Pattern and risk factors of congenital anomalies in a pediatric university hospital, Alexandria, Egypt

Congenital anomalies (CAs) are a worldwide problem. They are important causes of childhood deaths, chronic illness, and disability. The World Health Organization (WHO) estimated that annually, 303,000 newborns die within 4 weeks of birth worldwide due to CAs. The WHO defined CAs as structural, functional, or metabolic anomalies that originate during intrauterine life and can interfere with the body functions [1].They result from defective embryogenesis or intrinsic abnormalities in the development process [2].

Congenital anomalies are classified according to severity into major and minor anomalies [3]. They can also be classified into three groups of severity: minor, severe, and lethal anomalies. Severe and lethal anomalies together are considered as major anomalies [4].On the other hand, the international classification of diseases classified CAs according to the affected body system [5].

According to WHO (2015), about three million babies are born yearly with major CAs constituting about 3% of all newborns [1]. The global report of birth defects (2006) showed that the prevalence of CAs varied between high-, middle-, and low-income countries with 94% of all CAs occur in middle- and low-income countries. CAs were as high as 82/1000 live births in Sudan and as low as 39.7/1000 live births in France [6]. In 2006, the prevalence of CAs in the USA, UK, Germany, and Canada was between 45 and 50/1000 live births [6, 7]. In Africa and the Middle East, the reported prevalence was much lower. It ranged between 20 and 30/1000 live births in Kenya, Uganda, Nigeria, Saudi Arabia, and Pakistan [8–12]. In Egypt, the prevalence of CAs was 65.3/1000 live births in 2006 [6]. Within Egypt, the reported rates showed variations. They were the lowest in Assuit (20.6/1000) [13].

Congenital anomalies are a significant cause of infant morbidity and mortality. In 2006, worldwide, out of 2.68 million neonatal deaths, the WHO estimated that 11.3% of them died from CAs [2]. Approximately 95% of the children who died from CAs were from middle- and low-income countries [6]. In Egypt (2008), deaths from CAs constituted about 15% of all infant deaths [14]. Congenital anomalies can also result in long-term physical, mental, visual, and auditory disabilities if not managed appropriately and have significant negative impacts on individuals, families, health care system, and societies [1, 15].

The exact cause of CAs is unknown in about 40–60% of cases. Factors that may increase the risk of occurrence of CAs include genetic disorders, socioeconomic and demographic factors, nutritional factors including maternal obesity, infections during pregnancy, taking certain drugs, ionizing radiation, chemicals, and air pollution. Pregnancy-associated conditions such as insulin-dependent diabetes [2, 8], hypertension during pregnancy such as antepartum hemorrhage, twin pregnancy, oligohydramnios, and polyhydramnios were also found to be associated with more CAs [2, 13, 16, 17].

Some congenital anomalies can be prevented through removal of risk factors or reinforcement of protective factors. Important interventions include ensuring having healthy diet and maintain a healthy weight, ensuring adequate dietary intake of vitamins and minerals especially folic acid, avoiding harmful substances such as tobacco, avoiding infections known to be associated with CAs, and reducing environmental exposure to hazardous substances such as heavy metals and pesticides and exposure to certain medications and radiation [1].

The aim of this study was to estimate the frequency of CAs among infants presented to the Pediatric University Hospital in Alexandria, Egypt, in six consecutive years (2010–2015), to describe the nature of CAs among them, and to identify the possible risk factors of these anomalies.

The present study showed that among infants with CAs, 70.6% were males and 29.4% in females. These results were in agreement with a retrospective study conducted in El Shatby University Hospital [19] which found that males admitted to the surgery unit of the hospital during the years 2009–2011 were more than females.

In the current study, digestive system anomalies and musculoskeletal anomalies constituted 38.0% and 32.9% of the total CAs respectively. They were more than those recorded in a surveillance study conducted in Glasgow and Clyde in 2015–2016 where GIT anomalies constituted only 9% while musculoskeletal anomalies constituted 25% [20]. Different rates might be attributed to the fact that the present study was a hospital-based case series while the other study was conducted using a population-based surveillance program.

Circulatory system anomalies constituted 11% of the total CAs in the current study. The surveillance study conducted in Glasgow and Clyde found that the prevalence of circulatory system anomalies was 13.9% [20], and the EUROCAT records showed even higher figures for circulatory system anomalies (35%) [21]. Genetic disorders and genitourinary anomalies constituted 8.4% and 4.9% of total CAs, respectively, in the studied years. The percent of genitourinary anomalies was much lower than that of the EUROCAT records (24.2% of total CAs) [21]. The difference between the rates might be due to the difference in the methodology used and in exposure to various risk factors.

The case-control study revealed that males were 1.92 times at higher risk of having CAs than females. This result was in agreement with Tennant et al., who found a 15% increased risk of CAs in male infants than female infants in North England (1985–2003) [22].

The current study showed that children with CA were more among mothers aged above 35 years than mothers aged less than 35 years, but this was not statistically significant. A study done in Tanzania in 2013 [23] and a study done in Ain Shams University, Cairo, in 1995–2009 [14] showed a significant association between mothers aged above 35 years and CAs.

The present study showed that infants born to fathers aged 45 years or more were more than those having fathers aged below 45 years. In Knudsen, Danish in 1980–1996, there was no significant association between paternal age and the overall prevalence of CAs but there was a significant association between paternal age and limbs’ anomalies, multisystem syndromes, and Down syndrome [24]. Another study done in California, 1989–2002, showed that there was a significant association between paternal age and some selected CAs [25].

Obese females were at a higher risk of having infants with CAs. Mills et al., in New York 1993–2003 [26], found a strong association between obesity and CHDs. A systematic review concluded a contribution of obesity to certain types of CAs such as NTDs, CHDs, and orofacial defects [27].

The results of the present study agree with other studies that found a high frequency of CAs in infants born to females with a history of oligohydramnios. Oligohydramnios interferes with fetal movement resulting in a cascade of developmental events leading to fetal anomalies [28]. The same observation was seen in the case of polyhydramnios. Some studies indicated that CAs may be a potential cause for polyhydramnios but not the reverse. Some anomalies like oesophageal atresia, duodenal atresia, and some neuromuscular disorders impair the swallowing reflex and increase urine and amniotic fluid production resulting in polyhydramnios [29].

Mothers of children with CAs that gave history of hypertension during pregnancy were significantly more than mothers of the control group. A systematic review by Ramakrishnan et al. (2015), found an association between maternal hypertension and CVS anomalies. The association between treated hypertension and CVS anomalies was stronger than that for untreated hypertension which might suggest that antihypertensive drugs lead to an additional increase in the risk of CAs [30]. There was also a twofold increased history of preeclampsia among mothers of cases in the present study. Nelson et al., in Texas (2012), showed an increased rate of CAs in preeclampsia and suggested that fetal anomalies related to preeclampsia are limited to isolated microcephaly and hypospadias, and both microcephaly and hypospadias are associated with impaired fetal growth in females with preeclampsia [31]. There was also a one and half fold increased risk of CAs in infants born to females who experienced antepartum hemorrhage in the current study. Shawky et al. revealed an association between early antepartum hemorrhage in pregnancy and CAs [14].

Mothers of cases that gave history of taking different types of unprescribed medications were more than mothers of controls. Different studies showed an association between different types of drugs and CAs such as Uziel and Rozental [32] who showed that antiepileptic drug (AED) administration resulted in CNS anomalies and Etemad et al. [33] who found a high frequency of major anomalies, heart defects, and hypoplasia of the midface and fingers, known as anticonvulsant embryopathy, in infants exposed to anticonvulsant drugs in utero mainly AEDs. Yakoob et al., meta-analysis, suggested an increased risk of CVS anomalies, orofacial clefts, and NTDs following intake of oral beta-blockers in the first trimester of pregnancy [34].

History of exposure to chemicals during pregnancy was three and a half folds more among mothers of cases than mothers of controls. Desrosiers et al. [35], in the USA, observed an increased prevalence of NTDs among infants born to women exposed to chlorinated solvents during the peri-conceptional period, but they did not find an association between orofacial defects and exposure to chlorinated solvents. Hjortebjerg et al., in Denmark in the period 2001–2003, observed a positive association between exposure to paint fumes in the first trimester of pregnancy and the risk of CNS and ear, face and neck, and renal system anomalies [36].

Mothers of children with CAs indicated exposure to pesticides during pregnancy much more than mothers of controls. This result agrees with Kielb et al. [37], who found an elevated risk of having an infant with isolated gastroschisis among mothers aged 20 years old or more occupationally exposed to pesticides and with Liete et al. [38] who also found an association between exposure to pesticides and CAs in newborns. On the other hand, Clementi et al. [39] reported that there is no evidence that exposure of mothers to pesticides during pregnancy has any effect on the prevalence of CAs.

The present study showed that there was a significant association between living near strengthening mobile stations and the presence of CAs. Most of the human studies focused on the effects of mobile radiations and mobile base stations on the overall health of human beings. Very limited studies focused on the effect of mobile phones and mobile strengthening stations on the embryo development and CAs. The non-thermal interaction may lead to an increase in the production of reactive oxygen species leading to DNA damage in the sperms [40].

The current study showed that digestive system anomalies, musculoskeletal anomalies, circulatory system anomalies, and genetic disorders were the most common types of CAs in the Pediatric University Hospital. The major risk factors for CAs were old-aged parents, occurrence of complications during pregnancy, unprescribed medications and excessive vitamin A intake during pregnancy, exposure to chemicals and pesticides during pregnancy, and living near mobile strengthening stations.

There is a need for screening of females in preconception and peri-conception periods as well as for neonatal screening to early detect and treat CAs. Obstetricians should restrict the prescription of medications that may have a teratogenic effect. They should regularly assess pregnant females by ultrasound for early detection of CAs. Public awareness should be raised about the importance of folic acid in preventing CAs and the dangers of exposure of pregnant females to environmental hazards.