Table 1.
Overview of the reviewed studies.
| Reference | Country; setting (study period) | Study design | Sample size | Drugs of exposure | Exposure measures | Phenotypic outcomes | Outcome measures | |
|---|---|---|---|---|---|---|---|---|
| Antidepressants | Corti et al. (2019) | Italy (2011–2016) | Case × control | SRIs and maternal depression/anxiety, n = 32/30: Normal neonatal genotype, n = 10 Altered neonatal genotype, n = 22 Normal maternal genotype, n = 12 Altered maternal genotype, n = 1 |
Paroxetine, venlafaxine, sertraline, or citalopram | Medical records and follow-up of drug compliance during pregnancy in monthly obstetric and psychiatric visits | Preterm birth, neonatal complicationsa, and umbilical artery pH and base excess | Medical records and follow-up by multidisciplinary team at the hospital |
| Ackerman et al. (2017) | USA; sample from the Simons Simplex Collection | Cohort | Antidepressants and LGD mutations n = 9 Antidepressants and no LGD mutations n = 95 No antidepressants and LGD mutations n = 335 No antidepressants and no LGD mutations, n = 2,011 (All participants had ASD) |
Amitriptyline, bupropion, citalopram, escitalopram, fluoxetine, imipramine, paroxetine, sertraline, or venlafaxine | Parent interview; use of antidepressants in ≥1 trimesters | ASD severity | Clinician-measured (ADOS) or parent-reported (ADI-R) ASD severity | |
| Daud et al. (2017) | The Netherlands; the EUROCAT Northern Netherlands database (1997–2013) | Cohort | SRIs and congenital heart anomaly, n = 7 mothers/children No SRIs and congenital heart anomaly, n = 28 mothers/children |
Fluoxetine, paroxetine, or venlafaxine | Medical records verified by telephone interviews | Congenital heart anomalies | Diagnoses of congenital heart anomaliesb before 10 years of age based on ICD-9/10 registered in the EUROCAT Northern Netherlands database | |
| Nembhard et al. (2017) | USA; the US National Birth Defects Prevention Study (NBDPS; 1997–2008) | Case × control | SSRIs and congenital heart anomaly, n = 57 mothers/children SSRIs and no congenital heart anomaly, n = 54 mothers/children No SSRIs and congenital heart anomaly, n = 1,119 mothers/children No SSRIs and no congenital heart anomaly, n = 1,590 mothers/children |
Sertraline, fluoxetine, paroxetine, citalopram, or escitalopram | Maternal interview of consecutive drug use for at least 2 months between 2 months before conception and 3 months after conception | Congenital heart anomalies | Diagnoses of congenital heart anomalies based on the classification system specifically developed for the National Birth Defects Prevention Study, incorporating cardiac phenotype, complexity of the phenotype, and extra-cardiac anomalies | |
| Weikum et al. (2013) | Canada; part of a study on the effects of antenatal SSRI exposure | Cohort | SRIs and maternal mood disorder, n = 26 children No SRIs and maternal mood symptoms, n = 38 children |
Paroxetine, fluoxetine, sertraline, venlafaxine, or citalopram | Physician- or self-reported | Child mood, behavior, and executive functions | Child mood and behavior assessed with the mental health symptomatology section of the MacArthur Health and Behavior Questionnaire. Executive functions assessed by the Hearts and Flowers task | |
| Brummelte et al. (2013) | Canada (2006–2009) | Cohort | SRIs, n = 17 mothers/children No SRIs, n = 28/26 mothers/children |
Paroxetine, fluoxetine, sertraline, venlafaxine, citalopram, or escitalopram | Medical records on medication, dose, and indication | Levels of reelin in cord blood and maternal blood | Western blot analysis of protein levels in maternal and umbilical cord serum | |
| Oberlander et al. (2010) | Canada; part of a study on the effects of antenatal SSRI exposure | Cohort | SRIs and maternal mood disorder, n = 33 children No SRIs and maternal mood symptoms, n = 42 children |
Paroxetine, fluoxetine, sertraline, venlafaxine, or citalopram | Physician- or self-reported | Child behavior | Child behavior was evaluated with the Child Behavior Checklist at 3 years of age | |
| Hilli et al. (2009) | Finland; part of a controlled prospective study by Laine et al., 2003 (1997–2000) | Cohort | SSRIs, n = 20 children | Citalopram or fluoxetine | Medical records on the medication, dose, and indication | Perinatal serotonergic symptoms and neurotransmitter blood concentrations | Assessment of serotonergic symptoms by pediatricians (Sternbach, 1991). Neurotransmitter concentrations measured from whole blood and umbilical vein blood samples | |
| Oberlander et al. (2008) | Canada; part of a study on the effects of antenatal SSRI exposure | Cohort | SRIs, n = 37 mothers/children No SRIs, n = 47 mothers/children |
Paroxetine, fluoxetine, sertraline, venlafaxine, or citalopram | Medical records on medication and indication | Preterm birth and adverse neonatal outcomes (e.g., birth weight, Apgar score, muscle tone, respiratory distress, and jitteriness) | Medical records and follow-up at the hospital | |
| Antiepileptic drugs | Jose et al. (2014) | India; part of the Kerala Registry of Epilepsy and Pregnancy (KREP) | Case × control | AEDs, maternal epilepsy and children with congenital anomalies, n = 143 mothers AEDs, maternal epilepsy and children without congenital anomalies, n = 123 mothers |
Carbamazepine, valproic acid, phenytoin, clonazepam, or phenobarbital | Medical records of the registry | Congenital anomalies (main focus on cardio-vascular anomalies) | Clinical examination of malformations at birth. Echocardiography and abdomen ultrasonography at 3 months of age |
| Azzato et al. (2010) | USA; part of the Collaborative Perinatal Project (CPP) database (1959–1966) | Cohort | AEDs, n = 155/174 (mothers/children) | Phenytoin | Questionnaire data and maternal medical records | Craniofacial anomalies | Craniofacial anomalies considered if microcephaly, abnormal sutures, midfacial hypoplasia, cleft lip, palate or gum, or deformed/low-set ears were noted in medical records. A standardized evaluation form assessing the presence of anomalies was subsequently completed by physicians | |
| Dean et al. (2007) | Scotland (1976–2002) | Case × control | AEDs, n = 276/172/86 (children/mothers/fathers) No AEDs, n = 646 healthy blood donors |
Valproic acid, phenobarbitone, carbamazepine, phenytoin, lamotrigine, or polytherapy | Medical records and maternal interviews on AED use | Fetal anticonvulsant syndrome, major malformations, and neurodevelopmental disorders | Facial photographs reviewed by a physician for fetal anticonvulsant syndrome (diagnosed if ≥1 major and ≥1 minor feature appeared in the child, or if (s)he had ≥3 minor features). Children without fetal anticonvulsant syndrome were included in analyses of major malformations and neurodevelopmental disorders | |
| Kini et al. (2007) | United Kingdom (2000–2004) | Cohort | AEDs and epilepsy, n = 153 mothers/children No AEDs and no epilepsy, n = 236 mothers/children |
Valproic acid, carbamazepine, another monotherapy, or polytherapy | Medical records on AED use and dose | Major malformations | Major malformations defined as structural abnormalities requiring medical or surgical intervention to prevent disability using the EUROCAT list of congenital malformations as a guideline | |
| Dean et al. (1999) | Scotland | Case × control | AEDs, n = 46/36/19 (children/mothers/fathers) No AEDs, n = 152 adults matched to the parents |
Valproic acid, carbamazepine, and phenytoin | The Fetal Anticonvulsant Syndrome Association registry | Fetal anticonvulsant syndrome | Fetal anticonvulsant syndrome in the presence of a characteristic facial appearance and at least one compatible clinical finding (anticonvulsant-associated malformation, medical disorder, or developmental delay), and no other identifiable etiology | |
| Glucocorticoids | Van Der Voorn et al. (2015) | The Netherlands; part of the Project On Preterm and Small for gestational age infants (POPS) cohort (1983) | Cohort | Betamethasone, n = 71 children No betamethasone, n = 273 children |
Betamethasone | Medical records | Behavior and intelligence | Behavior assessed by the YASR (self-reported) and YABCL (parent-reported) questionnaires. Intellectual functioning examined with the Multicultural Capacity Test-Intermediate Level (Bleichrodt and van den Berg, 2000) |
| Haas et al. (2013) | USA; part of the betamethasone (BMZ) pharmacogenetics cohort | Cohort | Betamethasone, n = 109/117 (mothers/children) | Betamethasone | Medical records | Adverse neonatal respiratory outcomes | Neonates with respiratory difficulties included • Neonates needing respiratory support or surfactants (data extracted from neonatal charts) • Neonates diagnosed with bronchopulmonary dysplasia by pediatricians (standard criteria from the Neonatal Research Network of the National Institute of Child Health and Human Development) |
|
| Oretti et al. (2009) | Italy (2005–2006) | Cohort | Betamethasone, n = 62 preterm neonates | Betamethasone | Medical records | Respiratory distress syndrome | Diagnosis of respiratory distress syndrome based on clinical and radiographic criteria (tachypnea, chest retractions, cyanosis in room air persisting 48–96 h and typical chest X-ray) | |
| Bertalan et al. (2008) | Hungary; part of a neonate cohort at Semmelweis University | Cohort | Dexamethasone, n = 57 preterm neonates; No dexamethasone, n = 68 preterm neonates |
Dexamethasone | Medical records | Birth weight and perinatal complicationsc | Medical charts and diagnoses based on clinical and radiographic observations and testsd | |
| Thalidomide | Kowalski et al. (2020) | Brazil | Case × control | Thalidomide, n = 27 affected individuals (non-Finnish European population of ExAC, 1,000 Genomes, and ABraOM databases were used as a control group for genetic comparisons)e | Thalidomide | Medication use defined based on neonatal phenotype | Thalidomide embryopathy and their specific phenotypes | The authors characterized congenital anomalies related to thalidomide exposure according to a guideline they created. Congenital anomalies were consistent with typical thalidomide embryopathy |
| Gomes et al. (2019) | Brazil | Case × control | Thalidomide, n = 36 affected individuals; Assumption of no thalidomide by absence of congenital anomalies and thalidomide embryopathy, n = 135 individuals |
Thalidomide | Medication use defined based on neonatal phenotype | Thalidomide embryopathy and embryopathy-specific phenotypes | The authors characterized congenital anomalies related to thalidomide exposure according to a guideline they created. Congenital anomalies were consistent with typical thalidomide embryopathy | |
| Gomes et al. (2018) | Brazil | Case × control | Thalidomide, n = 35 affected individuals (non-Finnish European population of gnomAD database was used as a control groupf | Thalidomide | Medication use defined based on neonatal phenotype | Thalidomide embryopathy and embryopathy-specific phenotypes | The authors characterized congenital anomalies related to thalidomide exposure according to a guideline they created. Congenital anomalies were consistent with typical thalidomide embryopathy | |
| Kowalski et al. (2017) | Brazil | Case × control | Thalidomide, n = 36 affected individuals Assumption of no thalidomide by absence of congenital anomalies and thalidomide embryopathy, n = 136 individuals |
Thalidomide | Medication use defined based on neonatal phenotype | Thalidomide embryopathy and embryopathy-specific phenotypes | The authors characterized congenital anomalies related to thalidomide exposure according to a guideline they created. Congenital anomalies were consistent with typical thalidomide embryopathy | |
| Kowalski et al. (2016) | Brazil | Case × control | Thalidomide, n = 38 affected individuals Assumption of no thalidomide by absence of congenital anomalies and thalidomide embryopathy, n = 137 individuals |
Thalidomide | Medication use defined based on neonatal phenotype | Thalidomide embryopathy and embryopathy-specific phenotypes | The authors characterized congenital anomalies related to thalidomide exposure according to a guideline they created. Congenital anomalies were consistent with typical thalidomide embryopathy | |
| Vianna et al. (2016) | Brazil | Case × control | Thalidomide, n = 38 affected individuals Assumption of no thalidomide by absence of congenital anomalies and thalidomide embryopathy, n = 136 individuals |
Thalidomide | Medication use defined based on neonatal phenotype | Thalidomide embryopathy and embryopathy-specific phenotypes | The authors characterized congenital anomalies related to thalidomide exposure according to a guideline they created. Congenital anomalies were consistent with typical thalidomide embryopathy | |
| Vianna et al. (2013) | Brazil | Case × control | Thalidomide, n = 28/27 (affected individuals/their relatives) Assumption of no thalidomide by absence of congenital anomalies and thalidomide embryopathy, n = 137 individuals |
Thalidomide | Medication use defined based on neonatal phenotype | Thalidomide embryopathy and embryopathy-specific phenotypes | The authors characterized congenital anomalies related to thalidomide exposure according to a guideline they created. Congenital anomalies were consistent with typical thalidomide embryopathy | |
| Other medications | Bustos et al. (2017) | USA; part of a trial on omega-3 use and spontaneous preterm births | Cohort | 17-alpha hydroxyprogesterone caproate, n = 268 mothers | 17-alpha hydroxy-progesterone caproate | Medical records | 17-alpha hydroxy-progesterone caproate plasma concentrations and spontaneous preterm births | 17-alpha hydroxyprogesterone caproate plasma concentrations determined by high-performance liquid chromatography-mass spectrometry (limit of detection: 1 ng/mL). Preterm birth based on the gestational age at delivery |
| Van Der Zanden et al. (2012) | The Netherlands; subset of the AGORA biobank at Radboud University Nijmegen Medical Center (1980–2008) | Cohort | Estrogens and hypospadias, n = 29 children No estrogens and hypospadias, n = 580 children |
Estrogens | Questionnaires | Hypospadias | Medical records (no information on criteria for diagnosing syndromic hypospadias) | |
| Perzanowski et al. (2010) | USA (1998–2006) | Cohort | Acetaminophen, n = 103 mothers/children No acetaminophen, n = 198 mothers/children |
Acetaminophen | Questionnaires | Wheeze at 1–3 and 5 years, and seroatopy | Wheeze at 1, 2, or 3 years if ≥1 episode was reported in ≥1 interview during these years. Wheeze at 5 years if an episode was reported in the previous 12 months according to the ISAAC questionnaire. Seroatopy if IgE antibodies in serum ≥0.35 IU/mL against D. farinae, mouse, cockroach, cat, or dog | |
| Shaheen et al. (2010) | Unite Kingdom; Avon Longitudinal Study of Parents and Children (ALSPAC; 1991–1992) | Cohort | Acetaminophen in early pregnancy (< 18–20 weeks), n = 4,952 mothers/children Acetaminophen in late pregnancy (20–32 weeks), n = 4,822 mothers/children |
Acetaminophen | Questionnaires | Wheezing, asthma, eczema, hay fever, atopy, and lung function at 6.5–8.5 years | Children were defined as having wheezing, eczema, and hay fever if mothers responded positively to the question in the interview; asthma was considered based on diagnosis; atopy was defined as a positive reaction to D. pteronyssinus, cat, or grass; lung function was measured by spirometry |
a
Low birth weight (<2,500 g), small for gestational age, APGAR scores (1 and 5 min) < 7, neonatal breathing problems, neurological symptoms, respiratory distress syndrome, need of access to neonatal intensive care unit, persistent pulmonary hypertension of the neonate, poor neonatal adaptation syndrome; neonatal abstinence syndrome and transient tachypnea of the neonate.
b
Single heart anomalies, part of complex heart anomalies (including cardiovascular anomalies) or part of complex anomalies involving other organ systems. Diagnosis codes from ICD-9 included 745–746, 7,470–7,474 (excluding 74,550, persistent foramen ovale), and from ICD-10 included Q20–Q26 (excluding Q2111, persistent foramen ovale). These encompass common arterial truncus, transposition of great vessels, single ventricle, ventricular/atrial/atrioventricular septal defects, tetralogy of Fallot, tricuspid atresia and stenosis, Ebstein's anomaly, pulmonary valve stenosis, pulmonary valve atresia, aortic valve atresia/stenosis, hypoplastic left/right heart syndrome, coarctation of aorta, total anomalous pulmonary venous return and patent ductus arteriosus.
c
Perinatal complications included: necrotizing enterocolitis, intraventricular hemorrhage, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis.
d
The disorders were diagnosed as follows: necrotizing enterocolitis: clinical and radiological symptoms; intraventricular hemorrhage: neurosonograms; patent ductus arteriosus: echocardiography and clinical signs 5 days after birth; respiratory distress syndrome: need for respiratory support and oxygen upon presence of radiographic chest findings; bronchopulmonary dysplasia: oxygen dependency from 32 weeks of gestational age onwards; sepsis: clinical evidence and/or positive blood/cerebrospinal fluid cultures.
e
ExAC database, ExAC data is now available in the gnomAD browser; 1,000 Genomes, around 3,000 genomes from individuals of different populations; ABraOM database, 609 exomes from Brazilian individualscultures.
f
gnomAD database, 125,748 exomes and 15,708 whole genomes from individuals of different populations. ADI-R, Autism Diagnostic Interview-revised; ADOS, autism diagnostic observation schedule; AED, anti-epileptic drug; ASD, autism spectrum disorder; ICD-9/10, International Statistical Classification of Diseases and Related Health Problems 9th/10th Revision; LGD, likely gene-disrupting; SSRI, selective serotonin reuptake inhibitor; SRI, serotonin reuptake inhibitor; YABCL, Young Adult Behavior Checklist; YASR, Young Adult Self Report; TE, thalidomide embryopathy; ISAAC, International Study of Asthma and Allergies in Childhood.