Frequency of exposed to medicines during the first trimester of pregnancy in 58,514 subjects with single or multiple birth defects (excluding minor anomalies and syndromes) and 110,814 non-malformed newborns.

<p>References: (1): Prenatal medication exposure during the first trimester of pregnancy according to maternal report; (2): Exposed to the study medication, alone or in combination with other medications; (ATC code) Anatomical Therapeutic Chemical classification system.</p

Prenatal exposure to medications and birth defects occurrence.

<p>(<b>a</b>) Potential relationships between prenatal exposure to medications and birth defects occurrence in the population; (<b>b</b>) Three-by-three contingency table of malformed and non-malformed newborns with prenatal exposure to the study medication, exposure to other medications, and non-exposed; cell frequencies are represented by the letters <i>a</i>, <i>b</i>, <i>c</i>, <i>d</i>, <i>e</i>, <i>f</i>, <i>g</i>, <i>h</i>, and <i>i</i>.</p

Associations between medications and birth defects for SICK, OECA and HEALTHY designs.

<p>The smile plots summarize the associations between each birth defect and exposure to antiepileptics, insulin, and acetaminophen for the three case-control designs. In each smile plot, P-values are plotted on the y-axis on a reverse log scale against the estimated odds ratios on the x-axis. So, the higher the P-values up the y-axis the more significant they are. The vertical full red line represents no association between medication exposure and birth defect (OR equals to 1), and the horizontal dashed red line represents the cut-off P value (0.01).</p

Number of cases; rate per 10,000 births; and frequencies of exposed to antiepileptics, insulin, and acetaminophen registered by the ECLAMC during 1967–2008.

<p><u>References:</u> (1): Prenatal medication exposure during the first trimester of pregnancy according to maternal report; (2) Rate per 10,000 live births.</p

Statistically significant results obtained using SICK or OECA approaches.

<p><u>References</u>: (1): (M→BD) is the risk that the study medication (“M”) causes the birth defect studied (“BD”); (2): (M→OBD) is the risk that the study medication (“M”) produces congenital anomalies other than the birth defect under study (“OBD”); (3): (OM→BD) is the risk that other medicines (“OM”) produce the birth defect studied (“BD”); (4): (OM→OBD) is the risk that other medications (“OM”) cause other birth defects (“OBD”); (5): Exposure: (ANTI) antiepileptic medications, (INSU) insulin, (ACET) acetaminophen.</p

Bias in SICK, OECA and HEALTHY designs.

<p>The potential bias (%) is shown as a function of the proportion of exposed controls to acetaminophen (%) in the 31 birth defect groups and for the three evaluated designs. The linear function is defined as follows: Bias(%) = β₀+β₁*Exp(%); R-squared (R2) and the overall P value for the regression model are shown for each design.</p

Sex ratio changes for NTD cases and total births in Chile, Argentina, and Venezuela (1990–2013).

<p>NTD: neural tube defect; FAF: folic acid fortification; M/F: male/female; Sex ratio (male/female) for neural tube defect cases (full blue line), sex ratio for total births (dashed red line). Sex ratios estimated by multivariate regression models adjusted by hospital.</p

Changes in NTD rates by sex in Chile, Argentina and Venezuela (1990–2013).

<p>NTD: neural tube defect; FAF: folic acid fortification; Neural tube defects rates (per 10,000 births) for females (dashed orange line), and males (full blue line). Rates estimated by multivariate regression models adjusted by hospital.</p

Reduction in NTD rates (per 10,000 births) between pre- and post-FAF periods, by sex and country.

<p>Reduction in NTD rates (per 10,000 births) between pre- and post-FAF periods, by sex and country.</p

Sex ratio (M/F) changes for types of NTDs between FAF periods.

<p>Sex ratio (M/F) changes for types of NTDs between FAF periods.</p