Essi Whaites Heinonen

Purpose: Medication use during pregnancy has increased worldwide. The aim was to investigate patterns of prescription medication use during pregnancy and postpartum in Sweden 2007–2022. Methods: We conducted a population‐based drug utilization study with linked data from the Swedish Medical Birth and Prescribed Drug Registers. From 90 days before pregnancy to 90 days after delivery, all dispensed prescriptions for each full‐level ATC code were identified. The proportion of women, by year and age, with ≥ 1 dispensed medication was calculated, as well as the number of different medications and dispensed prescriptions of structural teratogens and specific medication groups. Results: Overall, 1 065 593 (60.5%) women were dispensed ≥ 1 medication during pregnancy and 900 536 (51.1%) within 3 months postpartum. The proportion of women with ≥ 1 dispensed prescription in the postpartum period was stable but increased during pregnancy from 57.1% in 2007 to 67.5% in 2022, with the largest increase in women ≥ 40 years. The proportion using ≥ 5 different medications increased, while the proportion with a recognized or suspected structural teratogen in the first trimester remained low (< 1%). There was a notable decrease in the use of antibiotics and prescribed analgesics, and an increase in antiemetics, psychotropics, acetylsalicylic acid, anticoagulants, antihypertensives, and antidiabetics. Conclusion: Medication use during pregnancy in Sweden increased from 2007 to 2022, particularly among women ≥ 40 years, while postpartum use remained stable. Shifts in the use of specific medication groups highlight evolving maternal characteristics and clinical practice, as well as the importance of continuous surveillance and investigation of medication safety.

Background: Human milk oligosaccharides (HMOs) are abundant carbohydrates in human milk, providing infants with numerous health benefits, but it is not known whether maternal medications could affect them. We aimed to study the association between antidepressant and anti-inflammatory medication use and HMO composition in human milk. Methods: This study included 544 human milk samples from the UC San Diego Human Milk Biorepository collected between October 2014 and November 2022 from participants treated with antidepressants, anti-inflammatories, or neither. Concentrations of 19 HMOs were analyzed by high-performance liquid chromatography and compared between groups stratified by secretor status. Results: In secretors ( n = 390), total HMO concentrations were significantly lower in samples exposed to antidepressants and anti-inflammatories than in unexposed samples, median (Interquartile Range [IQR]) 12.43 (5.32) and 12.71 (4.94) vs 16.10 (2.25) mmol/L, but not in non-secretors ( n = 154). In both secretors and non-secretors, samples exposed to antidepressants had higher percentages of several fucosylated oligosaccharides than unexposed. Conclusions: The HMO composition varied between human milk samples from mothers treated with antidepressant and anti-inflammatory medications and mothers treated with neither. Whether these associations are causal or could affect breastfed infants requires further investigation. The findings do not discourage the use of these medications during lactation. Impact: In human milk, maternal treatment with antidepressants and anti-inflammatories was associated with higher levels of several fucosylated oligosaccharides, particularly among antidepressant users, a trend toward lower sialylated and non-fucosylated, non-sialylated oligosaccharide levels, and lower total human milk oligosaccharide concentrations among secretors. It is unknown whether these associations are causal, and the overall clinical implications of these findings for the breastfed infant are not clear. Potential effects of maternal mood and inflammatory disorders also need to be clarified. These findings should not discourage the use of anti-inflammatory or antidepressant medication during lactation when the use is medically indicated.

Importance: The cognitive performance of children prenatally exposed to selective serotonin reuptake inhibitors (SSRIs) has in some studies been shown to be reduced compared with that of unexposed children, potentially by factors associated with the underlying maternal disorder. However, cognitive performance following exposure to SSRIs through breastfeeding has not been previously studied. Objective: To determine whether the cognitive performance of children exposed to SSRIs both during pregnancy and breastfeeding differs from that of children with SSRI exposure limited to pregnancy. Design, Setting, and Participants: This prospective cohort study included the offspring of pregnant women enrolled in the MotherToBaby California cohort from May 8, 1989, to April 14, 2008. Children whose mothers were treated with SSRIs during pregnancy completed neurodevelopmental testing at 4 to 5 years of age (April 30, 1996, to August 12, 2012). Data were analyzed from January 10 to May 16, 2025. Exposures: Children exposed to SSRIs during breastfeeding were compared with breastfed children not exposed to SSRIs during breastfeeding and nonbreastfed children. Main Outcomes and Measures: Full-scale, verbal, and performance IQ were measured with the Wechsler Scales of Preschool and Primary Intelligence and compared using analysis of covariance adjusted for child sex, prematurity, and age at testing. Results: The sample included 97 mother-child dyads. Of the 97 children, 52 (53.6%) were female and 45 (46.4%) were male, with a mean (SD) age at testing of 4.9 (0.7) years. Of these, 22 children (22.7%) were exposed to SSRIs during breastfeeding; 37 (38.1%) were breastfed without SSRI exposure; and 38 (39.2%) were not breastfed. There were no significant differences in any adjusted mean IQ scores between breastfed children with and without postnatal SSRI exposure. Compared with nonbreastfed children, breastfed children exposed to SSRIs postnatally had significantly higher adjusted mean full-scale IQ scores (109.4 [95% CI, 104.5-114.4] vs 103.1 [95% CI, 99.3-106.9]; P = .046) and performance IQ scores (112.3 [95% CI, 106.7-118.0] vs 104.2 [95% CI, 99.9-108.5]; P = .03), but these differences were no longer significant after adjustment for factors related to the maternal mood during pregnancy. Conclusions and Relevance: In this cohort study including children prenatally exposed to SSRIs, additional exposure to SSRIs through breastfeeding was not associated with reduced IQ scores. Although measures of performance other than IQ were not evaluated, these findings suggest that breastfeeding can be encouraged during treatment with SSRIs.

Objective: To evaluate if metformin treatment prior to pregnancy reduces the likelihood of nausea and vomiting in pregnancy (NVP) and hyperemesis gravidarum (HG) compared to no exposure.Design: Observational cohort study.Setting: The MotherToBaby Pregnancy Studies in the United States and Canada.Sample: Live‐born singleton pregnancies enrolled between 2012 and 2023, with HG diagnosis data available.Methods: Data were collected via maternal telephone interviews during pregnancy and medical records. Outcomes were compared between women with preconceptional metformin exposure and those unexposed to metformin before or during pregnancy.Main Outcome Measures: Risk ratios (RR) and 95% confidence intervals (CI) for HG and NVP, and mean duration of NVP symptoms.Results: Data from 80 women exposed to metformin before conception and 4411 non‐exposed women were analysed. In this cohort, the frequency of women with HG was lower among the exposed than the unexposed women (n = 1/80; 1.25% vs. n = 97/4411; 2.20%), but the study was not powered to detect statistical significance (adjusted RR 0.50, 95% CI 0.07–3.39). Rates of NVP were similar between groups (n = 32/80; 88.90% in the exposed and n = 1664/4111; 82.60% in the unexposed), with adjusted RR 1.06; 95% CI, 0.94–1.19. The mean duration of NVP symptoms was also similar between the groups.Conclusions: This cohort study found a lower rate of HG in the preconceptional metformin‐exposed group compared to unexposed, although the study was not powered to identify a significant association. Rated and durations NVP were similar between groups. These are relevant to guiding future clinical trials on the efficacy of metformin as a prophylactic agent for HG.

Background: Exclusive breastfeeding for 6 months is recommended, but breastfeeding safety data is insufficient for several medications. Aim: To determine if mothers treated with chronic medications are less likely to breastfeed. Methods: For this secondary analysis, 6383 pregnant women in the MotherToBaby cohort recruited from the United States and Canada between 2010 and 2022 were included. Participants treated with antirheumatic medications (ARM), selective serotonin reuptake inhibitors (SSRIs), and asthma medications during pregnancy were divided into two groups based on their medication use: continuers and discontinuers. Breastfeeding initiation, supplementation with commercial milk formula, and discontinuation of breastfeeding before 6 months were compared between those exposed and unexposed to medication use. Adjusted risk and hazard ratios (aRR, aHR) and 95% Confidence Intervals (CI) were calculated with modified Poisson and Cox regressions adjusted for year, parity, socioeconomic status, body mass index, smoking, illicit drug use, race and ethnicity. Results: The sample included 799 (12.5%) continuers and 475 (7.4%) discontinuers of ARM, 293 continuers (4.6%) and 63 (1.0%) discontinuers of SSRIs, and 217 (3.4%) continuers and 97 (1.5%) discontinuers of asthma medications. There were 4,439 (69.6%) participants who were unexposed to the study medications. Both ARM continuers and discontinuers were more likely to not breastfeed (aRRs 95% CI: 3.92 [3.03, 5.07] and 3.08 [2.19, 4.33]), to supplement (aRRs 95% CI: 1.12 [1.01, 1.26] and 1.25 [1.10, 1.43]) and stop breastfeeding before 6 months (aHRs 95% CI: 1.72 [1.29, 2.31] and 1.41 [0.92, 2.15]). SSRI continuers were more likely to supplement (aRR 95% CI: 1.26 [1.08, 1.47]). Conclusion: Participants treated with chronic medications, primarily ARMs, were less likely to breastfeed. Targeted lactation support for mothers with chronic illnesses is recommended along with development of breastfeeding safety data for these medications.

Importance: The association between maternal medications and the macronutrient composition of human milk has not been studied.Objective: To compare macronutrient levels in milk samples from mothers treated with long-term medications with samples from untreated healthy and disease-matched control mothers (DMCs).Design, Setting, and Participants: A cross-sectional study using samples collected between October 2014 and January 2024 from breastfeeding mothers in the US and Canada invited to participate to the Mommy’s Milk Human Milk Research Biorepository at the University of California, San Diego. Of 3974 samples from unique individuals in the biorepository, 310 were from mothers treated with 1 of 4 categories of medications, 151 from DMCs with the same underlying disorders, and 73 from healthy untreated mothers, frequency matched on infant age and sex. Of these, 150 were excluded because they had more than 1 medication exposure or were outliers. Data were analyzed from March to June 2024.Exposures: Continuous treatment with selective serotonin reuptake inhibitors (SSRIs), monoclonal antibodies (MABs), systemic steroids, and other anti-inflammatory drugs (ADs) in the 14 days before milk sample collection.Main Outcomes and Measures: Levels of protein, fat, carbohydrate, and total energy were measured with SpectraStar 2400 near infrared analyzer and compared across groups with analysis of covariance adjusted for infant and maternal age, parity, maternal body mass index, infant sex, exclusive breastfeeding, feeding frequency, collection time, maternal cannabis use, and occupation.Results: A total of 384 samples were collected; 194 infants (50.5%) were female; the mean (SD) age of the maternal cohort was 33.5 (4.4) years, and infant age at collection was 6.6 (5.4) months. Mean (SD) protein levels were 15% to 21% lower in samples from exposed mothers (0.92 [0.56] g/100 mL for 63 SSRIs, 0.85 [0.51] g/100 mL for 63 MABs, 0.88 [0.37] g/100 mL for 33 steroids, and 0.85 [0.54] g/100 mL for 20 other ADs) compared with 64 samples from healthy mothers (1.08 [0.50] g/100 mL). Adjusted differences were significant for SSRIs and steroids (F_{1, 91} = 4.32; P = .04 and F_1,59 = 5.00, P = 0.03, respectively). Mean (SD) fat and energy were 10% to 22% lower in samples from mothers with other ADs (3.40 [1.21] g/100 mL for fat and 69.56 [15.35] kcal/100 mL for energy) than from healthy (3.85 [1.66] g/100 mL for fat and 77.16 [22.08] kcal/100 mL for energy) and DMC (4.38 [1.90] g/100 mL for fat and 80.60 [24.70] kcal/100 mL for energy) mothers. Adjusted differences were only significant for fat compared with DMC (F_1,88 = 6.22; P = .01).Conclusions and Relevance: In this cross-sectional study, some maternal medications were associated with lower levels of protein and fat in milk, which could impose health risks for breastfed infants. Other factors that could influence macronutrient levels need to be clarified before the clinical implications of these findings can be confirmed.

Aim: We aimed to investigate plasma lamotrigine concentrations and clinical effects in infants exposed to lamotrigine through breastfeeding.Methods: This was a retrospective study of mother–infant dyads in a clinical follow‐up programme in Stockholm, Sweden. Data were collected from medical records.Results: We included 47 breastfed infants, born from 2011 to 2021, with a median gestational age of 39 + 6 weeks/days and a median birth weight of 3420 g. The median lamotrigine concentration in the infants' plasma was 2.5 (range 2.5–14.0) μmol/L. These concentrations correlated significantly with both the maternal plasma concentrations and the maternal doses (R = 0.79, p < 0.001 versus R = 0.54, p < 0.001). During the follow up, lamotrigine concentrations within the reference range for epilepsy treatment were detected in six (14%) infants and one had clinical symptoms that were probably related to lamotrigine exposure. Liver transaminases were elevated in three of 21 infants. All infants whose mothers had a dose of 150 mg or less had undetectable plasma concentrations and no symptoms during follow up.Conclusion: Infants exposed to lamotrigine through breastfeeding had a low risk of toxic effects. All infants whose mothers had low lamotrigine doses had unmeasurable plasma concentrations and no symptoms of lamotrigine exposure. These low‐risk infants might be offered a simplified follow up.

Background: Neonatal effects of late intrauterine and early postpartum exposure to lithium through mother’s own milk are scarcely studied. It is unclear whether described symptoms in breastfed neonates are caused by placental lithium transfer or postnatal exposure to lithium through breastfeeding. We aimed to investigate lithium clearance and neonatal morbidity in breastfed infants with high versus low serum lithium concentrations at birth. Methods: This retrospective study focused on breastfed infants to women treated with lithium during and after pregnancy, born between 2006 and 2021 in Stockholm, Sweden. Information on serum lithium concentrations and adverse neonatal outcomes was obtained from medical records. Neonatal symptoms and lithium clearance were compared between a high exposure group (HEG, lithium concentrations ≥ 0.6 meq/l) and a low exposure group (LEG, < 0.6 meq/l). Results: A total of 25 infant-mother dyads were included. Median lithium serum concentration at birth was 0.90 meq/l in the HEG as compared with 0.40 meq/l in the LEG (p < 0.05). The difference was still significant at follow-up (0.20 meq/l vs 0.06 meq/l, p < 0.05), despite reduction in maternal dose. The rate of neonatal symptoms was 85.7% in HEG and 41.2% in LEG (p = 0.08) at birth and 28.6% vs 11.8% at follow-up (p = 0.55). Furthermore, 28.6% of infants in HEG were admitted to neonatal care, vs 5.9% in LEG (p = 0.19). Two infants in the HEG had therapeutic lithium levels at follow-up. All infants with symptoms at follow-up were either in the HEG or exposed to additional psychotropic medication. Conclusions: Neonatal symptoms are common after late intrauterine lithium exposure, however transient, treatable and mostly mild. In this study, a high lithium concentration at birth was a risk factor for an increased lithium level at follow-up. Polypharmacy may constitute an additional risk factor. This study suggests that the late intrauterine exposure to lithium might add to the adverse effects in lithium-exposed, breastfed infants. Consequently we recommend breastfed infants with therapeutic lithium concentrations at birth to be followed up promptly to avoid lithium toxicity.

Objective To investigate the admission rate to neonatal care and neonatal morbidity after maternal use of antipsychotics during pregnancy. Design A population-based register study. Setting Information on all singleton births between July 2006 and December 2017 in Sweden including data on prescription drugs, deliveries and infants’ health was obtained from the Swedish Medical Birth Register, the Prescribed Drug Register and the Swedish Neonatal Quality Register. Exposed infants were compared with unexposed infants and with infants to mothers treated with antipsychotics before or after but not during pregnancy. Participants The cohort comprised a total of 1 307 487 infants, of whom 2677 (0.2%) were exposed to antipsychotics during pregnancy and 34 492 (2.6%) had mothers who were treated before/after the pregnancy. Outcome measures The primary outcome was admission rate to neonatal care. Secondary outcomes were the separate neonatal morbidities. Results Of the exposed infants, 516 (19.3%) were admitted to neonatal care compared with 98 976 (7.8%) of the unexposed infants (adjusted risk ratio (aRR): 1.7; 95% CI: 1.6 to 1.8), with a further increased risk after exposure in late pregnancy. The highest relative risks were seen for withdrawal symptoms (aRR: 17.7; 95% CI: 9.6 to 32.6), neurological disorders (aRR: 3.4; 95% CI: 2.4 to 5.7) and persistent pulmonary hypertension (aRR: 2.1; 95% CI: 1.4 to 3.1) when compared with unexposed infants. The absolute risks for these outcomes were however low among the exposed infants, 1.3%, 1.8% and 1.0%, respectively, and the relative risks were lower when compared with infants to mothers treated before/after the pregnancy. Conclusion Fetal exposure to antipsychotics was associated with an increased risk of neonatal morbidity. The effects in the exposed infants seem transient and predominantly mild, and these findings do not warrant discontinuation of a necessary treatment but rather increased monitoring of these infants. The increased risk of persistent pulmonary hypertension requires further studies.

Aim: Previous studies on breastfeeding during lithium therapy have shown conflicting results. The aim of this study was to evaluate the safety when practising thorough follow‐up of the infants.Method: This retrospective study focused on women with lithium medication, and their breastfed infants born between 2006 and 2021 in Stockholm, Sweden. Information about infant serum lithium concentrations and clinical status was collected from medical records.Results: In total, 30 infants exposed to lithium through breastmilk, 21 girls and 9 boys, were included. The median age at follow‐up was 40 days (range 8–364 days). The median lithium serum concentration was 0.10 mmol/L in the second week of life (range <0.05–0.7 mmol/L), 0.08 in week 2–4 (range <0.05–1.2), 0.06 in the second month of life (range <0.05–0.2) and 0.07 after 2 months of age (range <0.05–0.2). Unexpectedly high lithium concentrations were found in two infants in the first month of life. Apart from poor weight gain, no adverse effects were found.Conclusion: Serum lithium concentrations in breastfed infants were stabilised at barely measurable levels after the first weeks of life. Before that, concentrations higher than the mothers were found. Lithium treatment during breastfeeding can be considered safe under strict follow‐up.