Table 1.
Overview of the studies included in the literature review
| Reference | Country; setting (study period) | Sample sizen(groups) | Research aim(s) | Exposure(s) (data source) | Pharmacoepigenetic outcome(s) | |
|---|---|---|---|---|---|---|
|
Epigenome-wide association studies |
Yeung et al. (2020) [30] | USA; the EAGeR (Effects of Aspirin in Gestation and Reproduction) randomized trial (2006–2012) |
n = 358 (acetylsalicylic acid, n = 185; no acetylsalicylic acid, n = 173) |
Investigate the impact of maternal use of low-dose acetylsalicylic acid prior to and during pregnancy on cord blood DNAm | Acetylsalicylic acid (randomly assigned prior to conception; 81 mg/d until gestational week 36 [49]) | • Differential DNAm at 1 CpG associated with prenatal acetylsalicylic acid exposure (cg2002882; 3,500 bp upstream of the POU4F1 promoter) |
| Addo et al. (2019) [48,100] | USA; Extremely Low Gestational Age Newborns (2002–2004) |
n = 281 (paracetamol, n = 165; no paracetamol, n = 116) |
Examine DNAm of CpGs in placentae of paracetamol-exposed and non-exposed neonates | Paracetamol (≥ 1 during pregnancy; self-reported Tylenol use) | • Differential DNAm at 24 CpGs associated with prenatal paracetamol exposure | |
| Cardenas et al. (2019) [29] | USA; Project Viva (1999–2002) The Netherlands; Generation R Study (2002–2006) |
nProV = 479 (antidepressanta, n = 14; depression, n = 33; anxiety, n = 40) nGenR = 999 (antidepressant, n = 14; depression, n = 31; anxiety, n = 56) |
Identify DNAm differences in neonates associated with exposure to maternal anxiety, depression, or antidepressant use in pregnancy |
Antidepressants (≥ 1 prescription in pregnancy; medical record in Project Viva, self-reported and prescription-validated in Generation R) Maternal depression (EPDS at mid-pregnancy in Project Viva; BSI at 20 weeks in Generation R) Maternal anxiety (PRAS at mid-pregnancy in Project Viva; BSI at 20 weeks in Generation R) |
• Differential DNAm at 130 CpGs in Project Viva in neonates prenatally exposed to antidepressants compared to non-exposed neonates, 5 confirmed in Generation R (1 under Bonferroni significance; reduced DNAm on cg22159528 ZNF575 of exposed children) • No DMRs associated with prenatal antidepressant exposure |
|
| Gervin et al. (2017) [35] | Norway; the Norwegian Mother, Father and Child Cohort Study (1999–2008) |
n = 384 (no paracetamol & no ADHD, n = 96; paracetamol & no ADHD, n = 96; no paracetamol & ADHD, n = 96; short-term paracetamol & ADHD, n = 77; long-term paracetamol & ADHD, n = 19) |
Investigate if differential DNAm is associated with prenatal paracetamol exposure and ADHD development |
Paracetamol (long-term [≥ 20 d] and short-term [6–19 d] exposure; self-reported in questionnaires during pregnancy) ADHD (diagnosis in the Norwegian Patient Registry) |
• In children with ADHD, prenatal long-term exposure to paracetamol was associated with differential DNAm compared to children without ADHD not exposed to paracetamol (6211 CpGs), children with ADHD and not exposed to paracetamol (193 CpGs), and short-term paracetamol-exposed children with ADHD (2089 CpGs) | |
| Emes et al. (2013) [46] | UK; EFFECT-M study |
n = 18 (epilepsy & AEDsb, n = 9; no epilepsy & no AEDs, n = 9) |
Examine association between prenatal AED exposure and DNAm, and if AEDs affect the foetal DNAm by lowering the maternal folate level | AEDs (self-reported and validated by medical record) | • DNAm difference in 662 CpGs (652 different genes) in AED-exposed compared to non-exposed neonates • No difference in global DNAm levels between AED-exposed and non-exposed children |
|
| Smith et al. (2012) [47] | USA; the Emory Women’s Mental Health Program |
n = 201 (AEDsc & epilepsy/psychiatric disorderd, n = 53; no AEDs or epilepsy/psychiatric disorder, n = 148) |
Examine the impact of prenatal AED exposure on DNAm patterns in neonates |
AEDs (self-reported every 4–6 weeks in pregnancy and validated by concentrations of AEDs in maternal blood) Psychiatric disorder and/or epilepsy (questionnaire on medical and psychiatric history and SCID at intake, SCID and seizure history at 4–6-week intervals) |
• Prenatal AED exposure associated with decreased global DNAm in cord blood, not in placenta • Longer prenatal AED exposure associated with decreased DNAm in 14 cord blood CpGs • In placental tissue, 3 of the 14 cord blood CpGs also exhibited decreased DNAm (PGC, ZNF384, and C15orf2) • DNAm patterns neither specific to AED type nor more extreme differences for polydrug treatment |
|
| Schroeder et al. (2012) [43] | USA; the Emory Women’s Mental Health Program |
n = 201 (Several different comparisons†: • Current MDD, n = 118; no current MDD, n = 83 • Antidepressantse, n = 151; no antidepressants, n = 50) |
Investigate the association of maternal psychiatric disorder, symptoms and severity of depression, and medication treatment in pregnancy with neonatal DNAm patterns |
Psychotropics (medication evaluation upon visits every 4–6 weeks during pregnancy) Maternal mood disorder diagnosis (life-time history and MDEs; SCID every 4–6 weeks during pregnancy, SCID Mood Module assessed MDEs) Depressive symptoms (depression severity and clinically significant depressive symptoms; HRSD17 and BDI) |
• Prenatal antidepressant exposure associated with DNAm in 2 CpGs (1.9% decrease in TNFRSF21 and 3% increase in CHRNA4), independent of antidepressant type and duration • No association between prenatal hypnotic, antiemetic, benzodiazepine, or atypical antipsychotic exposure and differential DNAm, independent of duration of exposure • Prenatal exposure to atypical antipsychotics associated with DNAm at 1 CpG |
|
| Combined epigenome-wide and candidate gene studies | Gurnot et al. (2015) [31] | Canada; University of British Columbia |
nepigenome-wide = 23 (depressed & SRIsf, n = 11; depressed & no SRIs, n = 12) ncandidate gene = 44 (depressed & SRIsg, n = 19; depressed & no SRIs, n = 25) |
Examine if prenatal SRI exposure and/or maternal mood is associated with DNAm across the genome and in CYP2E1; investigate if DNAm is also associated with birth outcomes |
SRIs (cord blood/maternal blood drug ratios at birth; maternal whole blood and neonatal cord blood concentrations of SRIs, drawn directly after birth) Maternal mood (HAM-D at 26 and 36 weeks of pregnancy, mean score) |
• Prenatal SRI exposure associated with DNAm in 3 CpGs (CYP2E1, EVA1, and SLMAP; EWAS) • In CYP2E1, DNAm highly negatively correlated with prenatal maternal depressive mood only if prenatally exposed to SRIs concurrently • Pyrosequencing of CYP2E1 yielded DNAm values that correlated with the microarray findings |
| Non et al. (2014) [32] | USA; Harvard Epigenetic Birth Cohort (2007–2009) |
n = 58 (SSRIsh, n = 22; depression/anxiety & no SSRIs, n = 13; no depression/anxiety or SSRIs, n = 23) |
Examine differences in DNAm patterns across the genome in neonates prenatally exposed or non-exposed to SSRIs and/or maternal depression/anxiety |
SSRIs (medical charts) Maternal depression/anxiety (explicitly noted by obstetrician in labour and delivery forms) |
• No association between prenatal SSRI exposure and differential DNAm (EWAS) • No regional clusters of CpGs (1 kb) associated with prenatal SSRI exposure (EWAS) • Pyrosequencing: 6 CpGs in Col7a1 exhibited lower DNAm at all 6 CpGs and a lower mean DNAm in neonates prenatally exposed to SSRIs • Pyrosequencing: prenatal SSRI exposure associated with 1 CpG in NFKB2, 1 CpG in SLC6A4, 1 CpG in FKBP5, and 1 CpG in DNMT3a |
|
| Candidate gene studies | Galbally et al. (2020) [37] | Australia; Mercy Pregnancy and Emotional Wellbeing Study (2012–2015) |
n = 236 (antidepressants, n = 43; non-medicated & depression/dysthymia, n = 24; non-medicated & no depression/dysthymia, n = 169) |
Investigate associations between maternal depression during pregnancy and the DNAm of placental and buccal NR3C1 and NR3C2, which may mediate an indirect effect of maternal depression on 12-month infant cortisol reactivity |
Antidepressants (self-reported and hospital records, validated by concentration in cord and maternal whole blood, converted to SEDs) Maternal mental health (SCID at ≤ 20 weeks, EPDS/STAI in week 20, 3rd trimester, and 6 and 12 months after birth) Maternal stress (PRAMS at week 20 and in 3rd trimester) |
• 1 differentially methylated CpG in placental NR3C2 when comparing medicated and non-medicated depression • No differential methylation of NR3C1 or NR3C2 in buccal cells |
| Galbally et al. (2018) [51] | Australia; Mercy Pregnancy and Emotional Wellbeing Study (2012–2015) |
n = 239 (untreated current MDD, n = 24; antidepressant-treated current MDD, n = 28; antidepressant-treated not meeting MDD diagnostic criteria, n = 15; no current or past MDD, n = 172) |
Explore DNAm of OXTR in the placentae of women depressed during pregnancy and in women using antidepressant(s) during pregnancy |
Antidepressants (self-reported at recruitment and in 3rd trimester, hospital records in 3rd trimester [converted to SEDs], and measurement of whole blood and cord blood concentrations at birth) Maternal depression (SCID at recruitment and EPDS in 3rd trimester) |
• Decreased DNAm in OXTR CpG 8 upon foetal exposure to antidepressants (self-reported) • Increased DNAm of OXTR CpG 8 upon higher cord blood concentrations of antidepressants |
|
| McLaughlin et al. (2017) [34] | UK; Princess Royal Maternity Hospital |
n = 53 (methadone-maintained opioid-dependent mothers, n = 21; smoking, “deprived” & opioid-naive mothers, n = 17; non-smoking, “affluent” & opioid-naive mothers, n = 15) |
Explore if prenatal opioid exposure is associated with a differential DNAm in opioid-related genes (ABCB1, CYP2D6, and OPRM1) |
Methadone (venous blood concentration 24–72 hours after birth to methadone-maintained opioid-dependent mothers) Smoking (case records) Poverty (DepCat score calculated from postal codes provided in case records) |
• Increased DNAm in ABCB1, CYP2D6, and OPRM1 in neonates of methadone-maintained opioid-dependent mothers compared to neonates of opioid-naive mothers | |
| Mansell et al. (2016) [45] | Australia; The Barwon Infant Study (2010–2013) |
n = 481 (Various group comparisons: • Depressive symptoms, n = 88; • No depressive symptoms, n = 357 • Anxiety, n = 77; no anxiety, n = 368 • Stress scores, n = 481) |
Investigate the association between maternal mental well-being and the DNAm of cord blood NR3C1 |
Antidepressants (self-reported at 28 weeks) Depression (EPDS ≥ 10 at 28 weeks) Anxiety (EPDS anxiety subscale ≥ 5 at 28 weeks) Stress (PSS score week 28) |
• Increased DNAm of NR3C1 CpG 35 associated with prenatal antidepressant exposure, but the association diminished when included as a covariate in the multivariate model of maternal pregnancy well-being and neonatal DNAm of NR3C1 |
|
| Gartstein et al. (2016) [38] | Canada; University of British Columbia |
n = 115 (SSRI exposure, n = 46; no SSRI exposure, n = 69) |
Examine the association between prenatal SSRI exposure and neonatal SLC6A4 DNAm, and the influence on soothability |
SSRIs (self-reported prescription retrieval and number of days used) Maternal internalizing symptoms (sum of EPDS, HAM-D, and HAM-A scores in 33–36 weeks of pregnancy) |
• Prenatal SSRI exposure positively associated with neonate SLC6A4 CpG DNAm of CpGs 3, 5, 7, and 9 and mean DNAm status of CpGs 9 and 10 | |
| Ciesielski et al. (2015) [33] | USA; Women and Infants Hospital in Providence Rhode Island (2008–2010) |
n = 184 (psychiatric diagnosisi & antidepressantsj, n = 12; psychiatric diagnosis & no antidepressants, n = 13; no psychiatric diagnosis & no antidepressants, n = 159) |
Investigate how DNAm in placentae is related to growth restriction observed in mothers with psychiatric illnesses (some of which are treated with antidepressants) |
Antidepressants (medical records) Maternal psychiatric disease (depression, anxiety, and/or OCD/panic disorder prior to and/or during pregnancy; medical records) |
• No difference in likelihood of unequal median DNAm between the antidepressant-exposed group, and the group with no psychiatric diagnosis and no antidepressants | |
| Soubry et al. (2011) [52] | USA; the Newborn Epigenetics Study (2005–2008) |
nIGF2 = 356 (antidepressantsk, n = 35; depressed, n = 56; non-medicated non-depressed, n = 265) nH19 = 411 (antidepressants, n = 43; depressed, n = 65; non-medicated, non-depressed, n = 303) |
Examine the association between prenatal antidepressant and/or maternal depression exposure and DNAm of two DMRs in IGF2 (H19) |
Antidepressants (any use; medical charts) Depression during pregnancy (self-reported and interviewer-based questionnaires, diagnosis validated by clinical charts) |
• Prenatal antidepressant exposure not associated with DNAm in neonatal IGF2 or H19 DMRs • Higher DNAm in H19 DMR associated with prenatal antidepressant exposure in African-Americans but not in Caucasians |
|
| Devlin et al. (2010) [44] | Canada; cohort part of a study on how psychotropic medication exposure impact neonatal health |
n = 82 (SRIs, n = 33; no SRIs, n = 49) |
Examine the impact of maternal MTHFR C677T genotype on maternal mood, and the association with DNAm in maternal and neonatal SLC6A4 and BDNF |
SRIs (data source not stated) Depressed mood (EPDS and HAM-D in the 2nd [week 26] and 3rd [week 33] trimesters) |
• SRI exposure not associated with neonatal DNAm levels in SLC6A4 or BDNF | |
| Oberlander et al. (2008) [36] | Canada; cohort part of a study on how psychotropic medication exposure impact neonatal health |
n = 82 l (depression & SRIsm, n = 36; depression & no SRIs, n = 13; no depression & no SRIs, n = 33) |
Investigate any association between maternal depressed or anxious mood during pregnancy and DNAm of NR3C1 in neonates; examine the association between NR3C1 DNAm and stress reactivity at 3 months |
SSRIs (data source not stated) Maternal mood (EPDS, HAM-A and HAM-D in week 26 and 33; EPDS, HAM-A, HAM-D, PSI-SF 3 months after birth) |
• Prenatal SRI exposure not associated with neonatal NR3C1 DNAm status • Global neonatal DNAm did not differ between SRI exposed and non-exposed infants |
†Complete list of comparisons is available in Supplementary Table S4.
a1 amitriptyline; 1 bupropion; 2 citalopram hydrobromide; 2 desipramine; 3 fluoxetine; 2 paroxetine; 5 sertraline (12/14 women used SSRIs only).
b4 carbamazepine; 3 lamotrigine; 2 polytherapy (1 carbamazepine/valproic acid; 1 lamotrigine/valproate).
c36 lamotrigine; 3 valproate; 3 levetiracetam; 2 carbamazepine; 1 topiramate; 1 phenytoin; 1 gabapentin; 6 polytherapy (not specified).
d26 epilepsy; 27 psychiatric disorder (20 bipolar disorder; 5 MDD; 2 anxiety).
eDefine two classes: class 1 of SRIs (SSRIs; SNRIs; TCAs), and class 2 of bupropion.
f2 paroxetine; 2 fluoxetine; 2 sertraline; 1 citalopram; 4 venlafaxine.
g2 paroxetine; 3 fluoxetine; 2 sertraline; 2 citalopram; 10 venlafaxine.
h11 sertraline; 6 fluoxetine; 4 citalopram; 2 paroxetine.
iDepression, anxiety, obsessive-compulsive disorder, or panic disorder.
j18 SSRIs (13 sertraline); 5 atypical antidepressants.
kSSRIs (72%); SNRIs; TCAs; SARIs; bupropion.
lNumbers not fixed; some mothers in untreated, non-depressed group became depressed during the study, whereas others started receiving pharmacological treatment.
m18 paroxetine; 6 fluoxetine; 5 sertraline; 2 venlafaxine; 5 citalopram.
ADHD: attention-deficit/hyperactivity disorder; AED: antiepileptic drug; BDI: Beck Depressive Inventory; BSI: Brief Symptom Inventory; DepCat: measure of socioeconomic status in Scotland (affluent–deprived); DMR: differentially methylated region; DNAm: DNA methylation; EPDS: Edinburgh Postnatal Depression Scale; GO: Gene Ontology; HAM-A: Hamilton Rating Scale for Anxiety; HAM-D: Hamilton Rating Scale for Depression; HRSD17: 17-item Hamilton Rating Scale for Depression; IBQ: Infant Behaviour Questionnaire; MDD: major depressive disorder; MDE: major depressive episode; OCD: obsessive-compulsive disorder; PRAS: Pregnancy-related Anxiety Scale; PSI-SF: Parenting Stress Index – Short Form; PSS: Perceived Stress Scale; SARI: serotonin antagonist and reuptake inhibitor; SCID: Structured Clinical Interview for DSM-IV; SED: sertraline-equivalent dosage; SNRI: serotonin and noradrenaline reuptake inhibitor; (S)SRI: (selective) serotonin reuptake inhibitor; STAI: State-trait Anxiety Inventory; TCA: tricyclic antidepressant.