American Journal of Medical Genetics 42:643-646 (1992)

Preaxial Polydactyly of Feet in Infants of Diabetic Mothers: Epidemiological Test of a Clinical Hypothesis Maria Luisa Martinez-Frias, Eva Bermejo, and Ana Cereijo INSALUD, Hospital Universitarw San Carlos, and ECEMC, Facultad de Medicina, Universidad Complutense, Madrid, Spain ~~

~

~

Using data from the Spanish Collaborative Study of Congenital Malformations(ECEMC), we tested the hypothesis of Carey et al. (Proc Greenwood Genet Cent 995, (1990) on maternal diabetes and preaxial polydactyly of feet in infants born to diabetic mothers. Our results seem to confirm their suggestion, although the hallucal type of preaxial polydactyly that they describedseems to be much less frequent. Nevertheless, a high risk exists (OR = 24.60, P = 0.0004) for preaxial polydactyly of the feet in relation with other types of birth defects or postaxial polydactyly. This analysis shows the importance of clinical observations for epidemiologists, because such observations constitute hypotheses and provide actual issues for study, and clinicians will get epidemiological confirmation for their individual observations and hypotheses. KEY WORDS maternal diabetes, ECEMC, hallucal type INTRODUCTION At the Tenth David W. Smith meeting, Carey et al. [ 19901 suggested a causal relationship between maternal diabetes and preaxial polydactyly of the feet, specifically with an unusually proximal location of the extra hallux. They thought that this type of hallucal polydactyly would be of value in providing morphologic signs that could provide diagnostic assistance in infants with multiple congenital anomalies (MCA) in which gestational history is unobtainable. We have tested this hypothesis through an epidemiologic analysis using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC).

Received for publication January 23, 1991; revision received July 3, 1991. Address reprint requests to Dr. M.L. Martfnez-F’rfas, ECEMC, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain. 0

1992 Wiley-Liss, Inc.

MATERIALS AND METHODS The ECEMC is a hospital-based case-control study and surveillance system. All children born in about 45 collaborating hospitals from all over Spain are examined by a collaborating physician during the first 3 days of life t o identify major or minor defects. In each case, the next non-malformed infant of the same sex born in the same hospital is selected as a control subject. The physician interviews the mothers of case and control infants to gather information on family history and obstetrical data on prenatal exposures such as drugs, maternal illnesses, alcohol, etc. Mothers are asked in a specific question about gestational and non-gestational diabetes. We consider as gestational diabetes that form of diabetes that is evident only when women are pregnant. We included in the group of non-gestational diabetic mothers those who were diabetic before being pregnant. Detailed description of the ECEMC has been published elsewhere [Martinez-Frias et al., 1990a,b, 19841. From April 1976 to March 1990,the ECEMC surveyed a total population of 790,482 liveborn infants, and among these 16,037were malformed and 15,892 were selected as control. Among the malformed children, 15,678(97.8%)have supplied information on presence or absence of maternal diabetes, as have 15,594 (98.1%) among the control women. To test the hypothesis of Carey et al. [19901we used the total population of malformed infants, estimating the risk of mothers with diabetes having a child with polydactyly in relation with that of non-diabetic mothers. To quantify the risk, we calculated the odds ratio (OR) for pre- and postaxial polydactyly in malformed children born to mothers with non-gestational or gestational diabetes. We attempted to confirm if a specific relationship between diabetes and preaxial polydactyly exists in relation to other types of polydactyly or defects. Then, we used for comparison the rest of the malformed children. The OR and Fisher exact one-tailed P value were estimated, as well as the 95% exact confidence intervals (CI) when a significant association exists. Using the group of malformed children for comparison allows us to control the maternal and the interviewer recall bias of the maternal disease. RESULTS Table I shows the case and control infants with specified data on the type of polydactyly and maternal dia-

644

Martinez-Frias et al. TABLE I. Case and Control Infants With Swcific Data on TYIXof Polvdactvlv and Maternal Diabetes Non-gestational diabetes 4 0 0 4b 3 2 1 0 56 28

Children with Preaxial polydactyly Isolated Associated to other defects Syndromes Postaxial polydactyly Isolated Associated to other defects Syndromes Other malformations Contro1s

Gestational diabetes 2 1 1 0

Non-diabetic" 180

8 4 3 1' 202 155

530

14,693 15,411

"Among infants of non-diabetic mothers there were 19 with pre- and postaxial polydactyly. bDiabetic embryopathy. "kisomy 18.

betes. Table I1 presents the OR values for preaxial and postaxial polydactyly in children born to mothers with gestational diabetes without considering if the affected limbs were upper or lower. As we can see, the risk is low and not statistically significant for both types of polydactyly (OR = 0.81, P = 0.55 and OR = 1.10,P = 0.79, respectively). The OR for postaxial polydactyly vs. preaxial polydactyly was also not significant (OR = 1.4,P = 0.52).On the contrary, in Table I11 we observed a statistically significant high risk for preaxial polydactyly (affecting upper or lower limbs) in children born to mothers with non-gestational diabetes (OR = 5.83, P =

0.006). Ifwe estimate the OR for preaxial polydactyly vs. the postaxial one, the value is OR = 3.93, but the level of statistical significance is P = 0.08. When we analyze the data for upper and lower preaxial polydactyly independently, we observed (Table IV) t h a t the higher risk observed for preaxial polydactyly in children of mothers with non-gestational diabetes was mostly due to a high risk for this type of polydactyly affecting the feet (OR = 24.60, P = 0.0004);it was not significant for preaxial polydactyly of hands. Likewise, there was no statistically significant high risk for postaxial polydactyly of hands or feet in either non-gestational (Table V) or gestational diabetes (Table VI).

TABLE 11. Odds Ratio (OR) for Polydactyly in Children Born to Mothers With Gestational Diabetes Children with Preaxial polydactyly Postaxial polydact yly Other malfor-

Gestational diabetes 2

Non-diabetic 180

8

530

202

14,693

mations

OR 0.81 1.10 -

DISCUSSION This epidemiologic study shows a statistically significant risk for preaxial polydactyly of feet in children born P 0.55 to mothers with non-gestational diabetes. Thus, it seems to confirm the hypothesis of Carey e t al. [1990]. 0.79 However, none of the cases born to diabetic mothers in our study had the proximal hallucal polydactyly de- scribed by those authors. Among 186 cases of preaxial polydactyly detected in our program, only one patient

TABLE 111. Odds Ratio (OR) for Polydactyly in Children Born to Mothers With Non-Gestational Diabetes

Children with Preaxial polydactyly Postaxial polydactyly Other malformations

Non-gestational diabetes 4 3 56

Non-diabetic 180 530 14,693

OR 5.83 1.49 -

Exact 95% confidence interval (152-16.03)

-

P 0.006 0.34 -

TABLE IV. Children Born to Mothers With Non-Gestational Diabetes: Odds Ratio (OR) for Preaxial Polydactyly Affecting Upper or Lower Limbs Preaxial polydactyly affectine Upper limbs Lower limbs Other malformations

Non-gestational diabetes 1 3 56

Non-diabetic 131 32 14,693

OR 2.00 24.60

-

Exact 95% confidence interval -

(4.68-82.14) -

P 0.40 0.0004 -

Preaxial Polydactyly of Feet in Infants

645

TABLE V. Children Born to Mothers With Non-Gestational Diabetes: Odds Ratio (OR) for Postaxial Polydactyly Affecting Umer or Lower Limbs Postaxial polydactyly affecting

Non-gestational diabetes

Non-diabetic

OR

P

Upper limbs Lower limbs Other malformations

3 0 56

294 118 14.693

2.68

0.11

-

-

TABLE VI. Children Born to Mothers With Gestational Diabetes: Odds Ratio (OR) for Postaxial Polydactyly Affecting U m e r or Lower Limbs ~~~

Postaxial polydactyly affecting Upper limbs Lower limbs Other malformations

Gestational diabetes 5 2 202

~

Non-diabetic 294 118 14,693

~~

OR 1.24 1.23 -

P 0.61 0.68 -

had the same type of proximally located extra toe (Fig. 1) as that described by Carey et al. 119901, but this was the son of a mother who had hypoplasia of the fibula and tibiae and was non-diabetic. Figure 2 shows a child born to a non-gestational diabetic mother who presented the type of preaxial polydactyly of feet that we observed in children of mothers with diabetes in our Registry. It is likely that the high proportion of cases with hallucal

polydactyly observed by Carey et al. [19901 represents a bias of clinical selection. The epidemiological identification of the specificity for some of the structural defects observed in children born to diabetic mothers depends on the accurate observation and description of the whole pattern of malformations present in the children. In the ECEMC program we included a detailed clinical description of the different

Fig. 1. Preaxial polydactyly of the type reported by Carey et al. [19901.

Fig. 2. Reaxial polydactyly of the type we observed in infants of diabetic mothers.

646

Martinez-Frias e t al.

defects, major and minor, including photograph, X-ray, enhance our understanding of the biology and pathoand other supplementary information when available. genetic mechanisms of congenital defects. We do not find any reason to accept that in our data ACKNOWLEDGMENTS polydactyly affecting the feet was described more frequently than that affecting the hands. Thus, the ascerWe gratefully acknowledge all the physicians that tainment of the type and location of polydactyly in the constitute the collaborating Group of the ECEMC and ECEMC should be less biased than in the series ob- collected the information, and Dr. J.C. Carey (from served by Carey et al. [19901. Our results suggest that Utah) for his comments on the manuscript. This study preaxial polydactyly of feet is related to the maternal was supported, in part, by a grant from the Direction diabetes, although the proportion of hallucal polydac- General de Planificacion Sanitaria, and by a grant from tyly among children born to non-gestational diabetic the Fondo de Investigaciones Sanitarias de la Seguridad mothers seems to be much lower than that suggested by Social, Instituto Nacional de la Salud, Ministerio de Carey et al. [19901. F’reaxial polydactyly of feet may be Sanidad y Consumo, Spain. considered a diabetes-related malformation. Why this REFERENCES relationship holds only for lower limbs in unknown but could be a clue to be used in investigating the mecha- Carey JC, Hommell M, Fineman RM, Hall BD (1990):Hallucal polynism of lower limb dysmorphogenesis in experimental dactyly in infants of diabetic mothers: A clinical marker and possible clue to teratogenesis. Roc Greenwood Genet Cent 9:95. animals. The present study shows that epidemiologistsneed to Martinez-kias ML (1990a): Clinical manifestation of prenatal exposure to valproic acid using case reports and epidemiologic informabe aware of unique clinical observations for hypothesistion. Am J Med Genet 37:277-282. testing and be suspicious of cause-effect relationships in ML, F’rias JL, Salvador J (1990b): ClinicaUepidemorder t o attempt to identify risk factors in population Martinez-kias iological analysis of malformations. Am J Med Genet 35121-125. studies. Our study of Carey’s hypothesis also demon- Martinez-klas ML, Salvador J , Prieto L, Zaplana J (1984): Epidemstrates, once again, the value of close collaboration beiological study of gastroschisis and omphalocele in Spain. Teratology 29:377-382. tween clinicians and epidemiologists.This strategy will