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Association between antidepressant use in pregnancy and gestational diabetes mellitus: Results from the Norwegian Mother, Father and Child Cohort Study

This study sought to determine the association between gestational diabetes mellitus (GDM) and antidepressant exposure during early‐mid pregnancy, overall and according to antidepressant affinity to the histamine‐1 (H1) receptor.

• Early-mid pregnancy use of antidepressants with low affinity to the histamine-1 receptor, including the most common antidepressant group of selective serotonin reuptake inhibitors (SSRIs), does not increase the risk of GDM.
• Our study could rule out a two-fold increased risk of GDM following antidepressant exposure, although we were unable to confirm or refute whether a smaller increased risk exists.
• The risk for GDM was greater in pregnancies within women who took antidepressant with high affinity to histamine-1 receptor compared to unexposed women with depression and/or anxiety, but no adjusted association measured could be estimated due to low statistical power.

Language Summary
This study among pregnant women in Norway examined whether antidepressant use in earlymid pregnancy can increase the risk of gestational diabetes. The results suggest that women who used antidepressant medication in pregnancy do not have a greater risk for gestational diabetes than women who had depression or anxiety but did not take these medications.

| INTRODUCTION
Gestational diabetes mellitus (GDM), defined as glucose intolerance with onset or first recognition in pregnancy, 1 affect as many as 5% of pregnant women in Europe. 2,3 Its global prevalence varies markedly (from 1% to <30%), owing among other factors, to lack of consensus on diagnostic criteria and varying distribution of maternal life-style and genetic factors. 4 Beyond carrying risks for an array of adverse perinatal outcomes for both offspring and mother (e.g., early fetal loss, prematurity, macrosomia, and preeclampsia), 5 GDM is a strong predictor of diabetes mellitus type II in the woman later in life. 6 Studies in non-pregnant subjects have shown a link between antidepressant medication and risk for type II diabetes (T2DM) (21%-31% increased risk). 7 Multiple biological mechanisms have been proposed for this association, including serotonin dysregulation which controls food intake and weight regulation, 8,9 altered brain-gut relationship via the microbiome, 10 impairment of pancreatic beta cells, 11 or antagonism to the histamine-1 (H 1 ) receptor. 7,12 Because pregnancy per se predisposes to insulin resistance, understanding the metabolic safety of antidepressants in the pregnant women is a clinically relevant question.
Two studies 13,14 identified a moderate risk of GDM (31%-37% increased risk) with antidepressant exposure in early-mid pregnancy, compared to unexposed women who may or may not have a perinatal mental disorder. This comparison raises however concerns of confounding by indication. 15,16 Two additional studies 17,18 could not replicate these findings for the whole antidepressant group when using as comparator women with depression, albeit the GDM risk was elevated after use of venlafaxine, amitriptyline, or sertraline. 17,18 Although studies in non-pregnant subjects have shown that the risk of T2DM increases following the use of antidepressants with greater affinity to the H 1 receptor, 7,12 this research question has not been systematically studied in the context of GDM.
In this study we sought (i) to describe the risk of GDM according to maternal use of antidepressants with different affinity to the H 1 receptor in early-mid pregnancy; and (ii) to quantify the association between GDM and maternal use of antidepressants in early-mid pregnancy, overall and by drug affinity to the H 1 receptor, relative to non-medicated depressive/anxiety disorders.

| Study population and data collection
This study was based on data from the Norwegian Mother, Father and Child Cohort Study (MoBa), linked to records in the Medical Birth Registry of Norway (MBRN). Linkage of data was done using the unique personal identifier number of each citizen of Norway. MoBa is a nationwide, prospective population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health. 19 Pregnant women were recruited from all over Norway in 1999-2008 through a postal invitation in connection with a publicly offered routine ultrasound at 17-18 weeks of gestation. In MoBa, data were gathered prospectively via two prenatal questionnaires at week 17 (Q1) and week 30 (Q3) and multiple postnatal self-administered questionnaires at 6 months postpartum, and then at different child ages up to adolescence. 20 All MoBa questionnaires are available online. 20 The current study is based on version 9 of the quality-assured MoBa data files released for research. The cohort now includes 114 500 children, 95 200 mothers, and 77 300 fathers. 19 The participation rate for all invited pregnancies is 41%. Of those agreeing to participate, the response rate was 92%-95% for Q3 and Q1. 21 The MBRN is based on compulsory notification of all live births, stillbirths, and induced abortions after week 12. 3 The registry comprises maternal medical records during prenatal care, as well as mother and child health at the delivery ward. These include information on maternal chronic diseases (e.g., pre-existing diabetes), child health at birth, pregnancy health and outcomes, and gestational length.
This study included women who had returned both questionnaire Q1 and Q3, since these provide data on medication exposure in pregnancy, before the birth outcome was known ( Figure 1).

| Maternal depression and anxiety as inclusion criteria
In MoBa, Q1 and Q3 women were presented with a list of previous/ concurrent illnesses, including depression (both Q1 and Q3), anxiety (only Q1), and other mental disorders (both Q1 and Q3) (hereafter, clinical depression/anxiety). 20 Women were asked to check off if and when (i.e., before or during early or mid-late pregnancy) these disorders were present. To emulate the design of a target trial using observational data and to reduce risk of indication bias, 15,[22][23][24] this study included pregnancies with an underlying indication for treatment with antidepressants in pregnancy; that is, women who self-reported depression/anxiety specifically during pregnancy, and/or had depression/anxiety in the 6 months prior to pregnancy medicated with a psychotropic (cf. Figure 1).

| Outcome
The main outcome was GDM (yes/no), based on MBRN obstetric records throughout the course of pregnancy. In Norway, GDM screening is recommended for high-risk women at gestational weeks 24-28, 25 via administration of the "Glucose Challenge Test". Maternal use of any medication and psychiatric disorders are not criteria for the targeted screening. The diagnostic criteria for GDM are (i) fasting plasma glucose level ≥7.0 mmoL/L; or (ii) 2 h after glucose challenge test glucose level ≥11.1 mmoL/L. 25 The validity of any diabetes registration in the MBRN has been assessed against filled prescription records for antidiabetic medications, yielding a sensitivity and specificity of 72% and 99%. 26

| Exposure
Information on antidepressant exposure and indication for use was collected from MoBa Q1 (from week 0 to 12) and Q3 (from week 13 to >29). 20 Women reported the name of the medication taken and timing of use in 4-week intervals throughout pregnancy (e.g., week 0-4, 5-8, etc.). Drug classification was based on the Anatomical Therapeutic Chemical (ATC) Classification System. 27 Gestational exposure to each individual antidepressant (fifth level of the ATC system) was defined as exposure to a drug belonging to the ATC group N06A. Individual antidepressants were then assembled into two groups based on their affinity to the H 1 receptor, in alignment with prior research. 7,12,28 Group 1 included antidepressants with lower H 1 receptor affinity (but high serotonin receptor affinity), specifically: selective serotonin reuptake inhibitors (SSRIs, including sertraline, fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine); serotonin noradrenaline reuptake inhibitors (SNRIs, including venlafaxine and duloxetine); and clomipramine. Group 2 included antidepressants with higher H 1 receptor affinity: amitriptyline, trimipramine, maprotiline, nortriptyline, mianserin, mirtazapine, doxepin, and nefazodone. There was no exposure to bupropion, reboxetine, maprotiline in the sample.
Whenever women were taking antidepressants belonging to different groups, we assigned exposure to the group with higher H 1 receptor affinity. For comparison with prior research, we additionally examined exposure to any antidepressant.
Because screening for GDM in pregnant women Norway is done at gestational week 24-28, 25 we defined as primary antidepressant exposure window the period between start of pregnancy and gestation week 24 (hereafter, early-mid pregnancy).

| Data analysis
All statistical analyses were performed by using STATA MP version 15/16. Details about the study power are given in the Supplement.
Our study was underpowered for the antidepressant group 2, for which only descriptive statistics are presented.
To estimate the relative risk (RR) of GDM along with their corresponding 95% CI by antidepressant exposure in early-mid pregnancy, overall and by H 1 receptor affinity (group 1), crude and weighted analyses were conducted. Adjustment for a sufficient set of confounders was done via use of inverse probability of treatment weighting (IPTW), using the propensity score. 35,36 Logistic regression models were first fit to estimate the probability of "antidepressant exposure" in early-mid pregnancy as any and by H 1 receptor affinity (group 1), relative to no exposure in the time window, given the set of sufficient confounders. Modified Poisson regression within the generalized linear model framework with robust standard errors were then fit applying the IPTW. 37 A robust variance estimator was applied to account for women's participation with more than one pregnancy in the MoBa study. Balance of covariates (standardized difference) between the exposure group and comparator was assessed before and after the application of the IPTW, and was considered adequate whenever differences were ≤0.1. 35 Data are presented as crude and weighted RR with 95% CI.
Missing data on individual confounding variables ranged from less than 1% to 10%, leading to 19.3% missing data information in at least one of the sufficient confounders. Under the assumption that data were missing at random, we imputed incomplete data via multiple imputation with chained equation (10 replications). [38][39][40] More detail is provided in the Supporting Information. The distribution of key variables in relation to missingness is given in Table S1.

| Sensitivity analyses
We conducted a number of sensitivity analyses to assess the robustness of the study findings. In the main analysis, the weighted models included additional confounders beyond those considered in the sufficient set (i.e., multiple pregnancy, history of GDM, thyroid disorders, periconceptional use of folate). Because multiple imputation was adopted, a complete case analysis approach was also undertaken.
Because some women had more than one pregnancy included in the cohort, a sensitivity analysis restricted to the first pregnancy recorded was also conducted. To allow a longer lag time between antidepressant exposure and outcome onset, we additionally defined a stricter exposure window, from pregnancy start to week 20. We also examined the influence of some confounders measured in early pregnancy rather than before on our results (see the Supporting Information).

| RESULTS
We included 6647 pregnancies within 6421 women with clinical depression/anxiety in the 6 months prior to and/or during pregnancy. Figure 1 shows the data flow to achieve this final study population.
Use of antidepressants with higher H 1 receptor affinity (group 2) was less common (n = 76, 1.2%), and the mainly used substances were mianserin, mirtazapine, and amitriptyline. Table 1 Figure 2 shows the proportion of GDM with 95% CI by antidepressant exposure in early-mid pregnancy, which ranged from 1.1% in group 1 antidepressant exposed to 3.9% in group 2 antidepressant exposed. As shown in Table 2 Table 2).
T A B L E 1 Sociodemographic, lifestyle and health characteristics of the final pregnancy cohort by antidepressant group exposure during earlymid pregnancy (n = 6647) After weighting, there was balance (standardized mean difference ≤0.1) 35 in the distribution of confounding factors between nonmedicated and antidepressant group 1 or any antidepressant exposed ( Figures S1-S2).

| Sensitivity analyses
Adding multiple pregnancy, history of GDM, thyroid disorders, and periconceptional use of folate in the IPTW estimation did not materially change the main results for group 1 antidepressant. Results of the complete case analyses were generally in line with the main findings on GDM, although the 95% CI were wider due to lower study power.
Results of the sensitivity analyses restricted to the first registered pregnancy were in line with the main findings, and likewise when narrowing the exposure definition within the first 20 weeks of gestation (data not shown). When we included in the IPTW confounding variables measured in early pregnancy, the effect estimates were closer or greater than 1 (see Table S2) and the 95% CI still included the null.

| DISCUSSION
This study adds to the conflicting literature on the effect of antidepressants in pregnancy on risk of GDM and has the unique advantage of being able to account for severity of anxiety and depressive symptoms in early pregnancy. We found no evidence for a substantial association between GDM and maternal use in early-mid pregnancy of antidepressants with low H 1 receptor affinity, which mainly include SSRI and SNRI antidepressants. Our measure of association was 0.69, with an upper bound of the 95% CI equal to 1.51. This finding is clinically relevant, as SSRIs constitute the preferred therapeutic choice in the pregnant population. 41 Although the risk of GDM was elevated following the use of antidepressants with high affinity to the H 1 receptor, this finding is merely descriptive as the low statistical power impeded us to conduct adjusted association analyses.
Prior studies among non-pregnant subjects have linked antidepressant treatment to a modest elevated risk for T2DM, 7 and this association seemed to rise in magnitude as the antidepressant H 1 receptor affinity increased. 7,12,28 Our findings however do not support the notion that antidepressants with low H 1 receptor affinity, that is mainly where antidepressant-exposed women were compared to unexposed having an underlying indication for treatment with antidepressants in pregnancy, limiting the risk of indication bias. 15 Maternal depression in pregnancy has also been found to be associated with gestational diabetes, 16 for instance by triggering oxidative stress, chronic inflammation, and insulin resistance, 42 and thus disentangling the effect of medication exposure from that of the underlying maternal disease is crucial.
The unadjusted risk for GDM in pregnancies exposed to antidepressant with high H 1 receptor affinity was more elevated than in non-medicated or among pregnancies exposed to antidepressants with lower H1 receptor affinity. In the study by Dandjinou et al.,18 venlafaxine and amitriptyline were the sole antidepressants found to be associated with GDM, with amitriptyline posing the largest risk (52% increased risk). This antidepressant has indeed high H 1 receptor affinity and can possibly pose a greater metabolic risk than other antidepressants. 12  provides a reliable measure of the severity of these psychiatric conditions. 33,34 In addition, several sensitivity analyses were conducted to explore the robustness of the findings, and likewise to explore the impact of missing information on important covariates on the effect estimates.
One limitation is that depressive/anxiety disorders before and/or during pregnancy were self-reported in MoBa and thus based on maternal perception of illness and accuracy in reporting. In addition, anxiety was solely measured in MoBa Q1. However, the final study population of women with depression/anxiety was about 6% of the eligible population, which is equal to estimates of major depression with/without anxiety in pregnancy based on structural clinical interviews. 43 The use of antidepressants was also self-reported, and thus based on woman's accuracy in reporting and willingness to disclose information on her treatment. However, the impact of mis- for the targeted GDM screening, we cannot exclude the possibility of bias due to outcome misclassification. However, if present, such misclassification bias is most likely non-differential.
The MoBa study has a low response rate (41% of all women invited), with a possible self-selection of the healthiest women to the study. On the other hand, among those who accepted the invitation, the response rate was high. 21 One prior study by Nilsen et al. 46 has thoroughly examined self-selection and its potential for bias by comparing the MoBa study population with the total Norwegian birthing population, by comparing effect estimates for known associations (e.g., smoking and low birth weight). This study showed that although the prevalence estimates could not necessarily be generalized to all Norwegian women, the measures of association tested were valid in the MoBa study. Moreover, the available sample size limited our ability to detect small effect sizes and to examine individual antidepressants.
To conclude, antidepressants with low H 1 receptor affinity do not substantially increase the risk of GDM. This information may assist clinicians when evaluating the risk of treatment with this group of antidepressants, that is, SSRIs and SNRIs, versus that of non-medicated depressive/anxiety disorders, in particular among women with risk factors for metabolic disorders in pregnancy. The elevated risk of GDM among women exposed to antidepressants with high H 1 receptor affinity needs to be refuted or confirmed by additional studies with greater numbers of exposed cases.

CONFLICT OF INTEREST
The authors declare no conflict of interest

ETHICS STATEMENT
The establishment of MoBa and initial data collection was based on a license from the Norwegian Data protection agency and approval from