Although in almost half of congenital anomalies no specific cause is established, still there is a number of well-known risk factors .
In our study, the rate of women over 35 years represents one quarter of cases. However, it has been reported in the literature that the risk of CM is higher after the age of 35 years.
In general, as a literature review by Khoshnood reports, the prevalence of chromosomal and non-chromosomal abnormalities increases with maternal age . This finding has contributed to the recommendation of routine prenatal screening in women over 35 years old.
In the present study, we have recorded 35 cases of trisomy 21 cases, which corresponds to 14.3% of all cases with CM.
Half of Trisomy 21 cases were born to mothers over the age of 35 years. Indeed, advanced maternal age increases the risk of chromosomal abnormalities, particularly Down syndrome, as reported by Hook’s study that shows a rate of 2 per 1000 for the lowest maternal ages, 2.6 for 1000 to 30 years, 5.6 for 1000 to 35 years, 15.8 for 1000 to 40 years and 53.7 for 1000 to 45 years . Nevertheless, the risk of several CM exists even among young women. For this reason, in Canada, the Society of Obstetricians and Gynecologists of Canada (SOGC) recommends prenatal screening for fetal aneuploidy to all pregnant women regardless of age .
In our study the percentage of consanguinity is 22.4% of which three quarters (74.5%) of the cases are first degree0. In fact, consanguinity increases the risk of heart, brain, and other genetic disorders ; it increases the prevalence of rare genetic congenital abnormalities by doubling the risk of newborn and infant death, intellectual disability, and other congenital anomalies when the parents are first cousins.
Some ethnic communities, such as Ashkenazi Jews or Finns, have a relatively high prevalence of rare genetic mutations with an increased risk of CM.
A UK survey conducted between 2007 and 2010 on 11,300 newborns in the city of Bradford that includes a large Pakistani community characterized by a high percentage of consanguineous marriages concluded that the risk of CM goes from 3% when parents are not related to 6% when parents are cousins . In turkey, a study have reported a rate of 23.2% of consanguinity among parents of children with CM .
Family history of CM has been significantly associated with the risk of CM in several series such as Shawky’s study, which reported a family history of CM in 16.69% of cases . In our series, the rate was 10.2%.
In 94% of cases, severe CM occur in low- and middle-income countries where the mothers are exposed to malnutrition and infectious agents or teratogenic products that may induce abnormal prenatal development . In our series, 97.5% of women are of low to moderate socio-economic status.
Maternal infections such as syphilis, rubella, toxoplasmosis and cytomegalovirus and HIV infections are a major cause of CM in low- and middle-income countries.
In the present study:
- Rubella serology was performed in 47.7% of women of whom 26.9% were immunized.
- Toxoplasmosis serology was made in 51.8%, of which only 15.9% were immunized.
- Syphilitic serology was determined in 62% of cases with a single case of evolutionary infection found in the context of clubfoot.
- Hepatitis serology was only performed in 17.6% of cases for hepatitis B and 14% for hepatitis C.
- HIV serology was investigated in 12.6% and was positive in one case with Down syndrome.
Although the link between maternal infections and the occurrence of CM is confirmed, in our context, serology investigations are not systematically run due to the lack of prenatal and pre-conception consultations by women, which make our interpretation of the collected results very complicated. Also, it explains the unknown immune status of almost the half of our cases.
It is well-known that nutritional deficiencies are related to certain congenital anomalies. For example, folate deficiency increases the risk of neural tube defects in the newborn, and excessive vitamin A intake may affect the normal development of the embryo or fetus. However, in our series, folic acid supplementation was noted in only 27% of cases.
Overweight and unbalanced diabetes increase the risk of birth defects. Indeed, several studies based on patient registers or cohort studies have reported an increased risk of malformations in the context of diabetes. A literature review, conducted between 1990 and 2005, have analyzed the teratogenicity of diabetes during pregnancy, found that the risk of CM in diabetes was increased [11, 12]. In our study, diabetes was found in 7% of malformation cases, a rate that is similar to that reported in Egypt (7.28%) .
In our context, the intake of Fenugreek and plants during pregnancy was found in 28.6%. Fenugreek (Trigonella foenum-graecum) is a plant widely cultivated in the Mediterranean area, India and China. Its grains are commonly consumed for the management of diabetes and hypercholesterolemia. It is used as a spice in Indian (curry), African and Moroccan cuisine.
A study conducted by Skalli from the Moroccan Center of Pharmacovigilance reported the occurrence of CM such as hydrocephalus and spina bifida after ingestion of fenugreek during pregnancy .
Another study in mice exposed to a high dose of fenugreek seeds concluded that exposure to fenugreek is responsible for the appearance of microcephaly probably due to abnormal proliferation of neurons and glial cells with significant stunted growth and impaired motor performance . Kassem and al. observed a significant reduction in fetal and placental weight at 20 days of gestation, suggesting an embryo-fetal toxicity . Fenugreek extract causes intrauterine growth retardation and impairs brain development at the doses of 500 and 1000 mg/ kg per day .
Exposure to alcohol, tobacco or radiation during pregnancy increases the risk of having a fetus or newborn affected by CM. Working or living near or outside landfills, blast furnaces or mines is also a risk factor, especially if the mother is exposed to other environmental risk factors or suffers from nutritional deficiencies.
A case-control study conducted in Rhône-Alpes between 2001 and 2003 confirmed the presence of a link between the risk of the urinary tract malformations and exposure to emissions from municipal mass burn incinerators and that this risk is increased for mothers exposed to dioxins above a certain threshold in early pregnancy . In our context, no case of contact with teratogenic agents has been reported because the hypothesis of environmental pollution has not been explored.
In our study, drug intake; including paracetamol, acetyl salicylic acid, corticosteroids, antiretrovirals and antiepileptics; was noted in 2.8%.
Studies have shown that the use of acetyl salicylic acid at low doses of 50-150 mg/day in the prevention of preeclampsia is teratogenic in rodents, monkeys, dogs and cats. Also, it induces neural tube closure abnormalities, skeletal abnormalities and cleft palates. At the doses of 250 and 1000 mg / kg, miscarriage and FDIU are induced .
In humans, studies have shown that taking aspirin in the first trimester causes congenital heart defects  and gastroschisis [20, 21, 22]. However, epidemiological data did not show an association between taking aspirin in the first trimester and increasing the rate of CM .
At high dose during the 2nd trimester of pregnancy, aspirin may cause premature closure of the ductus arteriosus with pulmonary hypertension and renal effects and intracerebral fetal hemorrhage [24, 25, 26, 27]. In fact, all NSAIDs (nonsteroidal anti-inflammatory drugs) can lead to cardiac and / or renal fetal and / or neonatal toxicity, sometimes irreversible or even fatal .
Regarding corticosteroids intake, case-control studies have shown an increased risk of cleft lip or labiopalatine and IUGR when taking corticosteroids orally .
In our study, a case of short limb was identified in a woman who had taken corticosteroids associated with acetyl salicylic acid as part of Pemphigoid gestationis treatment.
Antiretrovirals were only taken by one case of HIV-positive mother put on treatment at the beginning of the pregnancy, which gave birth to a new born with Down syndrome.
A preliminary analysis of an observational study of 426 neonates conducted in Botswana in 2018 raised the risk of neural tube closure abnormality in 4 of the neonates of mothers treated with a combination of antiretrovirals with an incidence of 0.9% . Other studies have shown an increased risk of congenital heart disease , skin and musculoskeletal abnormalities .
Paracetamol intake was noted in three cases in our series; a case of hydrocephalus, a case of myelomeningocele, and a clubfoot case.
However, several studies have reported that Paracetamol exposure during pregnancy may result in developmental alterations both in the brain with behavioral disorders and hyperactivity, and autism spectrum symptoms and paracetamol for more than 4 weeks during the first and second trimesters of pregnancy may increase the frequency of cryptorchidism .
Sodium Valproate intake was reported by one mother who was followed for epilepsy and stopped her treatment at the beginning of the first trimester. The outcome of this pregnancy was marked by the occurrence of a chylothorax and the perpartum death of the newborn due to a severe respiratory distress.
According to the latest French report by ANSM (national agency of safety of the drug and health products) published in April 2019, the risk of malformation in case of valproic acid intake is multiplied by 4-5 compared to the general population. Besides, it’s associated with the risk of occurrence of neural tube closure, oral cleft, hypospadias, facial dysmorphism, craniosynostosis, cardiac, renal, urogenital and limb malformations, and polymalformative syndromes .
The existence of neurodevelopmental disorders (development quotient / intelligence quotient decrease, developmental delays, autistic spectrum disorders) in children exposed in utero to valproic acid has been established regardless of the term of pregnancy and the administered dose, and these disorders are extremely severe and can lead to educational and professional disabilities. Data also suggest an increase in attention deficit disorder and hyperactivity.