Eur J Epidemiol (2014) 29:411–418 DOI 10.1007/s10654-014-9913-4

PERINATAL EPIDEMIOLOGY

Risk of birth defects associated with maternal pregestational diabetes Marco Vinceti • Carlotta Malagoli • Kenneth J. Rothman • Rossella Rodolfi Gianni Astolfi • Elisa Calzolari • Aurora Puccini • Marco Bertolotti • Mark Lunt • Luisa Paterlini • Mariella Martini • Fausto Nicolini

•

Received: 11 December 2013 / Accepted: 13 May 2014 / Published online: 27 May 2014 Ó Springer Science+Business Media Dordrecht 2014

Abstract Maternal diabetes preceding pregnancy may increase the risk of birth defects in the offspring, but not all studies confirm this association, which has shown considerable variation over time, and the effect of having type 1 versus type 2 diabetes is unclear. We conducted a population-based cohort study in the Northern Italy Emilia-Romagna region linking administrative databases with a Birth Defects Registry. From hospital discharge records we identified all diabetic pregnancies during 1997–2010, and a population of non-diabetic parturients matched for age, residence, year and delivery hospital. We collected available information on education, smoking and drug prescriptions, from which we inferred the type of diabetes. We found 62 malformed infants out of 2,269 births among diabetic women, and 162 out of 10,648 births among non-diabetic women. The age-standardized prevalence ratio (PR) of

malformation associated with maternal pregestational diabetes was 1.79 (95 % confidence interval 1.34–2.39), a value that varied little by age. Type of diabetes strongly influenced the PR, with higher values related to type 2 diabetic women. Most major subgroups of anomalies had PRs above 1, including cardiovascular, genitourinary, musculoskeletal, and chromosomal abnormalities. There was an unusually high PR for the rare defect ‘extra-ribs’, but it was based on only two cases. This study indicates that maternal pregestational type 2 diabetes is associated with a higher prevalence of specific birth defects in offspring, whereas for type 1 diabetic mothers, particularly in recent years, the association was unremarkable.

M. Vinceti
C. Malagoli CREAGEN - Environmental, Genetic and Nutritional Epidemiology Research Center, University of Modena and Reggio Emilia, Reggio Emilia, Italy

G. Astolfi
E. Calzolari IMER Registry, Ferrara University Hospital, Ferrara, Italy

M. Vinceti (&) CREAGEN - Dipartimento di Medicina Diagnostica, Clinica e di Sanita` Pubblica, Universita` di Modena e Reggio Emilia, Via Campi, 287 - 41125 Modena, Italy e-mail: [email protected] K. J. Rothman RTI Health Solutions, Research Triangle Park, NC, USA K. J. Rothman Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

Keywords Diabetes mellitus
Congenital abnormalities
Cohort study
Risk assessment
Pregnancy outcome

A. Puccini Drug Policy Service, Emilia Romagna Regional Health Authority, Bologna, Italy M. Bertolotti Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy M. Lunt Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, UK M. Martini Local Health Unit of Modena, Modena, Italy

R. Rodolfi
L. Paterlini
F. Nicolini Local Health Unit of Reggio Emilia, Reggio Emilia, Italy

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Introduction A number of epidemiologic studies have indicated that diabetes that precedes pregnancy may increase the risk of birth defects in offspring [1–5]. The relation between pregestational diabetes and teratogenic risk, however, is still not entirely clear. Several recent epidemiologic studies indicated an excess teratogenic risk in mothers affected by pre-existing diabetes of either type 1 and/or type 2 [6–21], but most of these studies have yielded statistically unstable and variable results about the relative risks involved, possibly owing to methodological inconsistencies. Some studies even report null results [22, 23]. The role of potential confounders such as obesity and age, and the specific birth-defects or abnormality categories involved, also remain to be fully elucidated. Furthermore, in contrast with the large number of studies conducted in Northern Europe and the US [4, 24], no population-based study has been carried out in southern European populations, apart from small hospital-based caseonly investigations [7, 25] of diabetic pregnancies. To address these issues, we designed a population-based cohort study in a northern Italy area with a population of around 4 million people, using administrative databases and a Birth-Defect Registry.

Methods Study population Following approval of the study protocol by the Modena Province Ethics Committee, we identified all deliveries recorded in the National Health Service/Emilia-Romagna Region database that occurred from January 1, 1997 through December 31, 2010, as identified through the analysis of the hospital discharge (HD) records. We limited the selection of HD records to women residing in the Emilia-Romagna Region and to the hospitals located in the regional territory that were included in the coverage of the Emilia-Romagna Region Birth Defects Registry named IMER (see below). We linked the selected maternal HD with the newborns’ records, in order to identify possible twin pregnancies and retrieve maternal information on education and smoking, by carrying out a record-linkage procedure based on the five specific fields existing in both maternal and newborn HDs. We then selected all HD records in which a diagnostic code related to pregestational diabetes was present, by using the diagnostic codes of the ICD IX Edition no. 250.0 and 648.0. After selecting this population, we randomly extracted HD records of five non-diabetic mothers for each exposed mother. We matched these non-diabetic mothers on year of birth and delivery, province of residence within the Region, and hospital of referral. To carry out this sampling

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of matched non-diabetic mothers, we used the STATA-12 optmatch2 routine after appropriate modification by one of us (M.L.). If five non-diabetic women were not available to match to a diabetic woman in the study, we accepted a lower number. No matched woman was available for 52 diabetic women. For these women, we relaxed the matching criteria and then attempted to select a new set of up to 5 matched women. We first relaxed the requirement of matching on province of residence, which sufficed to get matched unexposed women for 45 of the 52 unmatched diabetic mothers, and then hospital of delivery (which added matches for 6 diabetic women), and finally year of delivery, which yielded matches for the one remaining diabetic woman. We then downloaded from the Birth Certificates Archive of the Emilia-Romagna Region all the records matched to the deliveries of the diabetic and non-diabetic parturients since 2002, the year from which a record-linkage procedure could be implemented following the availability of a joint code in both HD and Birth Certificate. Linkage was possible in 9,897 of the 10,464 eligible cases. The Birth certificates were searched to obtain clinical data otherwise unavailable from any other computerized sources for both the newborn and the mother, including in the latter case gestational age, nationality, education, and 5-year pre-pregnancy smoking habits. We also submitted to the Department of Health of the EmiliaRomagna Region the identity codes of all mothers included in the study, to link with information within the Archive of Drugs Prescriptions of the Region for any antidiabetic therapy, which contains since 2003 all prescriptions issued to regional residents and submitted to the National Health Service for reimbursement, or granted directly by hospital. We filtered all prescriptions issued to cohort members according to the Anatomical Therapeutic Chemical Classification System group ‘A10’, i.e. ‘‘Drugs used in diabetes,’’ including all insulin preparations and oral glucose-lowering agents. We thus identified women in our study who delivered a child since July 1, 2004 and who had any prescription of antidiabetic drugs from October 1, 2003 through December 2010. We defined as preconceptional prescription any prescription that occurred during the 3-months before and after the estimated date of conception. Finally, we consulted the two recently established population-based registries of diabetes in Modena and Reggio Emilia provinces [26], to confirm pregestational diabetes in women included in the present study and identify the type of diabetes. Birth defects detection We searched for any birth defects among newborns in both cohorts by matching all births to the Registry of Birth Defects of the Emilia-Romagna Region (IMER, established in 1978 as population-based Registry and part of the

Risk of birth defects

European Program EUROCAT [27]). Though most hospitals are covered by this Registry, this has not been true for some small hospitals during part of the 1999–2010 period. For these hospitals, we excluded the women who delivered during the periods that the hospitals were not covered. We obtained information on the isolated or multiple malformations occurring to newborns among cohort mothers that were originally identified in the Registry. We also grouped these malformations in major diagnostic categories according to the International Classifications of Diseases-IX edition diagnostic codes. If two or more malformations involved more than one organ and they were not coded as a ‘syndrome’, the affected offspring contributed to more than one organ-specific category of defects. Data analysis We computed the crude, age-adjusted and age-specific prevalence difference (PD) and ratio (PR) with associated 95 % confidence intervals (CI) of having a newborn with a congenital malformation at birth, by dividing age-specific prevalences of birth defects at birth for diabetic women by the corresponding prevalences for non-diabetic women, using Episheet statistical software (version of October 4, 2012, downloaded from http://krothman.org/Episheet.xls). The weights for age adjustment were the proportion of all study women falling into each age group. We also estimated PRs of specific groups of birth defects or single anomalies from odds ratios (OR) obtained using conditional or unconditional logistic regression models, also stratifying these analyses according to diabetes type, maternal age, period of delivery, and maternal ethnic origin.

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the study period. A final number of 10,648 non-diabetic women was included in the analysis, yielding a final exposedunexposed ratio of 1:5 for 1,829 matched sets, 1:4 for 307 sets, 1:3 for 51 sets, 1:2 for 40 sets and 1:1 for 42 sets. General characteristics of these study women are shown in Table 1. Table 1 Characteristics of diabetic and non-diabetic females residents of the Emilia-Romagna Region who delivered a child during 1997–2010 Diabetic women N = 2,269

Non-diabetic women N = 10,648

n

n

(%)

(%)

Province of residence Bologna

605

(26.7)

Ferrara Forlı`-Cesena

153

(6.7)

2,868 733

(6.9)

100

(4.4)

424

(4.0)

Modena

298

(13.1)

1,333

(12.5)

Parma

331

(14.6)

1,600

(15.0)

Piacenza

111

(4.9)

512

(4.8)

Ravenna

151

(6.7)

694

(6.5)

Reggio-Emilia

390

(17.1)

Rimini

130

(5.7)

1,839 645

(26.9)

(17.3) (6.1)

Smokinga Never

859

(37.8)

Yes, but quit before pregnancy Yes, but quit at the start of pregnancy

29 43

(1.3) (1.9)

135 254

(1.3) (2.4)

Yes, throughout pregnancy

61

(2.7)

316

(3.0)

Unknown

69

(3.0)

327

Unaivalable

1,208

(53.3)

4,083

5,533

(38.3)

(3.1) (52.9)

Maternal age B29

570

(25.1)

2,681

(25.2)

1,455

(64.1)

6,924

(65.0)

Results

30–39 40?

244

(10.8)

1,043

(9.8)

Through the HD Registry of the Emilia-Romagna Region, we retrieved a total number of 479,720 women delivering a child in Emilia-Romagna Region from 1997 through 2010 and residing in the Region at delivery. Out of these parturients, 2,301 were diagnosed with pregestational diabetes, and of these, 2,269 delivered a single child, 29 had a twin pregnancy and 3 a triplet pregnancy. We restricted subsequent analyses to diabetic women having singleton births. The 279 diabetic women who experienced more than one pregnancy and delivery during the study period were included in the study cohort as multiple observations, as was done for the 195 nondiabetic women with more than one pregnancy and delivery. Out of the 2,269 diabetic women included in the final analysis, 1,110 were found to be present in the Archive of Drug Prescription in the 2004–2010 period: 641 received only insulin prescriptions, 166 only oral glucose-lowering drugs prescriptions, and 303 received both categories of drugs during

Maternal ethnicity

298

(13.1)

1,333

(12.5)

Caucasian

1,981

(87.3)

10,073

(94.6)

Caucasian–Italian

1,523

(67.1)

8,783

Black Asiatic Unknown

(82.5)

111 165

(4.9) (7.3)

208 340

(2.0) (3.2)

12

(0.5)

27

(0.2)

Maternal educationb BPrimary school

136

(6.0)

Middle school

607

(26.7)

303 1,995

(2.9) (18.7)

High school

708

(31.2)

3,763

(35.3)

University

260

(11.5)

2,117

(19.9)

Unknown

119

(5.2)

Unaivalable

440

(19.4)

458 2,013

(4.3) (18.9)

a

Data about smoking available only through birth certificates, since 2007

b

Data about maternal education available only through birth certificates, since 2002

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414 Table 2 Prevalence difference (PD) per 1,000 and prevalence ratio (PR) of congenital anomalies associated with maternal pregestational diabetes, Emilia-Romagna region, 1997–2010

M. Vinceti et al.

Stratum (age)

Number

Diabetic women

Non diabetic women

Cases

Total

Cases

Total

12,917

62

2,269

162

10,648

\24 25–29

758 2,493

3 11

133 437

7 25

30–34

4,655

20

801

54

PD 9 1,000 (95 % CI)

PR (95 % CI)

All cases Total age standard

12 (5–19)

1.79 (1.34–2.39)

625 2,056

11 (-15 to 38) 11 (-2 to 28)

2.01 (0.53–7.72) 2.07 (1.03–4.18)

3,854

11 (0–22)

1.78 (1.07–2.96)

35–39

3,724

18

654

52

3,070

11 (-3 to 23)

1.63 (0.96–2.76)

[40

1,287

10

244

24

1,043

18 (-8 to 44)

1.78 (0.86–3.68)

2,331

5

408

25

1,923

-1 (-13 to 11)

0.94 (0.36–2.45)

Type 1 diabetes Total age standard \24

273

1

49

0

224

25–29

753

2

132

6

621

30–34

1,305

2

227

19

1,078

-8 (-23 to 6)

0.50 (0.12–2.14)

2,657

22

469

21

2,188

38 (18–57)

4.89 (2.71–8.82)

92

1

16

0

76

25–29

418

7

73

2

345

90 (21–158)

30–34

1,065

8

184

6

881

36 (7–67)

6.38 (2.24–18.21)

35–39

740

4

130

7

610

19 (-12 to 50)

2.68 (0.79–9.06)

[40

342

2

66

6

276

9 (-37 to 53)

1.39 (0.29–6.82)

– 5 (-16 to 27)

– 1.57 (0.32–7.72)

Type 2 diabetes Total age standard \24

Overall, 224 newborns birth defects were detected by the IMER Registry in the offspring of these women, 28 of whom (12.5 %) had more than one organ system affected by one or more anomalies. Sixty-two newborns to diabetic women had at least one congenital anomaly of whom 8 (12.9 %) had more than one organ system affected. The corresponding number for non-diabetic parturients was 162, of whom 20 (12.3 %) had involvement of multiple organ systems. The PDs and the PRs of having a congenital anomaly diagnosed in the offspring in the overall study population or in study subgroups, after adjusting for potential confounders, are reported in Tables 2, 3. Age-adjusted estimates and their CIs, which are reported below, were generally very close to the crude ones. PR was increased in the overall diabetic cohort (1.79; 95 % CI 1.34–2.39), as well as among women with any prescription for antidiabetic drugs (1.99; 1.28–2.99), while the overall crude PR was 1.80 (1.35–2.40). When we limited the analysis to diabetic women less than 35 years of age receiving only insulin therapy, and thus likely to have type 1 diabetes, or to women of any age with any prescription of oral glucoselowering drug, and thus likely to have type 2 diabetes, the PR was 0.94 (0.36–2.45) for type 1 diabetes and 4.89 (2.71–8.82) for type 2 diabetes. PRs were generally elevated in all age categories for type 2 diabetes, with the highest value for women aged 25–29 years (16.54, 95 % CI 3.49–78) and a decreasing trend with increasing maternal age at delivery.

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–

– 16.54 (3.49–78.33)

There was little discernible trend over maternal age for type 1 diabetes, though the number of pregnancies and cases of birth defects were too few to yield statistically stable estimates. Teratogenic risk decreased over the study period for both type 1 and type 2 maternal diabetes. After stratifying by ethnic group, PRs were elevated only for Caucasians and Italian nationality, with no increase for Blacks (Central-South Africa) and Asians. Effect estimates from either conditional or unconditional logistic regression models, both crude and adjusting for potential maternal confounders, such as age and residence, hospital and year of delivery, education and smoking habits, yielded results comparable with the above analyses. In the conditional logistic model, overall OR of birth defects was 1.73 (95 % CI 1.28–2.33), while the unconditional models yielded ORs ranging from 1.6 to 1.8 depending on the number of potential confounders included in the analysis and the number of subjects available for analysis. ORs for type 1 and type 2 maternal diabetes yielded by conditional logistic regression were 0.87 (0.33–2.32) and 4.51 (2.46–8.29), respectively. As shown in Table 3, PRs of specific categories of birth defects were elevated for most subgroups and particularly for cardiovascular, genitourinary, musculoskeletal, and chromosomal abnormalities. Breakdown of these congenital abnormalities according to minor diagnostic groups

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Table 3 Prevalence ratios (PR) for prevalence at birth of congenital anomalies of major groups and of specific congenital anomalies associated with maternal diabetes, Emilia-Romagna Region, 1997–2010, from a conditional logistic model that controlled for the matching factors of maternal age, province of residence, year and hospital of delivery

Table 3 continued

Congenital anomaly

Reduction deform. of lower limb

All anomalies

Diabetic women (n = 2,269) Cases 76

Non diabetic women (n = 10,648) Cases 202

PR

1.77

95 % CI

1.36–2.29

Major groups of congenital anomaliesa Nervous system

0

4

–

–

Eye, ear, face and neck

2

9

1.04

0.23–4.82

23 0

56 0

1.93 –

1.19–3.13 –

4

13

1.44

0.47–4.43

Cardiovascular Respiratory Cleft palate and/ or cleft lip Digestive system

4

18

1.04

0.35–3.08

Genito-urinary

13

31

1.97

1.03–3.76

Muscolo-skeletal

2.35

1.33–4.12

18

36

Integument

0

7

Chromosomal anomalies Other and unspecified

5

Multiple congenital anomalies

Congenital anomaly

Diabetic women (n = 2,269) Cases 0

Non diabetic women (n = 10,648) Cases 2

PR

95 % CI

–

–

Extra-ribs

2

0

–

–

Oral cleft

4

13

1.44

0.47–4.43

Oral clefta— adjusted for smoking

3

6

2.35

0.59–9.38

a

A child may be counted in more than one malformation category

indicated increased prevalence for tetralogy of Fallot, atrial septal defect, limb defects, and oral clefts. In addition, we observed two cases of an extremely rare defect, extra-ribs, both occurring in newborns from diabetic women. In analyses stratified by the sex of the newborn we found limited differences in the prevalence of birth defects for both male and female births, although the former had higher PR associated with maternal diabetes for cardiovascular defects, whereas the PR for musculoskeletal defects was greater in females. We also computed PRs of birth defects after restricting to the 688 diabetic women residing in the Reggio Emilia and Modena provinces who were confirmed to have either type 1 or type 2 diabetes according to local diabetes registries. These estimates were similar to those computed for type 1 diabetes in the overall study population, and stronger for overall and type 2 diabetes. PRs were 4.05 (1.37–11.95) for all diabetic women, 0.91 (0.11–7.78) for women confirmed to have type 1 diabetes, and 11.8 (2.3–59) for type 2 diabetes.

–

–

10

2.35

0.80–6.86

7

18

1.82

0.76–4.36

8

20

1.88

0.83–4.26

3

1.56

0.16–15.04

6

6

4.69

1.51–14.54

10

29

1.62

0.79–3.32

Atrial septal defect

5

8

2.93

0.96–8.96

Hypospadias and ot. penile anom.

5

14

1.68

0.60–4.65

Discussion

Renal agenesis and dysplasia

1

3

1.56

0.16–15.04

Obstructive defects of renal pelvis and uretere

5

4

5.87

1.58–21.83

Limb defects (total)

6

14

2.01

0.77–5.23

Varus deformity of foot

6

12

2.35

0.89–6.25

Polydactyly

2

7

1.34

0.28–6.45

Syndactyly

1

6

0.78

0.09–6.50

Reduction deform. of upper limb

2

1

9.39

0.85–103.5

Results of the present study indicate an excess prevalence of birth defects associated with pregestational diabetes, after controlling for potential confounders, consistent with previous observations [13, 16, 21, 28–30]. This excess was not evident, however, in women with type 1 diabetes, confirming some reports [31–33] but contradicting older studies of either type 1 or all diabetic women [23, 32, 34, 35]. Some of the latter studies had methodological limitations, such as the lack of adjustment for potential confounders. Women who met our criteria for type 2 diabetes (having at least one prescription for oral glucose-lowering drugs) had offspring with a much higher prevalence of birth defects, particularly those in the youngest age group (\30 years). These results are consistent with the proposal that

Specific congenital anomaliesa Transposition of 1 great vessels Tetralogy of Fallot Ventricular septal defect

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type 2 diabetes may actually convey higher risk to offspring than type 1 diabetes [36], confirming several observations [37–41] though not all [8, 42]. This finding might be also ascribed to concomitant maternal causes not investigated in our study, such as maternal metabolic control [3, 12, 43–45] and obesity, a condition commonly associated with type 2 diabetes that may independently increase birth defects risk [23, 29, 46–48]. It might also reflect a teratogenic effect of antidiabetic drugs and particularly of oral hypoglycemic agents [36, 49], which are expected to be discontinued before the beginning of pregnancy, or immediately after, according to Italian guidelines for diabetes therapy. Indeed, only 10 of the diabetic women in our study received a prescription of such drugs during their second trimester, and 4 during the third trimester. Unfortunately, the potential perinatal teratogenic effect of hypoglycemic drugs could not be directly addressed in our study, for two reasons: (1) we lacked data concerning relevant confounders such as metabolic control and obesity; and (2) we lacked information about the daily dose of these drugs immediately before or during pregnancy, as we knew only the total amount of hypoglycemic drug reimbursed during specific time windows. The presence of insulin resistance and elevated insulin levels might also play a role in the etiology of congenital anomalies, along with other potentially relevant pathogenetic mechanisms [2]. The excess prevalence at birth of defects reflected increased risks across a range of defect categories, with the strongest association for musculoskeletal defects. These results are in accord with other studies on occurrence of specific abnormalities in the offspring of diabetic women [6, 15, 16, 29, 42, 50–53]. Results for single types of defect were imprecise, although there was a strong association for atrial septal defects and limb abnormalities, as reported by others [6, 16, 29, 50]. Our study did not investigate severe malformations leading to embryonic or fetal death, such as most nervous system defects [54] or severe cardiovascular anomalies, because induced or spontaneous abortions were not available from the Birth Defects Registry. In the offspring of the diabetic women we unexpectedly found two rare skeletal malformations, extra-ribs, which were the only cases of this malformation in the overall study population. These cases occurred in newborns (in 1999 and 2000) to two diabetic women (aged 40 and 34) with history of prescription of oral-glucose-lowering drugs. This anomaly is rare, with only 15 cases among the 460,080 births covered by the IMER Registry in the 1997–2010 period, yielding an expected number among births to diabetic women of 0.07. We believe that the occurrence of two cases in this cohort of diabetic women is worth noting, also taking into account that congenital vertebral malformations have been recently associated with

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maternal diabetes during pregnancy [55]. Genetic factors, xenobiotics and maternal stress are associated with occurrence of extra-ribs [56]; in rats experimental diabetes may alter rib cartilage synthesis and composition [57, 58]. The possibility that pregestational diabetes exerts differential effects according to racial group, owing to both genetic and environmental causes as well as disparities in health care [59], has been suggested, albeit on the basis of sparse evidence [60], that is not entirely consistent [6, 12, 41, 61–63]. Our results appear to indicate that offspring of diabetic women from Asia and central-southern Africa may not have an increased teratogenic risk. We also observed a decreasing trend over time of the excess risk of congenital anomalies associated with both types of maternal diabetes, consistent with some though not all studies [11, 21, 64, 65]. This time trend might be a consequence of improved prepregnancy care offered to diabetic women planning pregnancy. Our study is based on administrative data, which lacked diagnostic information, as well as potentially useful information on metabolic status, concomitant obesity, folic acid consumption, [8] and other information that would have been useful [8, 66–68], and we did not collect prescription information for use of potentially teratogenic medications such as statins and ACE inhibitors for concomitant dyslipidemia and hypertension [8]. We inferred some of this information, notably the type of diabetes, from available information on birth certificates and from drug prescription history. As previously mentioned, we were also forced to limit our study to still- and live-births occurring to cohort members, and could not include prenatal occurrence of defects that were unobservable owing to spontaneous or voluntary abortions. This limitation hampered us from identifying early-developing anomalies incompatible with life, including chromosomal abnormalities and other problems that prompt voluntary pregnancy termination. Another potential bias arises from the possibility of enhanced ascertainment of congenital anomalies following the awareness of a diabetic pregnancy by the neonatologists of the Registry. This problem, to the extent it exists, is likely confined to minor defects or to defects requiring sophisticated diagnostic techniques in the absence of clinical signs. As such, it is unlikely to have affected the results for major defect categories. Acknowledgments We acknowledge the help of Drs. Eleonora Verdini (Emilia Romagna Regional Health Authority), Paola Ballotari and Paolo Giorgi Rossi (Local Health Unit of Reggio Emilia) and Gianfranco De Girolamo (Local Health Unit of Modena) for their cooperation in retrieving hospital discharge records and performing their linkage with the Reggio Emilia and Modena Diabetes Registries. Financial support to this study was provided by the Local Health Unit of Reggio Emilia and by the Pietro Manodori Foundation of Reggio Emilia. Conflict of interest of interest.

The authors declare that they have no conflict

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