LRDs constitute an important group of limb malformations that require accurate description of the defects and assessment of the risk of genetic causes versus environmental risk factors implicated in the etiology of these defects. The exact pathogenesis of the vast majority of limb reduction remains unknown, mainly because of its remarkable heterogeneity (Riaño Galán et al., 2000).
The present study showed an increase in the number of cases with negative parental consanguinity compared with those with positive parental consanguinity (80.5 and 19.5%, respectively). Temtamy and Aglan (2012) found parental consanguinity in 30% of their studied patients with isolated LRDs, which is consistent with parental consanguinity for the Egyptian population. Thus, the present study confirmed the lack of effect of parental consanguinity as an etiological factor for isolated LRDs.
A family history of limb defects as well as a history of any other congenital malformations is important because of the possibility of variability in phenotypic expression in cases affected by the same syndromes (Czeizel et al., 1993a, 1993b; Kozin, 2003).
In the present study 16 patients had a positive family history of birth defects: one patient with a positive family history of a second cousin affected with a different type of reduction defect and 15 with a family history of other birth defects. Our results agree with the findings of Calzolari et al. (1990) who studied 83 neonates with LRDs and noted that about 7.2% of first-degree relatives had defects involving the skeletal system (two cases with congenital hip dislocation; two cases with polydactyly; and two cases with a split hand, whose mothers were similarly affected). All cases with limb reduction studied by Calzolari et al. (1990) similar to our cases had no similarly affected sibs. Such observations suggest an increased susceptibility for birth defects in relatives of cases with LRDs, which needs to be investigated with genomic studies. It is important to point out that one of our probands whose father had congenital absence of vas deferens was conceived by intracytoplasmic sperm injection. Wen et al. (2012) conducted a meta-analysis of studies assessing the effect of in-vitro fertilization and intracytoplasmic sperm injection on birth defects and concluded that children conceived by assisted reproduction techniques are at significantly increased risk for birth defects.
Although the association between maternal age and the risks for birth defects has been well studied, the evidence from population data linking paternal age with birth defects was limited and inconsistent. Our results showed that age group 36–40 years for fathers and 26–30 years for mothers was associated with increased risk for LRD. The mean age of mothers of LRD patients was 28.45 years, whereas the mean age of fathers was 34.70 years; El Belbesy (2009) reported that older paternal age was associated with many sporadic limb malformations. Aglan et al. (2009) also reported the association of increased paternal age with achondroplasia. McIntosh et al. (1995) reported a general pattern of increasing relative risk estimates with increasing paternal age for neural tube defects, congenital cataract, reduction defects of the upper limb, and Down syndrome.
A variety of searches were conducted using combinations of the following terms for determining exposure: maternal occupation, occupational exposure, and occupational risk. The most common types of birth defects arising from different germ layers were selected: neural tube defects, cleft lip and cleft palate, congenital heart defects, urinary tract defects, and limb defects (Thulstrup and Bonde, 2006).
Our results showed that 60.9% of the studied cases had a history of maternal exposure during the critical period of limb organogenesis; these exposures included pesticide and insecticide exposure especially among cases living in agricultural settings, maternal smoking, and occupational exposures especially for mothers working in the medical fields. ORs and 95% CIs showed highly significant association between maternal exposures and LRDs. Consistent with our results Roberts et al. (2012) reported five studies that assessed various birth defects (central nervous system, oral cleft, limb defects) in relation to maternal agricultural occupation. In contrast, Lin et al. (1994) revealed that neither parental exposure to pesticides nor farming occupation had an effect on the risk of total LRDs. Engel et al. (2000) reported that the prevalence of all major birth defects was similar between the agricultural (36.5/1000 live births) and nonagricultural (34.7/1000 live births) offspring and was consistent with rates observed in the Birth Defect Monitoring Program and the Collaborative Perinatal Project.
Periconceptional multivitamin supplementation can reduce not only the rate of neural tube defects but also the rate of other major nongenetic syndromic congenital abnormalities (Czeizel et al., 1993a, 1993b; Wilson et al., 2007). In the present study 19.8% of mothers with affected offspring did not take folic acid during the first pregnancy, with OR (0.017) showing significant association between absence of folic acid intake during the first trimester and LRDs. Goh et al. (2006) revealed that the use of multivitamin supplements provided consistent protection against limb defects (OR 0.48, 95% CI 0.30–0.76, in case–control studies; OR 0.57, 95% CI 0.38–0.85, in cohort and randomized controlled studies). The Atlanta population-based case–control study also found a significant risk reduction for all birth defects (OR 0.80, 95% CI 0.69–0.93) even after excluding neural tube defects (OR 0.84, 95% CI 0.72–0.97). For limb deficiencies, three case–control studies and the randomized trial estimated ∼50% reduced risk (Botto et al., 2004). Although Czeizel (1996) showed that limb reduction, congenital pyloric stenosis, and omphalocele did not show a reduction after folic acid supplementation either in the first or in the second month of gestation, further studies carried out by them reported that a reduction in the occurrence of limb reduction was found only after the use of multivitamins in their intervention trials and other observational studies (Botto et al., 2004).
Treatment of common illnesses in early pregnancy is complicated because of the risk of teratogenic effects of drugs on the fetus. The period of greatest risk is between the first and eighth week of fetal age. Because much of this period occurs before a diagnosis of pregnancy is made, care must be taken in the treatment of common illnesses in all women susceptible to becoming pregnant. Few, if any, drugs have been tested for teratogenicity in controlled clinical trials (Ruedy, 1984). Our results revealed that 58.8% of the studied cases had a history of maternal drug intake during the first trimester of pregnancy in the form of hormonal intake for treatment of early vaginal bleeding (threatened abortion), OCPs, and NSAIDs. There was a highly significant association between maternal drug intake and LRDs. Similar results were reported by Temtamy et al. (2006) and Shawky et al. (2010).
Most catastrophic is the prescription of progesterone preparations for threatened abortion. In two instances with severe deficient limb anomalies, the mothers began the therapy, as prescribed by their attending obstetricians, and continued throughout the first 4–5 months of pregnancy and gave birth to a newborn with bilateral transverse hemimelia of the upper limbs in one case and a newborn with bilateral apodia in the other case (Shawky et al., 2010). Janerich et al. (1974) and Vessey et al. (1979) showed an association between exposure to exogenous sex hormones during gestation and congenital limb reduction deformities. Several case–control studies have shown significant associations between the use of steroid sex hormones and OCPs and a number of malformations such as cardiovascular defects and LRDs, with or without cardiac and other abnormalities (Harlap et al., 1975; Heinonen et al., 1977). A higher rate of use of one contraceptive pill type with a relatively high dose (ethynodiol diacetate 1.0 mg+ethinyl estradiol 0.05 mg) in the periconceptional period was found in the mothers of cases with a TTDs. This risk was minimized by the use of low-dose pills (Czeizel and Kodaj, 1995). Our results reported that among 24 mothers of cases 12 (50%) suffered from vaginal bleeding in the first trimester and received hormonal intake in the form of synthetic progesterone, whereas seven (29.1%) had taken OCPs as a way of contraception shortly before pregnancy.
Trauma in pregnancy remains one of the major contributors to maternal and fetal morbidity and mortality. Potential complications include maternal injury or death, shock, internal hemorrhage, intrauterine fetal demise, direct fetal injury, abruptio placentae, and uterine rupture (Mirza et al., 2010). Our findings showed that early maternal trauma was associated with significantly increased risk for limb defects among exposed cases. Tinker et al. (2011) reported that maternal injuries during pregnancy were common with a prevalence rate of 7%. They assessed the associations between periconceptional (the month before until the end of the third month of pregnancy) maternal injuries and birth defects; the associations with longitudinal limb deficiency, gastroschisis, and hypoplastic left heart syndrome were stronger for intentional injuries.
The present study showed that 17.1% of mothers with affected cases had been exposed to emotional stress during pregnancy with no statistical difference when compared with the control group. Suarez et al. (2003) stated that mothers who had experienced one or more stressful life events during the year before conception had increased risks for neural tube defects compared with mothers experiencing no events. Mothers who scored low on emotional support had an elevated risk compared with those who scored high (OR 4.6; 95% CI 2.2–9.7). Carmichael et al. (2007) reported that an increase in the stressful life events index was associated with increased risk for all types of birth defects, with the strongest association for isolated cleft lip with or without cleft palate and anencephaly. Hobel (2004) and Weinstock (2005) reported that increasing evidence suggests that stress during pregnancy is associated with adverse health effects among offspring.
The birth of a child with a LRD can be very disappointing for expectant parents; they require an adequate explanation, reassurance that experts are available to give them detailed advice regarding the rare condition, as well as practical assistance and counseling (Setoguchi, 1991). The results of this study call for a national survey to properly assess the problem of limb malformations as an isolated disorder or as part of a syndrome on etiological basis taking into consideration teratogenic, chromosomal, and single gene disorder causes, and providing proper premarital counseling especially in suspected families who have consanguinity and positive family history. Women in the reproductive age group should be advised about the benefits of folic acid and multivitamin supplementation and a healthy nutritional diet. They should also be aware about the effect of OCPs on pregnancy outcomes and its association with the increased risk for birth defects. The strict prohibition of any teratogen exposure during pregnancy should be highlighted.
There are no conflicts of interest.
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