every ultrasound scan took about 15-
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20 minutes with detailed anatomical scanning of the fetus according to the
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ISUOG guidelines (20).
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Cases of spina bifida (97 patients) were identified and complementary 3D
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ultrasound was done by senior operator with documentation of data as
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regards 1) the presence or absence of hydrocephalus 2) Level of the lesion
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3) proper assessment of the liquor volume. Control patients (100 patients)
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were enrolled randomly in the same period in which the fetal anatomy
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scan proved the presence of non-malformed fetus. (fig 1-4)
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Exclusion criteria include maternal age > 42 or <18 years old, presence of
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multiple fetal anomalies, non-viable fetus, multiple gestation. Risk factors
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were identified by simple verbal questions as regard: maternal age,
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gravidity, parity, residence (urban or rural), history of congenital
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anomalies in other offspring, parental consanguinity, positive family
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history,
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supplementations. Other risk factors assessed include preconceptual or
maternal
history
of
diabetes
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mellitus
and
folic
acid
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first trimester history of antiepileptic drugs (AEDs) intake, smoking,
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exposure to X-ray and infections namely; Rubella, CMV and HSV, which is
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confirmed by presence of virus- specific clinical presentation and elevated
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serum IgM (1ry infection) or the rising titer of virus- specific serum IgG
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(recurrent infection).
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Results:
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SB affected the lumbo-sacral region in most of the studied cases; 87 out of
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the 97 fetuses (89.7%). Only 10 cases (10.3%) had thoracic SB. It was
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associated with hydrocephalus in 66 cases (68%). Polyhydramnios was
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significantly more common in SB cases (p = 0.013); it was found in 12 cases
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(12.4%) compared to 3 cases (3%) of the control group.
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Table 1 shows the studied risk factors of SB in the two groups. The SB
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group showed significantly higher parity (p = 0.005), more frequent history
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of AEDs intake (p < 0.001), higher frequency of infection with CMV (p =
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0.004) and Herpes virus (p = 0.013) and less proportion of folate
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supplementation (p < 0.001).
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Discussion:
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This study demonstrated a rate of diagnosis of spina bifida (SB) of 5 per
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1000 examined pregnant women; mainly affecting the lumbo-sacral region
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(89.7%). SB was significantly associated with higher parity (p = 0.005) &
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more frequent history of AEDs intake (p < 0.001), CMV infection (p =
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0.004) and Herpes virus (p = 0.013). Also, significantly lower proportion of
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those with SB had folate supplementation during the current pregnancy (p
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< 0.001).
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We cannot rely on the proportion of SB found in this study as an indicator
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of the incidence of the defect among Egyptian population. This study is a
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hospital based one performed in a tertiary referral center. The exact
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incidence in Egypt needs a population based study which is lacking so far.
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The prevalence of SB is characterized by geographic and temporal
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variation in addition to racial and ethnic differences within location and
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time (21). The average worldwide incidence of SB is 1 case per 1000 births.
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Prevalence of neural tube defects (NTDs) ranges from 0.7 in central France
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to 7.7 in the United Arab Emirates and 11.7 in South America per 10,000
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births. In the United States, SB incidence is 7 per 10,000 live births (22).
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However, the birth prevalence of NTDs is influenced by the accessibility of
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prenatal diagnostic tools and the use of elective pregnancy termination
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(23)
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The etiology in most cases of SB is multifactorial, involving genetic,
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environmental and dietary factors. In the current study, lack of folic acid
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supplementation was associated with higher frequency of SB (p < 0.001).
.
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Similarly, many studies have reported significant relation between the low
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consumption of folic acid and NTDs in Europe (24) and Asia (25). It is believed
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that nearly half of cases of NTDs are related to a nutritional deficiency of
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folic acid, but the underlying mechanism is not clear. A genetic or
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nutritional defect in homocysteine metabolism was suggested
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research articles addressed the role of correction of folic acid deficiency
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for prevention of primary and recurrent NTDs (27). However, the underlying
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protective mechanism is still not identified, but possibly through their
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effects on genes that regulate folate transport and metabolism (28).
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According to the CDC, mandatory fortification of enriched cereal grain
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products with folic acid in the USA in 1998 resulted in 22.9% reduction of
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the yearly incidence of SB
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supplementation between 205 mothers of SB cases and 6357 mothers of
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controls; authors estimated a 13% reduced odds of SB for each 100 μg
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increase in daily folate consumed
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European health authorities recommend folic acid supplementation of 400
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μg for pregnant women to prevent NTDs
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studies involving 6105 women confirmed the protective effect of daily
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folic acid supplementation in prevention of NTDs (32).
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In the current study SB was significantly associated with higher parity.
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Relation between NTDs risk & parity is either U-shaped pattern (the risk is
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higher for the lowest and highest number of births
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proportionate (increased risk with increased parity) (34).
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In the current study, history of antiepileptic drugs intake (AEDs), namely
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Depakine (valproic acid sodium), Lamotrine (lamotrigine) and Tegretol
(26)
. Many
(29)
. In a large study, comparing folic acid
(30)
. Correspondingly, Most of the
9
(31)
. A systematic review of 5
(33)
or directly
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(carbamazepine), was significantly more common in the SB group; 21.6%
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vs. 1% in the control group (p < 0.001). These drugs are believed to be
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associated with SB being anti-folate.
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The association between SB and exposure to valproic acid during
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pregnancy was reported in a retrospective study in France
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subsequently confirmed in several studies
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presented as the antiepileptic drug of choice during pregnancy
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However, in utero exposure to Carbamazepine has been associated with
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an increased risk of NTDs (39), but a recent systematic review showed that
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the risk of SB development is significantly lower when compared to
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valproic acid
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its teratogenic effect in the form of dose-dependent growth retardation
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and neurodevelopmental toxicity. SB and anencephaly were associated
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with higher doses of the drug (41).
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Lamotrigine is an anticonvulsant & mood stabilizer drug that has weak
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antifolate properties
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many researchers considered its use relatively safe as the rates of
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congenital malformation in lamotrigine-exposed fetuses similar to those
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observed in the general population
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(45)
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triplets on Lamotrigine treatment; however, they did not observe
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significant changes in serum folate levels. Based on the above,
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preconceptual & 1st trimesteric folic acid supplementation (in a daily dose
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of 5 mg) had previously been recommended for all women taking AEDs (46).
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But recently many studies have revealed that folic acid supplementation in
(35)
. This was
(36,37)
. Carbamazepine has been
(38)
.
(40)
. A recent animal study found that carbamazepine exerts
(42)
. It is rated Pregnancy Category Risk C, however,
(43,44)
. On the contrary, Candito et al.
presented a case-report of double fetal NTDs in a patient pregnant with
10
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this population group had not added any protective value (47), however, It
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is still generally recommended that all women on AEDs should receive folic
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acid supplementation (at a dose of at least 0.4 mg daily)(48).
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Congenital cytomegalovirus (CMV) infection is the most prevalent viral
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cause of congenital neurological disabilities in children that occurs in 0.6–
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0.7% of all newborns worldwide (49). Vertical transmission can follow either
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a primary or recurrent maternal infection with 90% of affected fetuses is
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asymptomatic
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primary infection & in symptomatic fetuses. Hearing loss, visual
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impairment, or diminished mental and motor capabilities are the most
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common sequelae
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significantly more common in the SB group; 14.4% vs. 3% in the control
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group (p < 0.001). Cannon MJ et al. reported that CMV infection is more
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likely to occur among population of lower socioeconomic status
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study was carried out at a University Hospital in which most of the
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examined women are of low socioeconomic status.
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This study has identified some maternal periconceptional risk factors
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associated with an increased SB risk among Egyptian women. AEDs
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administration was associated with increased risk while folic acid
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supplementation was associated with reduced risk. This association raises
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the hypothesis that the disturbed folate/homocysteine metabolism is the
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underlying mechanism for SB development. Consequencely
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information can be included as a part of pre-conception counseling.
(50)
. There is a higher risk for neurological damage after
(50)
. In the current study history of CMV infection was
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11
(51)
& our
this
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Conflict of Interest:
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The authors have no conflicts of interest.
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Authors’ contributions:
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
M.Elsherbini: Drafting the manuscript.
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
W.Ramadan: Ultrasound scanning and case choice.
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
R. Elkomy: Made contributions to conception and design.
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
O.Helal: Analysis and interpretation of data.
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
D. Hatem: Risk factors assessment.
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
H.Gaafar: Ultrasound scanning and case choice.
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Acknowledgements:
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The authors do not have anyone to acknowledge.
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16
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Legends
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Figure 1
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2D ultrasound image of a sacral spina bifida
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428
Figure 2
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3D ultrasound image of spina bifida (same case)
430
431
Figure 3
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Neonate with SB (same case)
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436
437
438
439
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441
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446
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Table 1: Maternal characteristics and risk factors of SB in the two studied
449
groups
Normal Group
(n = 100)
25.1±4.7
76.2±5.2
2 (0-5)
1 (0-4)
p value
Age (years)
Maternal Weight (kg)
Gravidity
Parity
Residence
Rural
Urban
Positive Consanguinity
Previous anomalies
Family history of anomalies
Diabetes Mellitus
SB Group
(n = 97)
26.6±6.5
77.0±6.0
2 (0-8)
1 (0-8)
55 (56.7%)
42 (43.3%)
48 (49.5%)
14 (14.4%)
26 (26.8%)
3 (3.1%)
46 (46.0%)
54 (54.0%)
39 (39.0%)
24 (24.0%)
19 (19.0%)
6 (6.0%)
0.133
X-ray exposure
History of AEDs intake
Smoking
9 (9.3%)
21 (21.6%)
8 (8.2%)
6 (6.0%)
1 (1.0%)
5 (5.0%)
0.386
< 0.001*
0.359
CMV
Rubella
Herpes virus
14 (14.4%)
7 (7.2%)
6 (6.2%)
3 (3.0%)
4 (4.0%)
0 (0.0%)
0.004*
0.326
0.013*
Folate Supplementation
84 (86.6%)
100 (100.0%)
< 0.001*
450
*Statistically significant
451
SB= Spina Bifida
452
CMV= Cytomegalovirus
453
18
0.052
0.301
0.758
0.005*
0.138
0.089
0.192
0.498