Abstract
Background:
The associations of prenatal maternal depression and exposure to antidepressants and benzodiazepines/Z-drugs with the risks of offspring asthma and atopic dermatitis are unclear.
Methods:
The data from 1369 child–mother dyads with maternal depression and 13 690 birth year– and sex-matched child–mother dyads without maternal depression for the period from 2002 to 2009 were selected. Prenatal exposure to antidepressants and benzodiazepines/Z-drugs was also considered. All children were followed from their birth date to the end of 2011 to identify the development of asthma and atopic dermatitis.
Results:
The offspring of mothers with depression were more likely to develop atopic dermatitis (hazard ratio [HR], 1.16) and asthma (HR, 1.12) during the follow-up period relative to the control group. Prenatal exposure to benzodiazepines/Z-drugs was strongly associated with an increased risk (HR, 1.27) of offspring asthma. However, prenatal exposure to antidepressants was not associated with increased risks of offspring asthma and atopic dermatitis.
Conclusion:
The mechanisms underlying the complex relationship between maternal depression, exposure to benzodiazepines/Z-drugs, and the risk of offspring atopy warrant further investigation.
Keywords: Antidepressants, Benzodiazepines, Offspring asthma, Offspring atopic dermatitis, Prenatal maternal depression
Lay Summary: The present study assessed the association of prenatal maternal depression and prenatal exposure to antidepressants and benzodiazepines/Z-drugs with offspring asthma and atopic dermatitis risks. Prenatal maternal depression was associated with the risks of offspring asthma and atopic dermatitis. Prenatal exposure to antidepressants was not associated with the risks of offspring asthma and atopic dermatitis. Prenatal exposure to benzodiazepines/Z-drugs was associated with the risk of offspring asthma.
1. INTRODUCTION
A growing body of evidence suggests that prenatal maternal depression is associated with the development of atopic diseases in offspring, such as asthma and atopic dermatitis.1–3 The FinnBrain Birth Cohort Study of 1305 mother–infant dyads indicated that prenatal maternal distress, particularly depressive symptoms, was associated with the subsequent risk of offspring wheezing (odds ratio [OR], 2.74; 95% CI, 1.37-5.50) and atopic dermatitis (OR, 1.94; 95% CI, 1.06-3.54) before the age of 2 years.2 van der Leek et al4 reported that prenatal maternal distress (ie, depression) was associated with the childhood onset of atopic dermatitis (OR, 1.27; 95% CI, 1.11-1.46) and asthma (OR, 1.57; 95% CI, 1.29-1.91) in the offspring of affected mothers. Ramratnam et al3 suggested that a complex relationship between prenatal maternal depression and offspring cytokine dysregulation (ie, interleukin [IL]-4, IL-5, and IL-13) contributes to the aforementioned risk. A systematic review by Andersson et al1 further validated the aforementioned associations; however, because of the diverse quality of the reviewed studies, the review had a substantial risk of information bias (ie, self-reported measures) and false-positive results. In addition, whether these findings can be generalized to Asian populations requires further clarification.
However, the association between prenatal exposure to depression-related medications, including antidepressants and benzodiazepines/Z-drugs, with the risk of offspring atopy remains unclear.5 ter Horst et al5 reported that in utero exposure to antidepressants at any time was associated with the use (incidence risk ratio [RR], 1.17; 95% CI, 1.16-1.18) of drugs for pulmonary diseases, including asthma, among offspring. By contrast, a Danish birth cohort study of 733 685 children revealed an association between prenatal maternal depression and childhood asthma (HR, 1.25; 95% CI, 1.20-1.30), but it failed to identify an association between antidepressant use during pregnancy and childhood asthma (HR, 1.00; 95% CI, 0.93-1.08).6 No study has investigated the association between prenatal exposure to antidepressants and offspring atopic dermatitis, despite the comorbid occurrence of asthma and atopic dermatitis being a common phenomenon.
Animal studies have demonstrated the harmful effects of prenatal exposure to benzodiazepines, even at low doses, on the development of the immune system.7 Schlumpf et al8 reported that the offspring of Long Evans rats that were prenatally exposed to low-dose diazepam exhibited long-lasting alterations of the cytokine network, including changes involving tumor necrosis factor (TNF)-α, IL-1, IL-6, IL-2, and interferon-γ. However, the evidence supporting the association of benzodiazepine/Z-drug use during pregnancy with the risk of offspring atopic diseases is limited.9 Zetstra-van der Woude et al9 reported that the prescription rate of benzodiazepines during pregnancy was higher in mothers of children who took asthma medications than among those who did not take asthma medications (children who took asthma medications vs. children who did not take asthma medications, 3.3% vs 2.8%, p < 0.001).
In our longitudinal follow-up study, we investigated the association of prenatal maternal depression with offspring asthma and atopic dermatitis and attempted to further clarify the effects of exposure to antidepressants and benzodiazepines/Z-drugs on such associations. To this end, we retrieved data from the Taiwan National Health Insurance Research Database (NHIRD) to establish a large sample comprising child–mother dyads and adopted a longitudinal follow-up design. We hypothesized that prenatal maternal depression would be associated with an elevated risk of offspring asthma and atopic dermatitis and that exposure to antidepressants and benzodiazepines/Z-drugs further increases these risks.
2. METHODS
2.1. Data acquisition
For scientific investigations, the Taiwan National Health Research Institute audits and releases the Taiwan National Health Research Database (NHIRD). The database contains comprehensive information on insured persons, including demographic details, dates of clinical visits, and medical diagnoses. To protect privacy, the information about the individuals’ insurance claims is anonymized. All data were connected in this investigation using a distinct personal identification number assigned to each individual. Family kinships in the NHIRD were utilized for genealogy reconstruction using the approach developed by Chen et al and Cheng et al.10,11 The diagnostic codes used were based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many Taiwanese epidemiologic studies.10,12–14 The Institutional Review Board of our Hospital approved the study protocol and waived the requirement for informed consent because this investigation used de-identified data and no human subject contact was required.
2.2. Inclusion criteria for the offspring of mothers with depression and the control group
Individuals who were born between 2002 and 2009 and had mothers with a diagnosis of depression (ICD-9-CM codes: 296.2, 296.3, 300.4, 311) given by board-certified psychiatrists before their birth dates, including before pregnancy and during pregnancy, were included as the study cohort. Comorbidity of maternal anxiety disorders (ICD-9-CM codes: 300 except 300.4) was also assessed. Mothers who had any diagnosis of bipolar disorder or schizophrenia were excluded from the present study. The sex-, birth year-, income, and residence-matched (1:10) control cohort was randomly identified from the offspring of mothers who had no major psychiatric disorder (ICD-9-CM codes: 295, 296, 300, 311) and were never exposed to psychotropic drugs (antidepressants, benzodiazepines/Z-drugs, antipsychotics, and mood stabilizers) at any time in the database. Study and control cohorts were followed from birth to the end of 2011. Offspring asthma was diagnosed by board-certified pediatricians, emergency room physicians, and chest medicine physicians; offspring atopic dermatitis was diagnosed by board-certified pediatricians and dermatologists. Maternal exposure to antidepressants and benzodiazepines/Z-drugs was assessed during pregnancy. Antidepressants included selective serotonin reuptake inhibitors (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram), serotonin–norepinephrine reuptake inhibitors (venlafaxine, duloxetine, milnacipran), and norepinephrine–dopamine reuptake inhibitors (bupropion). Three Z-drugs (zolpidem, zopiclone, zaleplon) and common benzodiazepines, such as midazolam, brotizolam, estazolam, flunitrazepam, nitrazepam, flurazepam, alprazolam, lorazepam, triazolam, diazepam, medazepam, bromazepam, clonazepam, fludiazepam, chlordiazepoxide, nordazepam, oxazolam, clorazepate, and nimetazepam were included in our study. Cumulative defined daily doses (cDDDs) of antidepressants and benzodiazepines/Z-drugs during the pregnancy were calculated, respectively. In real-world practice, non-psychiatrist clinicians rarely initiate antidepressant therapy, especially in pregnant women. Income level (levels 1-3 per month: ≤19 100 NTD [New Taiwanese Dollars], 19 001~42 000 NTD, and >42 000 NTD) and urbanization level of residence (levels 1-5, most to least urbanized) were assessed as the proxy for healthcare availability in Taiwan.15
2.3. Statistical methods
Chi-square statistics and F tests were used to compare categorical and continuous variables, respectively, between study and control cohorts. Because some offspring were from the same mothers, resulting in a clustered study sample, the Poisson regression models with a robust error variance were performed to estimate the hazard ratios (HRs) and 95% CIs between groups.16 Children with the same mother were accounted for as maternal clustering. Demographic characteristics, including birth year, sex, residence, income level and the ages of mothers, were adjusted in the regression models. Furthermore, the association between maternal depression with or without exposure to antidepressants and benzodiazepines/Z-drugs and the likelihood of offspring asthma and atopic dermatitis was further analyzed compared with the control group. Furthermore, for associations identified using overall prenatal exposure, we conducted trimester-specific analyses of psychotropic medication exposure in relation to offspring risks of asthma and atopic dermatitis. Finally, we computed E-values to quantify the minimum strength of association. SAS 9.2 (SAS Institute, Cary, NC) was used for all statistical analyses. All tests were two-tailed, and p < 0.05 was considered statistically significant.
2.4. Data availability statement
The NHIRD is curated and released for scientific research by the Department of Health and the Bureau of the National Health Insurance Program. Access is granted upon approval of a formal application submitted via the official portal (https://www.apre.mohw.gov.tw/) and in accordance with the governing regulations.
3. RESULTS
In total, 1369 individuals of mothers with depression and 13 690 matched controls were included in our study, with a male predominance (54.3%) (Table 1). Among mothers with depression, 897 (65.5%) had a comorbid diagnosis of any anxiety disorder, and 131 (9.6%) and 339 (24.8%) were exposed to antidepressants and benzodiazepines/Z-drugs during the pregnancy, with average cDDDs of about 121 and 74, respectively (Table 1). Pregnant ages of mothers in the maternal depression group were slightly higher (30.24 vs 29.81 years) than those in the control group (Table 1). Prevalence of atopic dermatitis was significantly higher in the study group (47.5%) than in the control group (42.0%, p < 0.001) (Table 1). Prevalence of asthma did not differ between groups (p = 0.263) (Table 1).
Table 1.
Demographic characteristics and incidences of atopic dermatitis and asthma in the birth cohort
| Offspring 2002-2009 birth cohort (n = 15 059) | |||
|---|---|---|---|
| With maternal depression (n = 1369) |
Without maternal depression (n = 13 690) |
p | |
| Age at study end (yr, SD) | 5.65 (2.11) | 5.91 (2.16) | <0.001 |
| Birth-year (n, %) | 0.042 | ||
| 2002-2006 | 829 (60.6) | 8672 (63.3) | |
| 2007-2009 | 540 (39.4) | 5018 (36.7) | |
| Sex (n, %) | |||
| Male | 744 (54.3) | 7440 (54.3) | |
| Female | 625 (45.7) | 6250 (45.7) | |
| Incidence of atopic dermatitis (n, %) | 650 (47.5) | 5746 (42.0) | <0.001 |
| Age at diagnosis (yr, SD) | 1.11 (1.15) | 1.11 (1.20) | 0.914 |
| Incidence of asthma (n, %) | 356 (26.0) | 3361 (24.6) | 0.236 |
| Age at diagnosis (yr, SD) | 2.95 (1.58) | 2.88 (1.59) | 0.442 |
| Pregnant age of mothers (yr, SD) | 30.24 (5.13) | 29.81 (4.83) | 0.002 |
| Maternal depressive disorder diagnosis | |||
| Before pregnancy | 1274 (93.1) | ||
| First trimester | 146 (10.7) | ||
| Second trimester | 62 (4.5) | ||
| Third trimester | 48 (3.5) | ||
| Maternal anxiety disorder comorbidity (n, %) | 897 (65.5) | ||
| Exposure history during pregnancy (n, %) | |||
| Antidepressants | 131 (9.6) | ||
| First trimester | 105 (7.7) | ||
| Second trimester | 43 (3.1) | ||
| Third trimester | 33 (2.4) | ||
| Cumulative dose (SD) | 121.22 (185.27) | ||
| Benzodiazepines/Z-drugs | 339 (24.8) | ||
| First trimester | 225 (16.4) | ||
| Second trimester | 89 (6.5) | ||
| Third trimester | 153 (11.2) | ||
| Cumulative dose (SD) | 74.87 (203.16) | ||
| Level of urbanization (n, %) | >0.999 | ||
| 1 (most urbanized) | 330 (24.1) | 3300 (24.1) | |
| 2 | 526 (38.4) | 5260 (38.4) | |
| 3 | 185 (13.5) | 1850 (13.5) | |
| 4 | 150 (11.0) | 1500 (11.0) | |
| 5 (most rural) | 178 (13.0) | 1780 (13.0) | |
| Family income (n, %) | >0.999 | ||
| ≤19,100 NTD/mo | 331 (24.2) | 3310 (24.2) | |
| 19 001-42 000 NTD/mo | 556 (40.6) | 5560 (40.6) | |
| > 42 000 NTD/mo | 482 (35.2) | 4820 (35.2) | |
Some mothers used medications across multiple trimesters. Categories of medication exposures in three trimesters are not mutually exclusive.
NTD = New Taiwan dollar.
Table 2 shows that offspring of mothers with depression were more likely to develop (HR, 1.16, 95% CI, 1.07-1.26) atopic dermatitis during the follow-up compared with the control group. The elevated HRs of offspring with atopic dermatitis were only noted among offspring of mothers without exposure to antidepressants (HR, 1.16; 95% CI, 1.07-1.26) and benzodiazepines/Z-drugs (HR, 1.16; 95% CI, 1.06-1.27) but not among those of mothers with exposure to antidepressants and benzodiazepines/Z-drugs (Table 2).
Table 2.
Risk of developing atopic dermatitis between groups
| Offspring birth cohort | Atopic dermatitis | ||
|---|---|---|---|
| Events (n, %) | HR (95% CI) | E-value | |
| Without maternal depression | 5746 (42.0) | 1 (ref.) | – |
| With maternal depression | 650 (47.5) | 1.16 (1.07-1.26) | 1.59 |
| Without exposure to antidepressants during pregnancy | 591 (47.7) | 1.16 (1.07-1.26) | 1.59 |
| With exposure to antidepressants during pregnancy | 59 (45.0) | 1.14 (0.88-1.48) | 1.54 |
| Without exposure to benzodiazepines/Z-drugs during pregnancy | 494 (48.0) | 1.16 (1.06-1.27) | 1.59 |
| With exposure to benzodiazepines/Z-drugs during pregnancy | 156 (46.0) | 1.14 (0.98-1.34) | 1.54 |
Adjusted for birth year, sex, income, urbanization, and pregnant age of mothers. Bold values indicate statistical significance (p < 0.05).
HR = hazard ratio.
Maternal depression during pregnancy was associated with the offspring's asthma risk (HR, 1.12; 95% CI, 1.00-1.25) (Table 3). Furthermore, an association between maternal depression and offspring asthma was only noted among offspring of mothers without exposure to antidepressants (HR, 1.12; 95% CI, 1.00-1.26) but not among those of mothers with exposure to antidepressants (Table 3). We found a positive association of maternal depression with exposure to benzodiazepines/Z-drugs with the likelihood of offspring asthma (HR, 1.27; 95% CI, 1.05-1.53) (Table 3). In trimester-specific analyses of prenatal benzodiazepine/Z-drug exposure, only third-trimester exposure was associated with an increased risk of offspring asthma (HR, 1.43; 95% CI, 1.08-1.91), whereas first- and second-trimester exposures were not (HR, 1.03; 95% CI, 0.79–1.35 and HR, 0.71; 95% CI, 0.45-1.13, respectively). Finally, the E-values for associations between the prenatal exposures to antidepressants and benzodiazepines/Z-drugs and the risks of offspring asthma and atopic dermatitis ranged between 1.34 and 1.86. E-values near 1.3 suggest that weak-to-moderate unmeasured confounding could attenuate the associations toward the null, whereas values approaching 1.9 indicate greater robustness.17
Table 3.
Risk of developing asthma between groups
| Offspring birth cohort | Asthma | ||
|---|---|---|---|
| Events (n, %) | HR (95% CI) | E-value | |
| Without maternal depression | 3361 (24.6) | 1 (ref.) | – |
| With maternal depression | 356 (26.0) | 1.12 (1.00-1.25) | 1.49 |
| Without exposure to antidepressants during pregnancy | 320 (25.8) | 1.12 (1.00-1.26) | 1.49 |
| With exposure to antidepressants during pregnancy | 36 (27.5) | 1.10 (0.79-1.53) | 1.43 |
| Without exposure to benzodiazepines/Z-drugs during pregnancy | 247 (24.0) | 1.07 (0.94-1.21) | 1.34 |
| With exposure to benzodiazepines/Z-drugs during pregnancy | 109 (32.2) | 1.27 (1.05-1.53) | 1.86 |
Adjusted for birth year, sex, income, urbanization, and pregnant age of mothers. Bold values indicate statistical significance (p < 0.05).
HR = hazard ratio.
4. DISCUSSION
Our findings partially supported our study hypotheses. Specifically, prenatal maternal depression was revealed to be associated with increased risks of offspring asthma and atopic dermatitis, but prenatal exposure to antidepressants was not associated with the risks of offspring asthma and atopic dermatitis. However, exposure to benzodiazepines/Z-drugs during pregnancy was associated with an increased risk of offspring asthma.
Our findings that maternal depression was associated with offspring atopy risk and that prenatal exposure to antidepressants was not associated with the risk of offspring asthma correspond with the results reported by van der Leek et al, Puosi et al, and Liu et al.2,4,6 A meta-analysis of studies involving more than 6 million participants revealed that maternal exposure to all types of stressors, especially depression, was associated with an increased risk of offspring atopic dermatitis (OR, 1.34; 95% CI, 1.22–1.47) and asthma (OR, 1.15; 95% CI, 1.04-1.27).18 The Ma’anshan birth cohort study of 3131 mother–child pairs found that maternal antenatal anxiety was associated with an increased risk of asthma among preschool children.19 Rosa et al20 proposed an etiological hypothesis, suggesting that the stress-related physiological changes (ie, anxiety, depression) that occur during vulnerable life periods (ie, the prenatal period) interfere with the development of the immune system and further contribute to the risk of chronic atopic disease (ie, asthma and atopic dermatitis). However, the lack of association between exposure to antidepressants and the risk of offspring atopy may require further verification through a study with a larger sample size. This is because we identified a nonsignificantly higher prevalence of asthma among the group exposed to antidepressants than among the group not exposed to antidepressants.
The conflicting results pertaining to the associations of prenatal exposure to benzodiazepines/Z-drugs with the risks of offspring asthma and atopic dermatitis were the second major finding of our study. Animal studies have reported that prenatal exposure to benzodiazepines and related γ-aminobutyric acid (GABA) receptor modulators interfered with the development of the immune system and respiratory system.7,21 Picard et al21 demonstrated that prenatal exposure to diazepam altered the respiratory control system of newborn rats, including their normoxic breathing pattern, breathing frequency, and ventilatory response to hypoxia. Similarly, da Silva Junior et al22 further indicated that prenatal exposure to diazepam reduced the CO2 chemoreflex in both neonate and young rats. The additive harmful effects of prenatal benzodiazepine/Z-drug exposure on the development of both the immune and respiratory systems may explain the association of exposure to benzodiazepines/Z-drugs, but not antidepressants, with an increased risk of offspring asthma. However, the inconsistent findings of associations between exposure to benzodiazepines/Z-drugs and offspring asthma and between exposure to benzodiazepines/Z-drugs and offspring atopic dermatitis may imply the complicated embryonic development of the skin from the ectoderm, the immune system from the mesoderm, and the lung and bronchioles from the endoderm. This study was, to our knowledge, the first to implicate third-trimester exposure to benzodiazepines/Z-drugs in the risk of offspring asthma. Further studies involving larger sample sizes should be conducted to validate our findings.
Finally, associations of prenatal antidepressant and benzo-diazepine/Z-drug exposure with offspring asthma and atopic dermatitis were small to modest (E-values: 1.34-1.86). In a meta-analysis of 128 clinical studies, maternal asthma was associated with higher risks of offspring asthma (RR, 1.76, 95% CI, 1.57-1.96) and atopic dermatitis (RR, 1.17, 95% CI, 1.11-1.23).23 Another meta-analysis of 149 studies found that parental asthma was associated with higher odds of childhood atopic dermatitis (OR, 1.56, 95% CI, 1.18-2.05).24 The Avon longitudinal study of parents and children demonstrated that maternal atopic disease was associated with increased odds of offspring atopic dermatitis (OR, 1.37, 95% CI, 1.18-1.60).25 Specifically, the E-value for the association between prenatal benzodiazepine/Z-drug exposure and offspring asthma was 1.86, exceeding the magnitudes reported for maternal atopy in prior meta-analyses (offspring asthma RR ≈1.76).23–25 This indicates that maternal atopy alone is unlikely to eliminate the finding, although some attenuation is plausible.
The present study has several limitations. First, up to 65% of mothers with depressive disorder were comorbid with an anxiety disorder in our study. However, we did not include mothers who only had an anxiety disorder diagnosis and their offspring in the present study. Overlapping dysregulation of the hypothalamic–pituitary–adrenal axis and immune pathways in depression and anxiety provides a mechanistic rationale for additive effects of co-occurring prenatal depression and anxiety on offspring asthma risk.26–28 Further studies are required to elucidate whether pure maternal anxiety may be associated with subsequent offspring atopic diseases. Second, surprisingly, about one-fourth of mothers with depressive disorder were exposed to benzodiazepines/Z-drugs during pregnancy in our study. A recent Taiwan study showed that over thirty percent of mothers who were exposed to benzodiazepines/Z-drugs during pregnancy had a mental disorder diagnosis, including depression and anxiety.29 Although the high exposure rate of benzodiazepines/Z-drugs during pregnancy may be owing to the study’s broad definition of ever-use benzodiazepines/Z-drugs, this finding still calls for clinical attention on the potential risk, such as atopic diseases in our study, of the exposure of benzodiazepines/Z-drugs during pregnancy. Third, the prevalence of maternal depression and the prevalence of offspring atopic diseases may be underestimated because only those who sought medical help would be included in the database. The misclassification of atopic diseases may be possible in the register-data study. However, psychiatrists and relevant specialists (ie, pediatricians and dermatologists) made the diagnoses of depression and atopic disease, which increased the diagnostic validity. Fourth, information on disease severity of depression, nutrition supplementation during pregnancy, environmental factors, and lifestyle were not available in the database that we used. Fifth, the association between benzodiazepines/Z-drugs and asthma may be overestimated because this was a known factor causing bias in studies looking into drug use, as many drugs prescribed were eventually not used. A further clinical cohort of mothers with depressive disorders and their offspring would be required to validate our findings. Sixth, owing to the Taiwan National Health Insurance Program, which was established in 1995, the high medical accessibility and affordability of medical services may partially explain the high prevalence of atopic diseases in the present study. In addition, the inclusion of the ICD-9-CM code for asthma unspecified (493.9) may be associated with the identification bias in our study, which may result in an overestimation of the prevalence of atopic diseases. For example, an emergency room physician prescribed the bronchodilator, which is only indicated for an asthma diagnosis, to a child who had severe wheezing. In such a medical condition, the diagnosis of asthma, unspecified, may be given in Taiwan. Further in-person clinical cohort studies would be required to validate the findings of our register-data study. Seventh, the inclusion criteria for mothers in the control group were very strict, requiring them to have no major psychiatric disorder and to have never been exposed to psychotropic drugs at any time in the database. This may introduce selection bias toward an “overly healthy” maternal cohort. The generalizability of our findings to the broader population should be interpreted with caution. Finally, the data on maternal atopic diseases were not available in our study. Further studies would be required to clarify the complex relationship among maternal depression, exposure to psychotropic drugs during pregnancy, maternal atopic diseases, and offspring atopic diseases.
In conclusion, prenatal maternal depression was revealed to be associated with increased risks of offspring asthma and atopic dermatitis. By contrast, prenatal exposure to antidepressants was not associated with the risks of offspring asthma and atopic dermatitis. Notably, prenatal exposure to benzodiazepines/Z-drugs was not associated with an risk of offspring atopic dermatitis but associated with the risk of offspring asthma. For the risk of offspring atopic diseases, including asthma and atopic dermatitis, our findings suggest that clinicians should closely monitor maternal mental health during pregnancy. To balance the benefits and risks of the intervention of psychotropic drugs, including benzodiazepines/Z-drugs, they should always be evaluated and reevaluated throughout pregnancy if these medications must be used during pregnancy.
ACKNOWLEDGMENTS
The study was supported by grants from Taipei Veterans General Hospital (V113C-039, V113C-011, V113C-010, V114C-089, V114C-064, V114C-217); Yen Tjing Ling Medical Foundation (CI-113-32, CI-113-30, CI-114-35); Ministry of Science and Technology, Taiwan (MOST111-2314-B-075-014-MY2, MOST 111-2314-B-075-013, NSTC113-2314-B-075-042, NSTC 114-2628-B-A49-008-MY3, NSTC114-2314-B-075-022, NSTC114-2314-B-075-023); Taipei, Taichung, Kaohsiung Veterans General Hospital, Tri-Service General Hospital, Academia Sinica Joint Research Program (VTA112-V1-6-1, VTA114-V1-4-1); Veterans General Hospitals and University System of Taiwan Joint Research Program (VGHUST112-G1-8-1, VGHUST114-G1-9-1); and Cheng Hsin General Hospital (CY11402-1, CY11402-2). The funding source had no role in any process of our study.
We thank Mr I-Fan Hu, MA (Courtauld Institute of Art, University of London; National Taiwan University) for his friendship and support.
Footnotes
Author contributions: Dr. Li-Chi Chen and Dr. Wei-Sheng Huang contributed equally to the work.
Conflicts of interest: Dr. Tzeng-Ji Chen and Dr. Mu-Hong Chen, editorial board members at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article.
REFERENCES
- 1.Andersson NW, Hansen MV, Larsen AD, Hougaard KS, Kolstad HA, Schlunssen V. Prenatal maternal stress and atopic diseases in the child: a systematic review of observational human studies. Allergy 2016;71:15–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Puosi E, Korhonen LS, Karlsson L, Kataja EL, Lukkarinen H, Karlsson H, et al. Maternal prenatal psychological distress associates with offspring early-life wheezing—FinnBrain Birth Cohort. Pediatr Allergy Immunol 2022;33:e13706. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ramratnam SK, Visness CM, Jaffee KF, Bloomberg GR, Kattan M, Sandel MT, et al. Relationships among maternal stress and depression, type 2 responses, and recurrent wheezing at age 3 years in low-income urban families. Am J Respir Crit Care Med 2017;195:674–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.van der Leek AP, Bahreinian S, Chartier M, Dahl ME, Azad MB, Brownell MD, et al. Maternal distress during pregnancy and recurrence in early childhood predicts atopic dermatitis and asthma in childhood. Chest 2020;158:57–67. [DOI] [PubMed] [Google Scholar]
- 5.ter Horst PG, Bos HJ, de Jong-van de Berg LT, Wilffert B. In utero exposure to antidepressants and the use of drugs for pulmonary diseases in children. Eur J Clin Pharmacol 2013;69:541–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Liu X, Olsen J, Pedersen LH, Agerbo E, Yuan W, Li J. Antidepressant use during pregnancy and asthma in the offspring. Pediatrics 2015;135:e911–7. [DOI] [PubMed] [Google Scholar]
- 7.Schlumpf M, Parmar R, Schreiber A, Ramseier HR, Butikofer E, Abriel H, et al. Nervous and immune systems as targets for developmental effects of benzodiazepines. A review of recent studies. Dev Pharmacol Ther 1992;18:145–58. [PubMed] [Google Scholar]
- 8.Schlumpf M, Lichtensteiger W, Ramseier H. Diazepam treatment of pregnant rats differentially affects interleukin-1 and interleukin-2 secretion in their offspring during different phases of postnatal development. Pharmacol Toxicol 1993;73:335–40. [DOI] [PubMed] [Google Scholar]
- 9.Zetstra-van der Woude PA, De Walle HE, Hoek A, Bos HJ, Boezen HM, Koppelman GH, et al. Maternal high-dose folic acid during pregnancy and asthma medication in the offspring. Pharmacoepidemiol Drug Saf 2014;23:1059–65. [DOI] [PubMed] [Google Scholar]
- 10.Cheng CM, Chang WH, Chen MH, Tsai CF, Su TP, Li CT, et al. Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study. Mol Psychiatry 2018;23:1756–63. [DOI] [PubMed] [Google Scholar]
- 11.Chen MH, Hsu JW, Huang KL, Su TP, Li CT, Lin WC, et al. Risk and coaggregation of major psychiatric disorders among first-degree relatives of patients with bipolar disorder: a nationwide population-based study. Psychol Med 2019;49:2397–404. [DOI] [PubMed] [Google Scholar]
- 12.Tsai SJ, Chang WH, Cheng CM, Liang CS, Bai YM, Hsu JW, et al. All-cause mortality and suicide mortality in autistic individuals: an entire population longitudinal study in Taiwan. Autism 2023;27:2496–506. [DOI] [PubMed] [Google Scholar]
- 13.Hsu TW, Liang CS, Tsai SJ, Bai YM, Su TP, Chen TJ, et al. Risk of major psychiatric disorders among children and adolescents surviving malignancies: a nationwide longitudinal study. J Clin Oncol 2023;41:2054–66. [DOI] [PubMed] [Google Scholar]
- 14.Chen MH, Lan WH, Hsu JW, Huang KL, Su TP, Li CT, et al. Risk of developing type 2 diabetes in adolescents and young adults with autism spectrum disorder: a nationwide longitudinal study. Diabetes Care 2016;39:788–93. [DOI] [PubMed] [Google Scholar]
- 15.Liu CY, Hung YT, Chuang YL, Chen YJ, Weng WS, Liu JS. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Manag 2006;4:1–22. [Google Scholar]
- 16.Zou GA. Modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004;159:702–6. [DOI] [PubMed] [Google Scholar]
- 17.Serdar CC, Cihan M, Yucel D, Serdar MA. Sample size, power and effect size revisited: simplified and practical approaches in pre-clinical, clinical and laboratory studies. Biochem Med 2021;31:010502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Flanigan C, Sheikh A, DunnGalvin A, Brew BK, Almqvist C, Nwaru BI. Prenatal maternal psychosocial stress and offspring’s asthma and allergic disease: a systematic review and meta-analysis. Clin Exp Allergy 2018;48:403–14. [DOI] [PubMed] [Google Scholar]
- 19.Zhou JX, Guo Y, Teng YZ, Zhu LL, Lu J, Hao XM, et al. Maternal anxiety during pregnancy and children’s asthma in preschool age: the Ma’anshan birth cohort study. J Affect Disord 2023;340:312–20. [DOI] [PubMed] [Google Scholar]
- 20.Rosa MJ, Lee AG, Wright RJ. Evidence establishing a link between prenatal and early-life stress and asthma development. Curr Opin Allergy Clin Immunol 2018;18:148–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Picard N, Guenin S, Perrin Y, Hilaire G, Larnicol N. Prenatal diazepam exposure alters respiratory control system and GABAA and adenosine receptor gene expression in newborn rats. Pediatr Res 2008;64:44–9. [DOI] [PubMed] [Google Scholar]
- 22.da Silva Junior CA, Patrone LGA, Biancardi V, Vilela-Costa HH, Marques DA, Cristina-Silva C, et al. Sexually dimorphic effects of prenatal diazepam exposure on respiratory control and the monoaminergic system of neonate and young rats. Pflugers Arch 2022;474:1185–200. [DOI] [PubMed] [Google Scholar]
- 23.Roff AJ, Robinson JL, Hammond SJ, Bednarz J, Tai A, Clifton VL, et al. Maternal asthma during pregnancy and risks of allergy and asthma in progeny: a systematic review and meta-analysis. BJOG 2025;132:1045–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ravn NH, Halling AS, Berkowitz AG, Rinnov MR, Silverberg JI, Egeberg A, et al. How does parental history of atopic disease predict the risk of atopic dermatitis in a child? A systematic review and meta-analysis. J Allergy Clin Immunol 2020;145:1182–93. [DOI] [PubMed] [Google Scholar]
- 25.Wadonda-Kabondo N, Sterne JA, Golding J, Kennedy CT, Archer CB, Dunnill MG; ALSPAC Study Team. Association of parental eczema, hayfever, and asthma with atopic dermatitis in infancy: birth cohort study. Arch Dis Child 2004;89:917–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Costello H, Gould RL, Abrol E, Howard R. Systematic review and meta-analysis of the association between peripheral inflammatory cytokines and generalised anxiety disorder. BMJ Open 2019;9:e027925. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci 2008;31:464–8. [DOI] [PubMed] [Google Scholar]
- 28.Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016;16:22–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Chen VC, Wu SI, Lin CF, Lu ML, Chen YL, Stewart R. Association of prenatal exposure to benzodiazepines with development of autism spectrum and attention-deficit/hyperactivity disorders. JAMA Netw Open 2022;5:e2243282. [DOI] [PMC free article] [PubMed] [Google Scholar]