Adverse Birth and Child Outcomes in Children Fathered by Men Treated with Antidiabetics Prior to Conception: A Nationwide Cohort Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Design and Setting
2.2. Study Population
2.3. Exposed Cohorts
2.4. Unexposed Cohort
2.5. Birth and Child Outcomes
2.6. Confounders
2.7. Statistical Analyses
2.8. Approvals and Ethics
2.9. Patient and Public Involvement
3. Results
3.1. Preconception Paternal Use of Insulin
3.2. Preconception Paternal Use of Non-Insulin Anti-Hyperglycemic Agents
4. Discussion
Strengths and Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Children Fathered by Men Treated with Insulin (ATC A10A) N = 5527 | Children Fathered by Men Treated with Non-Insulin Anti-Hyperglycemic Agents (ATC A10B) N = 2121 | Children Fathered by Men Not Treated with Insulin or Antidiabetics N = 1,311,036 | |
---|---|---|---|
Paternal age at child birth, years (n, %) | |||
−30 | 1585 (28.7) | 103 (4.9) | 400,628 (30.6) |
31–40 | 3277 (59.3) | 859 (40.5) | 762,768 (58.2) |
41– | 665 (12.0) | 1159 (54.6) | 147,640 (11.3) |
Paternal Charlson’s comorbidity index (n, %) | |||
0 | 5042 (91.2) | 1756 (82.8) | 1,230,252 (93.8) |
>=1 | 485 (8.8) | 365 (17.2) | 80,784 (6.2) |
Maternal use of antidiabetics (n, %) | |||
No | 5437 (98.4) | 2029 (95.7) | 1,296,172 (98.9) |
Yes | 90 (1.6) | 92 (4.3) | 14,864 (1.1) |
Maternal age at child birth, years (n, %) | |||
−30 | 2604 (47.1) | 512 (24.1) | 612,733 (46.7) |
31–40 | 2760 (49.9) | 1328 (62.6) | 662,754 (50.6) |
41– | 163 (2.9) | 281 (13.2) | 35,549 (2.7) |
Maternal Charlson’s comorbidity (n, %) | |||
0 | 5130 (92.8) | 1963 (92.6) | 1,227,353 (93.6) |
>=1 | 397 (7.2) | 158 (7.4) | 83,683 (6.4) |
Maternal smoking (n, %) | |||
No | 4288 (77.6) | 1778 (83.8) | 1,002,296 (76.5) |
Yes | 831 (15.0) | 239 (11.3) | 180,175 (13.7) |
Missing | 408 (7.4) | 104 (4.9) | 128,565 (9.8) |
Maternal BMI a (n, %) | |||
<18.5 | 155 (2.8) | 48 (2.3) | 37,420 (2.9) |
18.5–24.9 | 2144 (38.8) | 621 (29.3) | 513,929 (39.2) |
>=25 | 1367 (24.7) | 1028 (48.5) | 276,856 (21.1) |
Missing | 1861 (33.7) | 424 (20.0) | 482,831 (36.8) |
Parity (n, %) | |||
First child | 2433 (44.0) | 582 (27.4) | 570,606 (43.5) |
Second or more | 3028 (54.8) | 1524 (71.9) | 705,333 (53.8) |
Missing | 66 (1.2) | 15 (0.7) | 35,097 (2.7) |
Child sex (n, %) | |||
Girl | 2682 (48.5) | 1032 (48.7) | 638,060 (48.7) |
Boy | 2845 (51.5) | 1089 (51.3) | 672,976 (51.3) |
Calendar year of birth (n, %) | |||
1997–2002 | 1512 (27.4) | 300 (14.1) | 377,636 (28.8) |
2003–2008 | 1594 (28.8) | 507 (23.9) | 367,847 (28.1) |
2009–2014 | 1469 (26.6) | 726 (34.2) | 336,183 (25.6) |
2015–2018 | 952 (17.2) | 588 (27.7) | 229,370 (17.5) |
Type of non-insulin anti-hyperglycemic agents b (n, %) | |||
Metformin | 1617 (76.2) | ||
Sulfonylureas | 664 (31.3) | ||
Others | 327 (15.4) | ||
Father’s use of methotrexate prior to conception (n, %) | 2 (0.0) | 1 (0.0) | 241 (0.0) |
Mother’s exposure to known teratogens c (n, %) | 39 (0.7) | 14 (0.7) | 4053 (0.3) |
Children Fathered by Men Treated with Insulin within Three Months before Conception | Children Fathered by Men Not Treated with Insulin or Non-Insulin Anti-Hyperglycemic Agents within Three Months before Conception | ||||||
---|---|---|---|---|---|---|---|
Events (%) | N | Events (%) | N | Crude OR (95% CI) | Adjusted OR a (95% CI) | Adjusted OR b (95% CI) | |
BIRTH OUTCOMES | |||||||
Preterm birth | 299 (5.4) | 5527 | 65,050 (5.0) | 1,311,036 | 1.10 (0.97–1.23) | 1.06 (0.94–1.19) | 1.10 (0.95–1.27) |
SGA | 164 (3.0) | 5512 | 47,770 (3.7) | 1,287,707 | 0.80 (0.68–0.93) | 0.83 (0.71–0.97) | 0.96 (0.78–1.18) |
Events/total time at risk (years) | N | Events/total time at risk (years) | N | Crude HR (95% CI) | Adjusted HR a (95% CI) | Adjusted HR b (95% CI) | |
EARLY CHILD OUTCOMES (FIRST YEAR OF LIFE) | |||||||
Major congenital malformations | 189/5316 | 5486 | 46,692/ 1,261,546 | 1,306,743 | 0.96 (0.83–1.11) | 0.94 (0.81–1.09) | 0.97 (0.82–1.15) |
Infections | |||||||
Overall infections | 767/5132 | 5527 | 179,618/ 1,214,168 | 1,311,036 | 1.01 (0.94–1.08) | 1.00 (0.93–1.07) | 0.99 (0.91–1.08) |
Respiratory | 443/5301 | 5527 | 96,765/ 1,256,729 | 1,311,036 | 1.09 (0.99–1.19) | 1.07 (0.97–1.17) | 1.05 (0.94–1.17) |
Gastrointestinal | 125/5462 | 5527 | 32,017/ 1,290,404 | 1,311,036 | 0.92 (0.77–1.10) | 0.91 (0.76–1.09) | 0.94 (0.77–1.15) |
Urological/gynecological | 29/5497 | 5527 | 6644/ 1,300,267 | 1,311,036 | 1.03 (0.72–1.49) | 1.03 (0.72–1.48) | 1.02 (0.67–1.55) |
Skin/subcutaneous tissue | 0/5514 | 5527 | 121/ 1,304,014 | 1,311,036 | |||
Bacteremia | 11/5504 | 5527 | 2372/ 1,302,387 | 1,311,036 | 1.10 (0.61–1.99) | 1.09 (0.60–1.98) | 1.32 (0.71–2.46) |
Other infections | 305/5370 | 5527 | 74,234/ 1,268,781 | 1,311,036 | 0.97 (0.87–1.09) | 0.96 (0.86–1.08) | 0.93 (0.81–1.06) |
Children Fathered by Men Treated with Non-Insulin Anti-Hyperglycemic Agents within Three Months before Conception | Children Fathered by Men Not Treated with Insulin or Non-Insulin Anti-Hyperglycemic Agents within Three Months before Conception | ||||||
---|---|---|---|---|---|---|---|
Events (%) | N | Events (%) | N | Crude OR (95% CI) | Adjusted OR a (95% CI) | Adjusted OR b (95% CI) | |
BIRTH OUTCOMES | |||||||
Preterm birth | |||||||
Metformin | 97 (6.0) | 1617 | 65,080 (5.0) | 1,311,540 | 1.22 (1.00–1.50) | 1.08 (0.86–1.35) | 1.07 (0.84–1.37) |
Sulfonylureas | 43 (6.5) | 664 | 65,134 (5.0) | 1,312,493 | 1.33 (0.97–1.81) | 1.21 (0.87–1.67) | 1.20 (0.79–1.83) |
Other | 19 (5.8) | 327 | 65,158 (5.0) | 1,312,830 | 1.18 (0.74–1.88) | 1.01 (0.61–1.65) | 1.10 (0.65–1.85) |
SGA | |||||||
Metformin | 71 (4.4) | 1613 | 47,794 (3.7) | 1,288,208 | 1.20 (0.94–1.52) | 1.17 (0.90–1.52) | 1.36 (0.99–1.86) |
Sulfonylureas | 38 (5.8) | 660 | 47,827 (3.7) | 1,289,161 | 1.59 (1.14–2.20) | 1.52 (1.06–2.18) | 1.80 (1.11–2.93) |
Other | 14 (4.3) | 326 | 47,851 (3.7) | 1,289,495 | 1.16 (0.68–1.99) | 1.05 (0.60–1.83) | 0.91 (0.45–1.83) |
Events/total time at risk (years) | N | Events/total time at risk (years) | N | Crude HR (95% CI) | Adjusted HR a (95% CI) | Adjusted HR b (95% CI) | |
EARLY CHILD OUTCOMES (FIRST YEAR OF LIFE) | |||||||
Major congenital malformations | |||||||
Metformin | 92/1517 | 1603 | 46,704/1,262,036 | 1,307,246 | 1.62 (1.32–1.99) | 1.55 (1.25–1.92) | 1.40 (1.11–1.76) |
Sulfonylureas | 30/632 | 663 | 46,766/1,262,921 | 1,308,186 | 1.27 (0.89–1.82) | 0.99 (0.68–1.43) | 1.24 (0.81–1.90) |
Other | 14/310 | 325 | 46,782/1,263,243 | 1,308,524 | 1.21 (0.72–2.05) | 0.90 (0.53–1.52) | 0.98 (0.58–1.65) |
Infections | |||||||
Overall infections | |||||||
Metformin | 264/1465 | 1617 | 179,703/1,214,628 | 1,311,540 | 1.22 (1.08–1.38) | 1.14 (1.00–1.30) | 1.03 (0.89–1.19) |
Sulfonylureas | 110/602 | 664 | 179,857/1,215,491 | 1,312,493 | 1.24 (1.02–1.49) | 1.13 (0.92–1.38) | 1.09 (0.84–1.42) |
Other | 63/291 | 327 | 179,904/1,215,801 | 1,312,830 | 1.46 (1.14–1.87) | 1.34 (1.03–1.73) | 1.31 (1.00–1.71) |
Respiratory | |||||||
Metformin | 160/1525 | 1617 | 96,805/1,257,209 | 1,311,540 | 1.36 (1.17–1.59) | 1.27 (1.07–1.50) | 1.10 (0.91–1.32) |
Sulfonylureas | 59/626 | 664 | 96,906/1,258,109 | 1,312,493 | 1.22 (0.95–1.58) | 1.04 (0.79–1.36) | 1.09 (0.78–1.54) |
Other | 35/305 | 327 | 96,930/1,258,429 | 1,312,830 | 1.49 (1.07–2.08) | 1.28 (0.90–1.81) | 1.37 (0.97–1.94) |
Gastrointestinal | |||||||
Metformin | 41/1590 | 1617 | 32,040/1,290,897 | 1,311,540 | 1.04 (0.76–1.41) | 0.91 (0.65–1.28) | 0.86 (0.60–1.23) |
Sulfonylureas | 30/647 | 664 | 32,051/1,291,839 | 1,312,493 | 1.87 (1.31–2.67) | 2.13 (1.44–3.15) | 1.76 (1.04–2.99) |
Other | 11/322 | 327 | 32,070/1,292,165 | 1,312,830 | 1.38 (0.76–2.48) | 1.32 (0.71–2.44) | 1.28 (0.68–2.42) |
Urological/gynecological | |||||||
Metformin | 15/1601 | 1617 | 6644/1,300,768 | 1,311,540 | 1.83 (1.11–3.04) | 1.77 (1.06–2.95) | 1.47 (0.83–2.60) |
Sulfonylureas c | 2/657 | 664 | 6657/1,301,712 | 1,312,493 | |||
Other c | 1/325 | 327 | 6658/1,302,044 | 1,312,830 | |||
Skin/subcutaneous tissue | |||||||
Metformin c | 1/1609 | 1617 | 121/1,304,515 | 1,311,540 | |||
Sulfonylureas c | 0/659 | 664 | 122/1,305,466 | 1,312,493 | |||
Other c | 0/325 | 327 | 122/1,305,799 | 1,312,830 | |||
Bacteremia | |||||||
Metformin | 6/1604 | 1617 | 2374/1,302,888 | 1,311,540 | 2.05 (0.92–4.58) | 1.85 (0.82–4.15) | 1.59 (0.66–3.86) |
Sulfonylureas c | 2/658 | 664 | 2378/1,303,834 | 1,312,493 | |||
Other c | 1/325 | 327 | 2379/1,304,166 | 1,312,830 | |||
Other infections | |||||||
Metformin | 108/1555 | 1617 | 74,272/1,269,264 | 1,311,540 | 1.19 (0.98–1.43) | 1.13 (0.91–1.40) | 1.09 (0.87–1.37) |
Sulfonylureas | 43/639 | 664 | 74,337/1,270,180 | 1,312,493 | 1.15 (0.85–1.55) | 1.06 (0.76–1.46) | 0.83 (0.53–1.31) |
Other | 26/312 | 327 | 74,354/1,270,507 | 1,312,830 | 1.42 (0.97–2.09) | 1.33 (0.89–2.00) | 1.26 (0.82–1.94) |
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Nørgård, B.M.; Fedder, J.; Jølving, L.R.; Damkier, P.; Nielsen, J. Adverse Birth and Child Outcomes in Children Fathered by Men Treated with Antidiabetics Prior to Conception: A Nationwide Cohort Study. J. Clin. Med. 2022, 11, 6595. https://doi.org/10.3390/jcm11216595
Nørgård BM, Fedder J, Jølving LR, Damkier P, Nielsen J. Adverse Birth and Child Outcomes in Children Fathered by Men Treated with Antidiabetics Prior to Conception: A Nationwide Cohort Study. Journal of Clinical Medicine. 2022; 11(21):6595. https://doi.org/10.3390/jcm11216595
Chicago/Turabian StyleNørgård, Bente Mertz, Jens Fedder, Line Riis Jølving, Per Damkier, and Jan Nielsen. 2022. "Adverse Birth and Child Outcomes in Children Fathered by Men Treated with Antidiabetics Prior to Conception: A Nationwide Cohort Study" Journal of Clinical Medicine 11, no. 21: 6595. https://doi.org/10.3390/jcm11216595