The term limb reduction defect (LRD) is used when a part of or the entire arm (upper limb) or leg (lower limb) fails to form completely during pregnancy. Temtamy and McKusick (1978) and Saeed et al. (2011) defined isolated LRDs as partial or complete absence of a part of one or more limbs in the absence of other abnormalities.
The overall prevalence of LRDs is reported to vary from 2.6 to 7.06 per 10 000 births in several population-based registries (Lin et al., 1993; McGuirk et al., 2001; Dillingham et al., 2002). In Egypt, Temtamy et al. (1998) studied 3000 consecutive live-birth and still-birth newborns and reported congenital limb malformations in 1.7/1000.
Temtamy and McKusick (1978) defined 10 main categories of limb malformations based on anatomic and genetic considerations. They broadly categorized limb malformations as isolated or as part of syndromes. Limb reduction or absence defect is one of the categories that was further subdivided according to anatomic criteria into terminal transverse defects (TTD) (which include ectrodactyly, acheira, amelia, hemimelia, and acheiropodia), preaxial defects, postaxial defects, phocomelia, and split hand/split foot deformity.
A teratogen is any substance that is known to cause birth defects in humans; common examples include alcohol, cigarette smoke, certain medications, and numerous industrial chemicals. These substances promote birth defects by altering the actual environment within the womb (Lobo, 2008). The teratogenic effect may occur during the organogenesis phase, and in humans the most vulnerable period is the first 3–8 weeks of postconceptional or fetal age. During this period, the three germ layers give rise to tissues and organs. Certain birth defects can occur after the critical period as well. It seems plausible that those different types of structural malformations may share biological mechanisms and that a given teratogenic factor may cause several types of malformations depending on the time window and level of exposure. Most known human teratogens seem to cause specific birth defects (Koren et al., 1998).
Although the vast majority of isolated congenital limb deficiencies are sporadic and not heritable, there are at least four ways in which limb deficiencies can be caused: intrauterine amputation from amniotic bands, disruption of the developing arterial supply, environmental factors, and errors in the genetic control of limb development (Ghanem, 2008). LRDs are regarded as indicators of teratogen exposure and are easily recognizable (Knobloch et al., 2008), having been known for more than 2000 years (Temtamy and McKusick, 1978). They gained special attention after the thalidomide tragedy in the early 1960s as a possible indicator of human teratogen exposure (Lenz and Knapp, 1962). Other LRD patterns have been associated with prenatal exposure to anticonvulsants, oral contraceptive pills (OCPs) (De Santis et al., 2004), misoprostol (Gonzalez et al., 1998; Marchese et al., 2012; Bayman et al., 2013), and NSAIDs (Hernandez et al., 2012).
Chen et al. (2012) observed a weak increased risk for congenital LRDs associated with maternal dietary caffeine consumption; however, the risk did not vary by amount of caffeine consumed. Smoking during pregnancy has been identified as a potential risk factor for LRDs, especially isolated transverse limb reduction defects (Czeizel et al., 1994).
The maternal occupational exposure to agricultural chemicals may increase the risk of giving birth to a child with limb defects (Thulstrup and Bonde, 2006). Schwartz et al. (1986) observed the birth outcomes in an agricultural community and found the prevalence of congenital LRDs to be increased in the entire community (2–10-fold higher than available US rates) and also among the progeny of agricultural workers. Garry et al. (2002) studied the association between pesticide use and the risk for birth defects, and found an increased risk for birth defects in the musculoskeletal system. Occupation as a healthcare worker, hairdresser, textile worker, or leather or shoe worker has been associated with limb reduction defects (Engel et al., 2000).
An association between the occurrence of LRDs and the following risk indicators – vaginal bleeding, threatened abortion, duration of gestation under 37 weeks, placental weight 400 g or less, birth weight 2500 g or less, and any type of malformation in relatives – has been reported by Aro et al. (1983). Procedures during pregnancy, including chorionic villus sampling and dilatation and curettage, produce defects of vascular disruption (Holmes, 2002).
The Hungarian randomized control trial has also demonstrated that the risk for congenital anomalies of the cardiovascular system, LRDs, and urinary tract defects was reduced significantly after periconceptional multivitamin supplementation (Czeizel, 2004). Maternal overweight and obesity are associated with structural birth defects including cardiovascular defects, orofacial clefts, hydrocephalus, and limb reductions (Stothard et al., 2009). Also, maternal diabetes has an effect on the development of the embryo and significantly increases the risk for congenital malformations in humans (Farrel et al., 2002).
Limb absence or reduction defects constitute an important group of genetic disorders that requires thorough assessment. It is not an uncommon condition among Egyptian children (Temtamy et al., 2006).
The present study aims at the proper diagnosis and genetic evaluation of cases with isolated LRD and the identification of environmental risk factors that predispose to their occurrence, aiming at prevention.
Patients and methods
Forty-one Egyptian patients with isolated LRDs were recruited from the Limb Malformations and Skeletal Dysplasia Clinic, Medical Centre for Scientific Excellence, National Research Centre. Patients were seen at the clinic between 2003 and 2013. Their ages ranged from 1 day to 19 years. Twenty-five matching Egyptian controls were selected from Child Health Clinic, Ain Shams University.
A written informed consent form was signed by the studied participants or their parents after they were given a full explanation of the study. The consent form of the Medical Ethics Committee of the National Research Centre was used.
Each case was subjected to the following: medical history, which includes age, sex, residence, birth rank; father’s age, occupation, residence, exposure (X-ray, irradiation, pesticides), special habits (smoking, alcohol, cocaine); mother’s age, residence, occupation, exposure, nutrition, special habits (smoking, alcohol, cocaine), acute and chronic diseases, pregnancy history [drug intake (name, dose duration), hormonal intake, contraception use, infections to which the mother had been exposed (preconception and during pregnancy), prenatal diagnosis procedures, previous abortion]; three-generation pedigree construction, including details of consanguinity and of other affected members in the family; and general physical examination including different body systems with special emphasis on the skeleton and limbs. The affected limb segment was documented by photography. Anthropometric measurements including weight, height, and head circumference in addition to measurement of limb length were recorded for each case in addition to calculation of BMI for the mothers. Radiological examination of the affected limb(s) and for other parts of the body, whenever indicated, was performed. Other investigations such as chromosomal analysis, TORCH screen, abdominal ultrasonography, echocardiography, and random blood sugar testing for the mothers were carried out, whenever indicated.
Data were evaluated by the χ2 or Fisher’s exact test for comparison of proportions, and the Student t-test was used to compare means. Odds ratios (ORs) and their 95% confidence intervals (CI) were calculated to evaluate the association between risk factors and the occurrence of an isolated LRD. P value of 0.05 or less was considered statistically significant. Analyses were performed using SPSS (version 16; SPSS Inc., Chicago, Illinois, USA).
The study was carried out on 41 patients (23 male and 18 female patients) with isolated LRDs. Their ages ranged from 1 day to 19 years. The results showed an increase in the number of patients with negative parental consanguinity compared with those with positive parental consanguinity, with no statistically significant difference between patients and controls. Parental consanguinity was positive among 19.5% of cases and 24% of controls. Sixteen patients had a positive family history of genetic disorders (both for similar and different birth defects), whereas in the control group only one patient had positive family history, by way of a relative with congenital heart disease. The patients with a positive family history among relatives were as follows: one patient with bilateral amelia had a second cousin with unilateral split hand deformity; 15 patients had a family history of other birth defects: one patient had a second cousin with autosomal dominant postaxial polydactyly (uncle and his three children); the father of another patient had congenital absence of vas deferens (the proband who had unilateral acheira was conceived by intracytoplasmic sperm injection, and her twin was normal); another patient had a family history of one sib and two second cousins with scoliosis; five patients had a family history of second cousins with Down syndrome; three patients had a family history of intra uterine fetal death (of unspecified etiology), or early neonatal deaths with multiple congenital anomalies (in these families we noticed positive parental consanguinity); the last four patients had a family history of second cousins with delayed milestones of development.
We categorized father’s and mother’s age into standard 5-year age groups: 20–25, 26–30, 31–35, 36–40, 41–45, 46–50, and 51–55 years. The mean maternal age was 28.4 years and the mean paternal age was 34.7 years. Our results showed an increased risk for LRD in the maternal age group of 26–30 years and paternal age group of 36–40 years (Fig. 1). We also found that most of the couples had their affected case with birth rank less than 3, with a relative percentage of 73.6%.
The environmental risk factors that cause LRDs were evaluated among patients and controls. The OR and 95% CI were calculated for both patients and controls (Table 1). The results showed a statistically significant increase in the risk for LRD among patients with maternal exposure to pesticides, insecticides, and irradiation and maternal history of drug intake in the form of hormonal intake and NSAIDs. In addition, the risk was increased among mothers who had not taken folic acid during the first trimester of pregnancy. Early maternal trauma played a role as a risk factor for LRD.
Among 25 (62.5%) mothers of affected cases who had a history of exposure to environmental hazards 15 (60%) had been exposed to pesticides or insecticides and/or had lived in an agricultural setting during the first trimester, five (20%) had been exposed to X-rays during the first trimester, three (12%) had had occupational history in the medical field, and two (8%) had had a history of smoking during the first trimester. In five of 25 control mothers, four (80%) had been exposed to pesticides and lived in an agricultural setting and one (20%) had had occupational history in the medical field (Fig. 2). Eight (19.8%) and 10 (24.4%) mothers had not taken folic acid and had been exposed to trauma during the first trimester, respectively (Figs 3 and 4).
Of 41 mothers of affected cases and 25 control mothers, 24 (58.5%) mothers of affected cases and four (16%) control mothers had taken drugs during the first trimester. Among 24 mothers of affected cases 12 (50%) had suffered from vaginal bleeding during the first trimester and had received hormonal treatment (synthetic progesterone) to save these pregnancies, whereas seven (29.1%) had taken OCPs as a way of contraception shortly before pregnancy and five (20.8%) had received analgesics in the form of aspirin or ibuprofen during the first trimester. Among four control mothers, two (50%) had had vaginal bleeding and had received progesterone, one (25%) had taken OCPs, and one (25%) had received analgesics in the form of ibuprofen (Fig. 5).
Fifteen (36.6%) mothers of affected cases had maternal disease and five (20.0%) control mothers had maternal disease (Fig. 6). The most commonly reported maternal disease in mothers of affected cases was diabetes, which was observed in 10 (24.4%) cases; these mothers had an increased BMI (range 30–45). Among control mothers, five (20%) had diabetes and increased BMI (range 29–40). Five mothers of affected cases had maternal fibroid. Also, 10 (17.1%) mothers of affected cases and one (4%) control mother had been exposed to emotional stress during the first trimester (Fig. 7).
The 41 studied cases were classified according to the method followed by Temtamy and McKusick (1978) into 23 (56.0%) patients with a TTD and 14 patients with a longitudinal LRD, who were further classified into three (7%) patients with preaxial defect, four (9%) patients with postaxial defect, seven (17%) patients with a split hand and one (4%) patient with a split foot, and finally three (7%) patients with phocomelia (Fig. 8). The upper limbs were more affected than the lower limbs and the right side was more affected than the left side (Figs 9 and 10). Figures 11–17 show examples of the main LRD categories.
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).
In the present study we followed the classification of Temtamy and McKusick (1978) for isolated LRDs as it is based on both genetic and anatomic criteria. Our findings showed that TTDs were more in number compared with longitudinal defects and the number of affected male patients was more than the number of affected female patients. This was in accordance with the study by Lin et al. (1993). Also, in an epidemiological study by Czeizel A (February 2014; personal communication) on 998 Hungarian patients with LRD, the incidence of isolated LRD in 555 patients was as follows: transverse defects in 35.1% (mostly unilateral), amniotic bands in 24.1%, postaxial defects in 20.5%, preaxial defects in 7.2%, split hand or foot in 9.7%, proximal femoral dysplasia in 2.2%, phocomelia in 0.4%, and unspecified in 0.7%. However, more recent data indicated that longitudinal defects were more common (McGuirk et al., 2001; Dillingham et al., 2002; Makhoul et al., 2003). Our study indicated that unilateral affection was more common than bilateral affection with the upper limbs more commonly affected than the lower limbs. Also, affection of the right side was more common than affection of the left side. Most of the previous studies of LRDs have shown that upper limb defects were more common than lower limb defects (60–80% vs. 25–40%) (Froster and Baird, 1992; Lin et al., 1993; Evans et al., 1994; McGuirk et al., 2001). About 15–20% of cases have both upper and lower limb involvement (Calzolari et al., 1990; Goutas et al., 1993; Lin et al., 1993). Unilateral involvement is more common in isolated LRDs but bilateral involvement is more common in infants with other organ anomalies (Lin et al., 1993; Evans et al., 1994). This explains the higher frequency of unilateral limb involvement in our patients since the limb defects were isolated.
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.
Desrosiers et al. (2012) reported an increased prevalence for various birth defects among various professionals – for example, scientists in the fields of mathematics, physics, and computer science; artists; photographers and photo processors; food service workers; landscapers and groundskeepers; hairdressers and cosmetologists; office and administrative support workers; sawmill workers; petroleum and gas workers; chemical workers; printers; material moving equipment operators; and motor vehicle operators. In the present study most of the mothers were housewives.
Czeizel et al. (1994) and Hackshaw et al. (2011) recorded a significant positive association with maternal smoking and LRDs and missing/extra digits. Our results showed that 8% of mothers exposed to environmental factors were smokers in the initial months of pregnancy and shortly before the beginning of pregnancy, whereas among controls there was no history of maternal smoking.
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.
Hernandez et al. (2012) found that, among women in the National Birth Defects Prevention Study, 22.6% reported the use of NSAIDs in the first trimester of pregnancy, most commonly ibuprofen, aspirin, and naproxen. However, Van Gelder et al. (2011) reported that no associations were found between the exposure to any NSAID in the first 12 weeks of gestation and the occurrence of birth defects such as congenital heart defects and orofacial clefts.
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 risk of birth defects among women with pre-existing diabetes mellitus (DM) remains very high. Correa et al. (2012) reported that good glucose control before and early during pregnancy is associated with a lower risk for birth defects based upon observational data. In the present study, 15 (36.6%) mothers of our cases had a history of maternal disease during pregnancy; 10 (24.4%) patients had DM with increase in BMI that showed no significant association between DM, increased BMI, and LRDs. In contrast, Åberg et al. (2001) reported that among infants born of women with pre-existing diabetes, increased risk was seen specifically for some types of congenital malformations including limb reductions. Human studies have shown that hyperglycemia during organogenesis is associated with an increased risk for birth defects and that this risk correlates directly with maternal glucose levels (Miller et al., 1981; Kitzmiller et al., 1991; Schaefer Graf et al., 2000; Dunne et al., 2003). It is worth pointing out that none of our patients with LRDs had the typical proximal femoral deficiency or caudal regression syndrome commonly seen in diabetic embryopathy.
Correa et al. (2008) reported that ∼70% (95% CI 54–80) of isolated birth defects among infants who were born to mothers with pregestational diabetes mellitus (PGDM) may be attributable to DM. Analyses that explored the independent and joint effects of prepregnancy BMI and DM showed that the association between PGDM and birth defects is consistent, irrespective of maternal BMI, for both isolated and multiple defects. These findings support the hypothesis that the embryopathy that is associated with PGDM is nonspecific and that complex underlying metabolic disorders that are associated with DM increase the likelihood that different signal transduction pathways and morphogenetic processes might be disturbed (Reece and Homko, 2000).
Oteng-Ntim et al. (2013) reported that increasing maternal BMI was associated with increasing risk for adverse pregnancy outcome, including diabetes and postpartum hemorrhage. Waller et al. (2007) revealed that mothers of offspring with spina bifida, heart defects, anorectal atresia, hypospadias, LRDs, diaphragmatic hernia, and omphalocele were significantly more likely to be obese than mothers of controls, with ORs ranging between 1.33 and 2.10. Blomberg and Källén (2010) screened the Swedish Medical Health Registries and found that, in addition to neural tube defects, cardiac defects, and orofacial clefts, obesity also increased the risk for limb reduction anomalies.
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.
Conflicts of interest
There are no conflicts of interest.
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