Table 3.

Time Frame Analysis for Metformin Exposure^*

Crude and Adjusted Result	>1 y Before SDev (n = 1861)	1 y Before SDev (n = 1751)	SDev (n = 1451)	1 y After SDev (n = 2484)	>1 y After SDev (n = 28 112)
Major birth defect, % (n)	4.0 (74)	4.4 (77)	5.2 (75)	4.3 (107)	3.3 (921)
aOR (95% CI)	0.86 (0.61–1.21)	0.88 (0.59–1.31)	1.75 (1.18–2.61)	0.92 (0.68–1.26)	1.05 (0.98–1.12)

aOR = adjusted odds ratio; SDev = sperm development.

^*Compared are metformin more than 1 y before SDev, 1 y before SDev, during SDev, the first year after SDev, and more than 1 y after SDev. One birth could have exposure to metformin use during more than one of these time frames. Reference group is offspring of fathers who had no exposure at any point in time. The crude birth defect frequency increases as SDev, the biologically vulnerable period, is approached, and decreases again as metformin exposure happens after SDev. When put into a single regression model, the birth defects are attributed to metformin exposure during SDev, but not at other moments. Results are from robust SEs from a bootstrapped approach to account for clustering by father. Group profiles are given in Supplement Table 2 (available at Annals.org).