Table 1.
Overview of cohort studies included in the systematic review
| Study | Country | Data source and sample size | Exposure | Co-medicine in different exposure groups | Adjusted for confounders | Outcomes | Main conclusion | NOS | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Drugs(N) | Measurement | Time window | Exposure during pregnancy | Exposure before/after pregnancy | Non-exposure | Measured | Unmeasured | ||||||
| Haervig et al, 2014[49] | Denmark | Administrative Database/Registry; 1,054,494 | MPH:393 (0.04%) Modafinil: 45(0.004%) ATX:42 (0.004%) |
Redeemed prescriptions recorded in the National Prescription Registry | 28 days before the first day of LMP to end of pregnancy | Anxiety medicine: 27 (5.5%) SSRI:104 (21.7%) |
NA | Anxiety medicine: 7,591 (0.7%) SSRI: 21,129 (2.0%) |
Age, region, ethnicity | Compared exposed pregnancies to unexposed pregnancies of the same woman to account for unchanged factors between pregnancies: gene, early-life exposure | Abortion Miscarriage Stillbirth Congenital malformations |
ADHD medication in pregnancy was associated with different indicators of maternal disadvantage and with increased risk of induced abortion and miscarriage | 8 |
| Pottegard et al, 2014[52] | Denmark | Administrative Database/Registry; 2,442 | MPH: 222 (9.09%) | Redeemed prescriptions recorded in the National Prescription Registry | 14 days before the beginning of the first trimester up to the end of the first trimester | Antipsychotics: 20 (9.0%) Antidepressants: 76 (34.2%) Anxiolytics: 6 (2.7%) NSAIDs:14 (6.3%) |
NA | Antipsychotics: 139 (6.3%) Antidepressants: 768 (34.6%) Anxiolytics: 58 (2.6%) NSAIDs: 139 (6.3%) |
Maternal age, smoking status, body mass index, length of education, calendar year of completion of pregnancy, concomitant use of antipsychotics, antidepressants, anxiolytics, and NSAIDs | NA | Major malformations Cardiac malformations |
First-trimester MPH exposure does not appear to be associated with a substantial increased risk of major congenital malformations | 7 |
| Bro et al, 2015[46] | Denmark | Administrative Database/Registry; 989,932 | MPH/ATX:186 (0.02%) | Redeemed prescriptions recorded in the National Prescription Registry | For spontaneous abortion, the exposure window spanned from 30 days before the estimated day
of conception until the day prior to abortion or gestational age. For live births and stillbirths, the exposure window spanned from 30 days before the estimated day of conception until the day prior to birth. |
Anti psychotics: 17 (9.1%) Antidepressants: 57 (30.6%) Antiepileptics: 7 (3.8%) |
NA | Anti psychotics: 25 (9.1%) Antidepressants: 35 (12.7%) Antiepileptics: 10 (3.6%) |
Maternal age, smoking, parity, education, cohabitation, comorbidity and comedication | Compared to women diagnosed with ADHD who did not take MPH/ATX | Spontaneous abortion Birth weight Gestational age Small for gestational age Low birth weight Apgar score < 10 |
MPH/ATX was associated with a higher risk of SA, but results indicated that it may at least partly be explained by confounding by indication. Treatment with MPH/ATX was however associated with low Apgar scores, an association not found among women with ADHD who did not use MPH/ATX. | 9 |
| Diav-Citrin et al, 2016[48] | Israel, Germany, England, Canada | Ad Hoc Clinical Sample; 764 | MPH:382 (50%) | Structured questionnaire administered to women who contacted teratology information services before outcome of pregnancy was known. | Conception to the end of pregnancy | NA | NA | NA | Maternal age, gestational age, year at initial contact | NA | Major congenital anomalies Miscarriages and elective termination of pregnancy Preterm birth |
MPH does not seem to increase the risk for major malformations. Further studies are required to establish its pregnancy safety and possible associations with miscarriages. | 5 |
| Cohen et al, 2017[47] | United States | Administrative Database/Registry; 1,466,792 | Amphetamine/Dextroamphetamine:3331 (0.23%) MPH:1515 (0.10%) ATX: 453(0.03%) |
Medicaid insurance prescription records | LMP to LMP plus 140 days | Atypical antipsychotic: 18,080 (1.2%) Antidepressant: 138,074 (9.5%) Benzodiazepine: 45,483 (3.1%) Opioid: 323,505 (22.1%) Triptan: 16,202 (1.1%) NSAID: 244,501 (16.7%) Acetaminophen: 389,759 (26.7%) Anticonvulsant or lithium: 18,186 (1.2%) |
NA | Atypical antipsychotic: 876 (16.5%) Antidepressant: 2,639 (49.8%) Benzodiazepine: 1,063 (20.1%) Opioid: 2,140 (40.4%) Triptan: 184 (3.5%) NSAID: 1,290 (24.3%) Acetaminophen: 2,240 (42.3%) Anticonvulsant or lithium: 680 (12.8%) |
Demographic characteristics maternal and pregnancy characteristics, certain chronic conditions, indications for stimulants, other psychiatric and pain conditions, proxies for health care utilization intensity, and cotreatment with psychiatric and pain medication. | ATX used as a negative control exposure (ATX is a non-stimulant ADHD medication) | Preeclampsia placental abruption small for gestational age preterm birth | Psychostimulant use during pregnancy was associated with a small increased relative risk of preeclampsia and preterm birth. The absolute increases in risks are small and, thus, women with significant ADHD should not be counseled to suspend their ADHD treatment based on these findings. | 9 |
| Nörby et al, 2017[51] | Sweden | Administrative Database/Registry; 964,734 | MPH/Amphetamine/Dexamphetamine/Lisdexamfetamine/Modafini/ATX: 1591 (0.2%) | Self-reported use recorded in the Medical Birth Register or filled prescription recorded in the Prescribed Drug Register | one month before pregnancy to the end of pregnancy | Opioids: 15.0% Antiepileptics: 9.7% Psycholeptics: 34.9% Antidepressants: 31.8% Alimemazine: 4.1% Promethazine: 28.1% |
Opioids: 12.1% Antiepileptics: 3.2% Psycholeptics: 15.1% Antidepressants: 20.0% Alimemazine: 1.3% Promethazine: 18.6% |
Opioids: 4.4% Antiepileptics: 0.5% Psycholeptics: 2.3% Antidepressants: 3.3% Alimemazine: 0.1% Promethazine: 7.7% |
Year of birth, maternal age, primiparity, BMI, maternal smoking, noncabitating with father, mother born outside the Nordic countries, and maternal use of opioids, antiepileptics, psycholeptics, antidepressants alimemazine, or promethazine during pregnancy | Compared to ADHD medication use before or after pregnancy | Gestational age Small for gestational age Large for gestational age Apgar score <7 at 5 minutes Birth defects Perinatal death NICU admission Respiratory disorders Hyperbilirubinemia Hypoglycemia Feeding difficulties CNS-related disorders Withdrawal symptoms for therapeutic drugs |
Treatment with ADHD medication during pregnancy was associated with a higher risk for neonatal morbidity, especially central nervous system-related disorders such as seizures. Because of large differences in background characteristics between treatment women and controls, it is uncertain to what extend this can be explained by the ADHD medication per se. | 8 |
| Huybrechts et al, 2018[50] | United States, Nordic countries | Administrative Database/Registry; 1,813,894 | MPH:2072 (0.11%) Amphetamine/Dextroamphetamine: 5571 (0.31%) |
Medicaid insurance prescription records | First 90 days of pregnancy |
MPH exposed Anticonvulsants: 302 (14.6%) Antidepressants: 1,033 (49.9%) Anxiolytics: 43 (2.1%) Antipsychotics: 375 (18.1%) Barbiturates: 39 (1.9%) Benzodiazepines:336 (16.2%) Other hypnotics: 245 (11.8%) Amphetamine/dextroamphetamine exposed Anticonvulsants: 833 (15.0%) Antidepressants: 2,537 (45.5%) Anxiolytics: 128 (2.3%) Antipsychotics: 749 (13.4%) Barbiturates: 130 (2.3%) Benzodiazepines:1,315 (23.6%) Other hypnotics: 678 (12.2%) |
NA | Anticonvulsants: 35,644 (2.0%) Antidepressants: 155,155 (8.6%) Anxiolytics: 7,187 (0.4%) Antipsychotics: 22,661 (1.3%) Barbiturates: 18,023 (1.0%) Benzodiazepines: 54,893 (3.1%) Other hypnotics: 63,265 (3.5%) |
Demographic characteristics, obstetric characteristics, psychiatric conditions, chronic comorbid medical conditions, markers of general comorbidity, and prescribed medications. | NA | Major congenital malformations Cardiac malformations |
Findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for ADHD disorders in women of reproductive age and during early pregnancy. | |
| Poulton et al, 2018[53] | Australia | Administrative Database/Registry; 30,305 | MPH/Dextroamphetamine 175 (0.58% for ADHD medication) | Prescription records recording in the Pharmaceutical Drugs of Addiction System | One year before the expected delivery date | NA | NA | NA | Maternal age, infant year of birth, pre-existing diabetes mellitus, pre-existing hypertension, smoking, parity and multiple pregnancy | Compared to women treated before or after pregnancy | Gestational diabetes Instrumental vaginal delivery Postpartum hemorrhage Birthweight < 2500g Birthweight > 4000 5-min Apgar < 7 Perinatal death Spontaneous labor onset Cesarean delivery Active resuscitation Neonatal admission > 4hours Pre-eclampsia Preterm birth 1-min Apgar < 7 |
Compared with no treatment, ADHD stimulant treatment at any time was associated with small increases in the risk of some adverse pregnancy outcomes; treatment before, or before and during pregnancy, was associated with additional adverse outcomes, even after a treatment-free period of several years. None of these associations can be confidently attributed to stimulant treatment; in all cases ADHD per se or correlates of it could be responsible for the association. | 8 |
MPH: Methylphenidate
ATX: Atomoxetine
LMP: last menstrual period
SSRI: Selective Serotonin Reuptake Inhibitor
NSAID: Nonsteroidal anti-inflammatory drug
ADHD: Attention deficit/hyperactivity disorder
BMI: Body Mass Index
NA: No information
NICU: Neonatal intensive care unit
NOS: Newcastle-Ottawa Scale
SA: Spontaneous abortion