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. 2026 Feb 14;2025:1557–1566.

Evaluating the Effectiveness of Complementary and Integrative Health Therapies in Preventing Postpartum Depression: A Target Trial Emulation Study

Huixue Zhou 1,6, Yiye Zhang 2, Zhenxing Xu 2, Chang Su 2, Kelvin Lim 3, Andrea Johnson 4, Nili Solomonov 5, Fei Wang 2, Rui Zhang 6
PMCID: PMC12919610  PMID: 41726527

Abstract

Subject: This study aims to evaluate the effectiveness of Complementary and Integrative Health (CIH) therapies in reducing the incidence and severity of Postpartum Depression (PPD) using real-world data and target trial emulation.

Methods: Using electronic health records (EHR) from a large healthcare system, we emulated target trials for CIH approaches including acupuncture, chiropractic, aromatherapy, and omega-3 fatty acids. CIH usage was identified and extracted from clinical notes using natural language processing (NLP) techniques. Logistic regression-based propensity score matching was employed to address confounding factors. The primary outcome was the incidence of PPD within 12 months postpartum, defined by diagnostic codes or antidepressant initiation. Secondary outcomes included changes in PHQ-9 scores and subgroup analyses by treatment type.

Results: For the primary outcome, none of the treatments significantly reduced PPD risk intervals (CIs). However, omega-3 fatty acids and chiropractic care significantly reduced PHQ-9 scores in the treatment groups (omega-3 fatty acids: p<0.001, chiropractic care: p = 0.021), with no comparable improvements in controls. Aromatherapy showed mixed results, with reduced severe depression in the treatment group but increased severity in controls. Acupuncture had no significant effect (p > 0.05). These findings suggest that omega-3 fatty acids and chiropractic care may alleviate PPD symptoms, while the effects of aromatherapy, acupuncture and chiropractic remain inconclusive and warrant further investigation.

Conclusion: This study provides approach to evaluating CIH interventions in real-world settings. These findings underscore the importance of integrating non-traditional treatment options into clinical practice to improve outcomes for individuals affected by PPD.

Introduction

Postpartum Depression (PPD) affects ~18% of women [1] and predicts poor long-term outcomes for mothers and infants [2-4]. PPD is underdiagnosed [5] and undertreated: 50-70% of women with symptoms go undiagnosed, and only a fraction receives treatment [6-8].

Traditional treatments for PPD, such as pharmacotherapy and psychotherapy are efficacious. However, many women seek alternatives and remain symptomatic even when completing full course of psychotherapy or antidepressant treatment [9]. Barriers such as side effects, personal preferences, and concerns about the safety of antidepressants during breastfeeding often limit their use [10]. As a result, there is growing interest in Complementary and Integrative Health (CIH) therapies as potential alternatives or adjuncts to conventional treatments [11,12]. According to a national survey, 37% of pregnant women and 28% of postpartum women aged 19 to 49 in the United States reported using CIH in the past 12 months, compared to 40% of nonpregnant/non-postpartum women [13].

However, the evidence base for many CIH approaches remains limited, with a lack of well-designed studies and randomized controlled trials (RCTs) specifically focused on PPD [14,15]. For example, while some studies have explored interventions such as omega-3 fatty acids, acupuncture, bright light therapy, and exercise, the data are often insufficient to draw definitive conclusions [16].

In recent years, the availability of large-scale real-world data (RWD), such as electronic health records (EHR) and administrative claims, has opened new avenues for research. These data sources enable the emulation of randomized clinical trials (RCTs) through methods like target trial emulation, which aims to estimate treatment effects while addressing challenges such as confounding control [17]. This approach holds significant promise for evaluating the efficacy of CIH therapies in real-world settings.

Despite the potential of RWD, significant challenges remain. As highlighted in our previous study [18,19], structured EHR data often lack specificity in documenting CIH therapies. For example, a single Current Procedural Terminology (CPT) code may encompass a wide range of CIH interventions, making it difficult to conduct target trial emulation for specific therapies. Furthermore, limited documentation of CIH in EHRs poses additional barriers to research [20, 21].

To address these challenges, this study aims to leverage target trial emulation to assess the effectiveness of selected CIH interventions in reducing the incidence and severity of PPD, specifically acupuncture, chiropractic care, aromatherapy, and omega-3 fatty acids. We utilize clinical notes to identify and analyze CIH usage, overcoming limitations in structured EHR data. By addressing gaps in the existing literature and utilizing innovative methodologies, this research aims to contribute to a deeper understanding of non-traditional treatment options for PPD, ultimately informing clinical practice and improving outcomes for affected individuals and their families.

Methods

Data Source and Cohort Construction

Data were extracted from the University of Minnesota Academic Health Center’s Information Exchange (AHC-IE) clinical data repository (CDR). We emulated the target trial using a pregnancy cohort spanning 2001 to 2024, which included patient demographics, medical diagnoses, drug prescriptions, anthropometric measurements, laboratory test results and Patient Health Questionnaire-9 (PHQ-9) scores. This study was Approval from the University of Minnesota’s Institutional Review Board (STUDY00022892). Eligible patients were required to have a diagnosis of pregnancy, identified using International Classification of Diseases (ICD) codes, and at least one year of continuous enrollment in inpatient or outpatient services prior to treatment initiation.

Target Trial

The target trial aimed to evaluate the effect of CIH treatments on PPD in pregnant individuals. Below is a description of the target trial’s design:

Eligible criteria

Eligible subjects were aged 18 years or older and had a documented pregnancy. Individuals with missing data on birth year or sex were excluded. All eligibility criteria had to be met at baseline.

Treatment assignment

In the target trial, eligible individuals would have been randomly assigned to either the complementary and integrative health (CIH) treatment group or the non-treatment group. For each CIH trial, in this observational study, adults who underwent CIH treatment were identified as the CIH treatment group. For each individual in the CIH treatment group, an age-, race- and baseline comorbidity-matched individual who had not yet received CIH treatment was randomly selected from the eligible pool to serve as a non-treatment control. Treatment initiation was defined as the first date of CIH treatment. Baseline comorbidities included selected conditions from the pregnancy cohort and established risk factors for PPD, each defined using relevant ICD-9/10 codes. The time zero for both the treatment and control groups was defined as the date of CIH treatment initiation for the matched treatment group.

Outcome

The primary outcome, PPD, was defined based on the occurrence of any of the following within 12 months after childbirth, as recorded in electronic health record (EHR) data: (1) a diagnosis of PPD, (2) a new diagnosis of depression, or (3) initiation of antidepressant treatment. The secondary outcome was the Patient Health Questionnaire-9 (PHQ-9) scores, which were further classified into severity levels: 0-4 (no depression), 5-9 (mild depression), 10-14 (moderate depression), 15-19 (moderately severe depression), and 20-27 (severe depression).

Follow-up

Follow-up for each eligible individual began since CIH treatment was initiated and ended at the earliest of the following events: death, loss to follow-up, non-live birth, administrative end of follow-up (12 months from baseline), or occurrence of the PPD outcome.

Causal associations of interest

The causal association of interest in this study is the effect of initiating CIH treatment during pregnancy on the subsequent risk of PPD. We estimated the observational analog of the intention-to-treat (ITT) effect, meaning participants were analyzed in the treatment group once CIH initiation was documented, regardless of adherence or completion.

Target Trial Emulation

Using the pregnancy cohort described above, we emulated the target trial to estimate the effect of each CIH treatment on PPD, as outlined in Table 1. The eligibility criteria of the target trial were replicated, requiring patients to have a documented diagnosis of pregnancy (identified using ICD codes) and at least one year of continuous enrollment in inpatient or outpatient services prior to treatment initiation. Additionally, patients were required to have continuous enrollment in inpatient or outpatient services within one year of delivery. To minimize the potential confounding effects of antidepressant use, individuals taking selective serotonin reuptake inhibitors (SSRIs) or norepinephrine reuptake inhibitors (NSRIs) during CIH treatment were excluded.

Table 1.

Target Trial Protocol and Corresponding Observational Study Emulation.

Aspect Target Trial Trial Emulation
Eligibility Criteria
  • -

    Aged 18 years or older and pregnant.

  • -

    Excluded: Missing birth year or sex data.
  • -

    Replicated eligibility criteria from the target trial.

  • -

    Required a diagnosis of pregnancy (ICD codes) and ≥1 year of continuous enrollment prior to treatment initiation and Full 1-year follow-up period after delivery.
Treatment Assignment
  • -

    Random assignment to CIH treatment group or non-treatment group.

  • -

    CIH group: Received CIH treatments during pregnancy (e.g., acupuncture, aromatherapy, chiropractic care) without antidepressants.

  • -

    non-treatment group: Received standard postpartum care without CIH interventions and antidepressants.

  • -

    Time Zero:

    Treatment group: Date of CIH initiation.

    Control group: Date of Matched index date.
  • -

    CIH group: Identified as individuals who underwent CIH treatment without antidepressants.

  • -

    Control group:

    Controls were selected through 1:1 propensity score matching on Age, race and comorbidity from an eligible pool of non-CIH users, excluding any subjects with antidepressant use during the CIH treatment period.

  • -

    Time Zero: Same as target trial.
Outcome
  • -
    Primary outcome: Postpartum depression (PPD) within 12 months after childbirth, defined as:
    1. Diagnosis of PPD.
    2. New diagnosis of depression.
    3. Initiation of antidepressant treatment.
  • -

    Same as target trial: PPD defined using EHR data within 12 months postpartum, based on diagnosis or antidepressant treatment.
Follow-Up
  • -

    Follow-up began at the first clinical visit where CIH treatment was initiated.

  • -
    Ended at the earliest of:
    1. Death.
    2. Loss to follow-up.
    3. Non-live birth.
    4. Administrative end of follow-up (12 months from baseline).
    5. Occurrence of PPD outcome.
  • -

    Same as target trial: Follow-up period and endpoints replicated using observational data.
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To address confounding, we adopted linear regression models for propensity score estimation (LR-PS) and followed the inverse probability of treatment weighting (IPTW) framework. Propensity scores were estimated using LR-PS, incorporating baseline covariates including based on demographic variables, pregnancy-related complications, and comorbidities (e.g., diabetes, hypertension, anxiety, depression, substance use, and antidepressant use). The selection of these covariates was informed by our previous studies [22,23]. Additionally, we applied 1:1 nearest-neighbor matching without replacement to construct the matched cohort. Covariate balance was assessed using standardized mean differences (SMD), with an SMD < 0.1 indicating negligible imbalance.

Identification of CIH treatments

To identify Complementary and Integrative Health (CIH) treatments, we employed a word embedding tool (e.g., word2vec) [24], trained on clinical notes from the CDR, to expand terms related to CIH approaches. This method also captured lexical variants, including misspellings, within our corpus. Using this approach, we identified CIH treatments from clinical notes, consistent with our previous study [18]. The CIH group included individuals who received one of the following therapies: acupuncture, aromatherapy, chiropractic care or omega-3 fatty acids.

Statistical Analysis

The primary analysis utilized Cox proportional hazards regression to model time-to-event data for postpartum depression diagnosis, reporting adjusted hazard ratios with corresponding 95% confidence intervals. All models incorporated adjustments for age, race, baseline depression status, baseline anxiety status and other baseline comorbidities. For continuous measures of depressive symptom severity, we employed paired t-tests to evaluate within-group changes in PHQ-9 scores from baseline to follow-up, while between-group comparisons were conducted using independent t-tests. For comparative analyses of PHQ-9 depression severity levels, we employed x2 test or the G-test based on sample size. All hypothesis tests were two-tailed with statistical significance defined at α = 0.05.

Sensitivity Analysis

To evaluate the robustness of our findings and address potential biases, we conducted sensitivity analyses using the following approaches: We performed subgroup analyses by including patients who were also taking anti-depression medications during CIH treatment, which were excluded in the primary analysis. Additionally, we also evaluated the sensitivity of our results by testing an alternative propensity score model using the k-nearest neighbors (k-NN) machine learning approach to assess the robustness of our confounding adjustment method.

Results

A total of 25,480 individuals in the CDR pregnancy cohort met the eligibility criteria. To ensure comparability between treatment groups, we employed LR-PS for each CIH treatment emulation, incorporating covariates such as age, BMI, race, ethnicity, and medical histories (e.g., diabetes, hypertension, anxiety, depression, substance use, and antidepressant use). After matching, the SMDs for most variables decreased significantly, demonstrating improved balance across all treatment groups as shown in Figure 1. For instance, all covariates achieved balance post-matching (SMDs < 0.1) in the Omega-3 Fatty Acids, chiropractic care, and aromatherapy groups.

Figure 1.

Figure 1.

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Standardized Mean Differences for Matched and Unmatched Groups in Different CIH Trial Emulations.

Results in primary outcome analyses

The results presented in Table 2 indicate that none of the evaluated treatments demonstrated a statistically significant reduction in the risk of PPD compared to their respective control groups. This conclusion is supported by the fact that all adjusted hazard ratios (HRs) included 1 within their 95% confidence intervals (CIs), indicating no significant difference in PPD risk between the treatment and control groups.

Table 2.

The incidence of postpartum depression by 1 year after delivery.

treatment Postpartum depression, n/N (%) Hazard ratio (95% CI)
Treatment Control Unadjusted Adjusted
Acupuncture 15/67 13/67 1.26(0.60, 2.64) 2.14(0.82, 3.56)
Aromatherapy 114/549 98/549 0.95 (0.72,1.25) 0.88 (0.66,1.16)
Omega-3 fatty acids 164/998 182/998 1.41(1.09,1.80) 1.26(0.98,1.64)
Chiropractic care 125/492 107/492 1.37(1.04,1.79) 1.27(0.97,1.69)
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Notably, the adjusted HRs for acupuncture exhibited wider confidence intervals (0.82–3.56), suggesting greater variability in its effect estimates. This variability may stem from a smaller sample size (n=67 per group) or heterogeneity in treatment responses. In contrast, aromatherapy showed relatively narrower confidence intervals (0.66–1.16), reflecting more consistent but still non-significant effects. Omega-3 fatty acids and chiropractic care had HRs closer to the null (1.26 and 1.27), with confidence intervals marginally crossing 1.0 (0.98–1.64 and 0.97–1.69), implying a lack of significant protective or harmful effects on postpartum depression risk.

Results in secondary outcome analyses

The treatment groups showed significant reductions in depression scores with omega-3 fatty acids and chiropractic care. As indicated in Table 3, the paired t-test results demonstrated a statistically significant effect for omega-3 fatty acids (p<0.001) and chiropractic care (p = 0.021). These results suggest that omega-3 supplementation and chiropractic care could be beneficial in reducing symptoms of postpartum depression. The Figure 2 visually corroborates these findings, with lower median PHQ-9 scores post-treatment in these groups compared to baseline, suggesting consistent symptom improvement. Importantly, no comparable improvements were observed in the control groups, further supporting the potential efficacy of omega-3 fatty acids and chiropractic care as treatments for postpartum depression.

Table 3.

Paired t-test Results for PHQ-9 Score Changes Within Groups.

Treatment Group Mean Difference Std. Dev. Confidence Interval P-value
Acupuncture control -0.106 3.989 (-3.172,2.960) 0.938
treatment 2.258 6.001 (-3.292, 7.809) 0.358
Aromatherapy control -0.305 3.012 (-1.548, 0.939) 0.618
treatment -0.117 4.402 (-1.130,0.895) 0.818
Omega-3 fatty acids control 1.437 4.450 (-9.617,12492) 0.632
treatment 1.681 4.373 (0.903, 2.458) <0.001
Chiropractic care control -0.280 3.805 (-3.461,2.902) 0.841
treatment 1.328 5.813 (0.203, 2.453) 0.021
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Figure 2.

Figure 2.

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Distribution of PHQ-9 Across Groups.

For aromatherapy, the χ2 test (Table 4) revealed significant changes in the distribution of depression levels for both the control (p=0.029) and treatment (p<0.001) groups following aromatherapy. However, the results were mixed. As shown in the Figure 3, there was an increase in the number of individuals with severe depression in the control group and decrease of individuals with minimal symptoms, suggesting a potential worsening of symptoms over time. In contrast, the treatment group showed a reduction in severe depression cases, indicating that aromatherapy may have a beneficial effect for some individuals. For acupuncture, no significant changes in depression scores were observed in either the treatment or control groups following acupuncture. The paired t-test results for both groups were non-significant (p=0.358 for treatment, p=0.938 for control), indicating that acupuncture did not have a measurable impact on reducing postpartum depression symptoms in this study.

Table 4.

Longitudinal Changes in Depression Severity Categories Within Groups.

Treatment Group N χ 2 P
Acupuncture control 9 11.062 0.271
treatment 7 11.287 0.257
Aromatherapy control 25 51.988 0.029
treatment 75 48.321 <0.001
Omega-3 fatty acids control 3 6.592 0.159
treatment 124 57.104 <0.001
Chiropractic care control 8 7.333 0.501
treatment 105 25.257 0.065
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Figure 3:

Figure 3:

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Distribution of PHQ-9 Levels Across Groups.

Statistical comparisons using independent t-tests for PHQ-9 scores and χ2 tests for PHQ-9 severity levels revealed no significant differences between treatment and control groups at either baseline or post-treatment time points across all CIH interventions (acupuncture, aromatherapy, omega-3 fatty acids, and chiropractic care), as detailed in Tables 5 and 6 (all p-values > 0.05).

Table 5.

Between-Group Comparisons of Depression Scores Using Independent t-tests.

Treatment Group N Mean Difference Std. Dev. P-value
Control Treatment Control Treatm ent Control treatment
Acupuncture baseline 9 7 7.537 8.288 5.621 5.295 0.803
After treatment 9 7 7.643 6.030 4.831 2.506 0.465
Aromatherapy baseline 25 75 6.755 7.226 4.121 5.516 0.699
After treatment 25 75 7.060 7.343 5.377 5.306 0.820
Omega-3 fatty acids baseline 3 124 7.963 7.587 3.173 5.263 0.902
After treatment 3 124 6.526 5.906 2.673 4.137 0.798
Chiropractic care baseline 8 105 10.140 9.441 4.195 5.379 0.723
After treatment 8 105 10.420 8.113 4.996 5.231 0.234
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Table 6.

Between-Group Differences in Depression Severity Classifications.

Treatment Group N χ 2 P
Acupuncture baseline 16 6.992 0.136
After intervention 16 4.825 0.305
Aromatherapy baseline 100 4.413 0.353
After intervention 100 2.178 0.703
Omega-3 fatty acids baseline 127 2.049 0.726
After intervention 127 1.282 0.864
Chiropractic care baseline 113 4.511 0.341
After intervention 113 4.667 0.254
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Sensitivity Analysis

To assess the robustness of our findings, we conducted sensitivity analyses by varying key methodological assumptions. First, we included patients who were also taking anticipants (e.g., SSRIs or SNRIs) during CIH treatment, which were excluded in the primary analysis. Despite the inclusion of this subgroup, the primary outcome for all CIH treatment and secondary outcome for acupuncture, aromatherapy and omega-3 fatty acids remained consistent, as the proportion of patients taking anti-depression medications was small relative to the overall sample and did not significantly alter the effect estimates. Additionally, we evaluated an alternative propensity score model using k-NN. Covariate balance was reassessed in the sensitivity analysis, with SMD remaining below 0.1 for aromatherapy, chiropractic care, and omega-3 fatty acids, indicating negligible imbalance. This finding is consistent with a previous study [25]. These analyses confirmed the robustness of our primary findings to variations in study population and methodological choices.

Discussion

These key findings of this study suggest that omega-3 fatty acids and chiropractic care were associated with significant reductions in PPD symptoms, as evidenced by both statistical significance and clinically meaningful effect sizes. For omega-3 fatty acids, these results corroborate existing evidence of antidepressant effects [26,27], potentially mediated through their anti-inflammatory properties and neuroprotective mechanisms. The observed benefits of chiropractic care, while less extensively studied in PPD specifically, align with emerging literature suggesting that effective management of persistent postpartum pain may help mitigate concurrent depressive symptoms [28]. In contrast, acupuncture and aromatherapy showed more modest effects, with varying statistical significance across models. This variability may reflect differences in treatment protocols, patient adherence, or the mechanisms underlying different interventions.

This study offers valuable insights into the effectiveness of CIH interventions for preventing and alleviating PPD. By employing target trial emulation and RWD, it fills significant gaps in current research and provides a thorough assessment of alternative treatments for PPD. There are notable challenges in conducting rigorous trials for CIH therapies, such as limited documentation in electronic health records, variability in treatment protocols, and challenges in precisely identifying CIH interventions. These factors often lead to a lack of robust evidence supporting the efficacy of CIH therapies, especially for conditions like PPD. Our research tackles these issues by using target trial emulation and RWD to examine the impact of various CIH interventions, including acupuncture, aromatherapy, chiropractic care, and omega-3 fatty acids on the incidence and severity of PPD. By extracting CIH usage data from clinical notes and implementing stringent propensity score matching, our study introduces a novel methodology for evaluating CIH therapies in practical, real-world scenarios.

Despite its strengths, this study has several limitations. First, the reliance on EHR data introduces the possibility of misclassification or underreporting of CIH interventions, particularly given the limited documentation in EHR. Second, while we used a word2vec-based approach to identify CIH terms from unstructured text, this method lacked formal validation. Future work will include expert-guided term validation and explore LLMs to enhance extraction performance and semantic coverage. Third, while propensity score matching and sensitivity analyses were employed to address confounding, residual bias may still exist due to unmeasured variables.

This study estimates the observational analog of the ITT effect, which provides a conservative yet policy-relevant measure of CIH effectiveness by evaluating outcomes based on treatment initiation rather than adherence. This mirrors real-world clinical decision-making, where patients may initiate but not necessarily complete a therapy. While this approach enhances generalizability and avoids post-treatment bias, it may underestimate the true effect size, especially for interventions with variable compliance.

To strengthen generalizability and robustness, future research should incorporate additional real-world data sources such as insurance claims or multi-institutional EHR networks, allowing for larger, more diverse cohorts and more granular assessment of treatment adherence. Prospective studies with standardized CIH protocols and improved NLP-based identification pipelines will also be essential to validate findings and advance our understanding of CIH’s potential in preventing or managing PPD.

Conclusion

In conclusion, this study contributes to the growing body of evidence supporting the use of CIH therapies PPD and demonstrates the utility of RWD for emulating CIH-related trials. By demonstrating the efficacy of CIH and highlighting the potential of target trial emulation for real-world data analysis, this research underscores the importance of integrating non-traditional treatment options into clinical practice. Our study highlights the potential clinical benefits of acupuncture, aromatherapy, chiropractic care and omega-3 fatty acids for PPD, expanding possible first-line treatments for this vulnerable and untreated population.

Acknowledgement and Funding

This work was supported by the National Institutes of Health’s National Center for Complementary and Integrative Health under grant numbers R01AT009457 and U01AT012871, the National Institute on Aging under grant number R01AG078154, the National Cancer Institute under grant number R01CA287413, the National Institute of Diabetes and Digestive and Kidney Diseases under grant number R01DK115629, and the National Institute on Minority Health and Health Disparities under grant number 1R21MD019134-01. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.

Figures & Tables

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