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Diabetes mellitus and drug abuse during pregnancy and the risk for orofacial clefts and related abnormalities 1

Abstract Objective: to assessed the prevalence of diabetes mellitus (DM) and drug abuse in mothers of children with orofacial clefts (OFC). Methods: 325 women who had children (0-3y) with clefts were interviewed. Data regarding type of diabetes, use of legal/illegal drugs during pregnancy, waist girth and fasting blood sugar at the first prenatal consult were collected. Results: twenty seven percent of the women had DM, out of these, 89% had gestational DM, 5,5% type 1 DM and 5,5% type 2 DM. The prevalence of DM in mothers of children with OFC was 27%, it is significantly higher than the average Brazilian population which is 7.6% (p<0.01) (OR=4.5, 95%CI=3.5-5.8). Regarding drug abuse during pregnancy, 32% of the mothers used drugs and a significant positive correlation was observed between drug abuse and the occurrence of clefts and other craniofacial anomalies (p=0.028) (OR=2.87; 95%CI=1.1-7.4). Conclusions: DM and drug abuse during pregnancy increases the risk for OFC and related anomalies and early diagnosis of DM and prevention of drug abuse, especially in pregnant women, should be emphasized.


Introduction
Diabetes mellitus (DM) is a metabolic disease resulting in hyperglycemia, either because of the low insulin levels or due to insulin resistance. According to the World Health Organization (WHO) definition, metabolic syndrome is significantly associated with age, physical activity, dyslipidemia, hypertension, treatment with oral antihyperglycemic medication, and HbA1c levels >7% (1) .
The global prevalence of DM for all ages was estimated to be 8,3% and is projected to almost double in 2035 (2) , even in low and middle-income countries such as Brazil (3) . Data obtained by the Brazilian government show that the prevalence of DM in the adult population was 6.3% (4) .

Gestational diabetes mellitus (GDM) is defined as
a carbohydrate intolerance initially diagnosed during pregnancy. Author (5) stated that the pregnancies of women who were both obese and diabetic were 3 times as to result in an offspring with a craniofacial defect than were those of nonobese, nondiabetic women, suggesting that obesity and diabetes mellitus contributes in the pathogenesis of congenital anomalies.
The assumption that GMD is associated with increased occurrence of syndromes and malformations might be attributed to the deleterious effect of hyperglycemia in the early stage of pregnancy. This indicates that poor glycemic control during pregnancy increases the risk of congenital defects (6) . However, it is still controversial as to whether ---severe levels of hyperglycemia are associated with higher risk of adverse events during pregnancy.
As well as hyperglycemia, drug abuse (DU) during pregnancy represents a high risk behavior for the occurrence of several congenital malformations including orofacial clefts (7) and represents one of the most significant social problems around the world (8) . Among the environmental factors are maternal nutritional status (hypo-and hypervitaminosis), smoking and alcohol consumption during pregnancy, occupational exposures to chemicals (solvents and pesticides), exposure to X-rays, maternal illness during pregnancy including diabetes mellitus, epilepsy and viral infections, and the inadvertent use of some medications such as benzodiazepines and corticosteroids (13)(14)(15)(16) .
DM have shown that it represents a potential etiological factor for several anomalies, indicating that women with diabetes present higher chances of having children with congenital anomalies, including OFC (14) .
However, no data from the Brazilian population was found in the literature.

Method
This study was approved by the IRB of HRAC/USP. Data was collected on a private room by one the authors of the present study, a nurse trained for the application of the questionnaire. All children were followed up at HRAC/USP. Mothers were examined and the results from the fasting glucose test (level of glucose during pregnancy expressed in mg/dL) were collected by recording data from the first pre-natal exam.
Abdominal circumference was assessed and measures >80cm were considered as an indicative of obesity (17) .
In addition to the clinical data, a questionnaire with 24 questions was given to the mothers and they answered questions regarding the type of diabetes (Type 1, Type 2 or Gestational) and any other comorbidities associated with the disease. Women were also asked to answer Proportions were compared by calculating the rate difference and its 95% CI (confidence interval). One way Analysis of Variance test and the Student´s t test were used to assess the possible effects of glucose level and maternal age in determining different types of clefts and related anomalies, respectively. Chi-Square test and Fisher exact test were used to determine the significance of the association between the use of licit and illicit drugs and the type of cleft and related anomalies, respectively.
Results were assessed by the Statistica software. A p value of < 0.05 was considered statistically significant.

Results
The mothers ranged in age from 15 to 50 years old, with a mean age of 29 years old, while the children reported asthenia, as seen on Table 1. Out of these 88 women, 78 were diagnosed with GDM (89%), 5 with type 1 (5,5%) and 5 with type 2 DM (5,5%) ( Table 2). This finding is significantly higher than the average Brazilian population which is around 7% (3-4) (p<0.01).    Table 3. It can be seen that the greater the level of glucose, the severe is the type of cleft. For example, mothers who gave birth to children with CLP had a mean level of glucose of 169mg/dL while mothers who gave birth to children with cleft lip had a mean level of glucose of 117mg/ dL However, no significant differences were observed. It was also observed that increasing age is associated with the severity of the cleft type and with the presence of related anomalies. In other words, older mothers gave birth to children with more severe clefts and with related anomalies associated to CLP, such as Pierre Robin sequence, hand and feet malformations, hydrocephalus and Down syndrome, among others. Yet again, no significant differences were observed.  Due to the high prevalence of DM in this population, the comorbidities associated with congenital anomalies were excluded to assess exclusively maternal hyperglycemia as a possible causal factor of OFC.
Thus, factors such as consumption of legal or illegal drugs during the gestational term were excluded (20)(21) .
Women with abdominal circumferences >80cm were considered obese and were not included in the second analysis (17) . Hypertension and dyslipidemia were additionally excluded, because these clinical conditions are commonly associated with diabetes and represent risk factors for the development of metabolic syndrome (22)(23) . Women that were treated with antibiotics, anti-hypertensive, anti-emetics, nonsteroid anti-inflammatories, anticonvulsant, corticoids and other types of analgesics were also excluded from the analysis since the use of these medications during pregnancy could be a factor for the development of OFC (15)(16) . It is important to mention that the majority of women reported that they have had supplements of folic acid (58%), iron (59%), and multi-vitamins (23%) during the gestational period for prevention of congenital anomalies.
Therefore, when the comorbidities during pregnancy previously mentioned were excluded, the prevalence of DM dropped to 16%, however it still represents more than twice the percentage of DM in the global population. In other words, it is possible to infer that hyperglycemia during pregnancy increases the risk for the occurrence of OFC. These results are in accordance with the findings of other study (24) that have mentioned that maternal diabetes can induce congenital malformations in laboratory animals and in humans, including facial deformities and defects in neural tube closure. These authors have also stated that the incidence of birth defects in newborns of women with diabetes is approximately 3-5 times higher than among women without diabetes.
The findings presented in this study reinforce the need for rigorous control of DM during the gestational period. Among women with DM (n=88) from this sample, 60 (68%) did not have any control of glycemic levels during gestation, suggesting that these fetuses were exposed to maternal hyperglycemia during embryogenesis. This poor glycemic control is probably due to the low social status of this population.
Regarding their educational level, the majority of them completed middle school and in some cases, they reported that the birth of a child with a congenital anomaly forced them to stop studying to take care of the child. There are also reports from those mothers of anxiety and depression when they were surprised with the information that their children were diagnosed with some type of congenital anomalie (25) .