Investigation of Hypothalamic Pituitary Adrenal Axis and Oxytocinergic System Changes in a Pragmatic Randomized Controlled Feasibility Trial of Acupuncture for Antenatal Depression

Abstract

Background:

Antenatal depression is common and associated with detrimental impacts on women and their families. Disrupted neuroendocrine functioning is reported in women experiencing perinatal mental health disturbances. Preliminary randomized controlled trial (RCT) evidence suggests acupuncture may provide a safe and effective adjunct treatment; however, underlying mechanisms of effect are unclear. We conducted an RCT examination of acupuncture for the management of antenatal depressive symptomologies, which included oxytocinergic and hypothalamic pituitary adrenal (HPA) axis system evaluations. This article reports postintervention changes to cortisol: dehydroepiandrosterone (DHEA) ratios, and oxytocin (OT) hormone concentrations.

Methods:

Fifty-seven women with Edinburgh Postnatal Depression Scale (EPDS) scores ≥13 were randomized to receive individually tailored depressed specific acupuncture, progressive muscle relaxation (PMR) attention comparator, or treatment as usual (TAU). Weekly 1-h sessions were conducted for 8 weeks (24–31 of pregnancy). Preintervention and postintervention saliva samples were collected.

Results:

Postintervention mean cortisol: DHEA ratio differences were not significantly predicted by group allocation (n = 46, p = 0.065). Two-group comparisons demonstrated cortisol: DHEA ratios were significantly increased and predicted by group allocation when acupuncture was compared to TAU (p = 0.039); however, not between acupuncture and PMR (p = 0.179), or PMR and TAU (p = 0.421). Postintervention OT concentrations were not significantly predicted by group allocation.

Limitations:

Small sample size and posthoc analysis

Conclusion:

Findings suggest positive regulation of the HPA axis may be an underlying mechanism by which acupuncture provided the significant improvements to antenatal depression, stress, and distress observed in this cohort. Trial Registration: Registered on March 19, 2015, with the Australian New Zealand Clinical Trials Registry (ACTRN12615000250538).

Introduction

Antenatal depression and conventional treatment

Antenatal depression is common, affecting ∼12% of women,¹ with higher rates being reported in specific at-risk groups.² Detrimental consequences include maternal self-neglect;³ obstetric and birth complications;^4,5 disrupted maternal-infant bonding;^6,7 postnatal depression;^5,8 and suicide.^9,10 For children, dysregulated social, emotional, and physiological development,^11
–13 and life-long and inter-generationally transmitted mental health (MH) vulnerabilities^3,13 are reported.

Antenatal antidepressant use is reported to be between 3% and 6% in Europe, and around 10% in the United States.^14,15 After adjustment for the confounding influences of underlying illness, it is suggested that risks of exposure to offspring may be minimal^16

–19; however, some cautionary views remain regarding possible undesirable effects.^20
–22 Previous experience with or personal views regarding incomplete medication effectiveness^23,24 and unpleasant side effects^23,25,26 has led some women to express decisional conflict regarding antenatal use,^24,27,28 with only one-third in one study considering antidepressants if recommended.²⁹ In addition, antidepressant response rates are reported to range from 10% to 15%³⁰; however, study design limitations, including low to moderate certainty of evidence, and unclear to high risk of bias, have led to some speculation regarding real-world effectiveness.^22,30
–32 As a result, additional options are needed, such as acupuncture,^22,33 for which preliminary evidence is promising.^34

–37

Disrupted neuroendocrine system functioning in women with perinatal MH disturbances

Disrupted neuroendocrine system functioning in women experiencing perinatal MH disturbances is postulated to be an underlying mechanism for observed detrimental consequences,^38,39 with both overactivation and underresponsiveness of the hypothalamic pituitary adrenal (HPA) axis being reported. For example, early life adversity and significant stress exposure before and during pregnancy are associated with elevated cortisol awakening responses (CARs)^40,41 and evening cortisol levels, as well as blunted morning HPA axis secretions during pregnancy.^41,42 Lowered antenatal CARs,⁴³ and hypocortisolemia have also been observed under conditions of prolonged distress.⁴⁴ Antenatally detected placental and HPA axis dysfunctions have additionally been associated with antenatal depression,^45

–48 anxiety,⁴⁹ mood disorders,^45,46 and postpartum depressive symptomology;^38,45,47 adverse birth outcomes;^38,50 and altered cortisol responses,^51
–53 maladaptive behaviors,^39,48 and MH vulnerabilities in children.^54,55

Disruptions to the oxytocinergic system have likewise been associated with perinatal MH disturbances, with similar findings of dysregulated secretions being reported. Lower pregnancy oxytocin (OT) levels, for example, are associated with anxiety⁵⁶; perinatal depressive symptomologies^57
–59; and lower infant birth weights.⁶⁰ Significant associations between prenatal anxiety and depression and reduced postnatal OT levels have similarly been reported.⁶¹ Elevated perinatal OT levels have also been observed in depressed and anxious postpartum women,⁶² and associated with lower gestational age at birth and increased childhood emotional disorders.⁶³ Elevated OT levels have interestingly been associated with higher psychosocial stress, fewer depressive symptoms, and more sensitive maternal behaviors,⁶⁴ potentially due to homeostatic upregulation to counteract environmental impacts.^62,64

Regulatory effects of acupuncture

Mechanistic investigations into acupuncture suggest broad regulatory influences to neuroendocrine and autonomic nervous systems.^65,66 Studies of impacts to the HPA axis report bidirectional findings, possibly reflecting homeostatic mechanisms to restore sympathetic/parasympathetic balance.^66,67 For example, acupuncture demonstrated significant inhibitory effects on muscle sympathetic nervous system surges in cardiac failure patients experiencing acute stress.⁶⁸ Significant reductions in pain and cortisol levels were also seen in patients after electroacupuncture (EA) for osteoarthritis of the knee.⁶⁹ Schneider et al. similarly described significantly decreased heart rate and cortisol levels in patients receiving acupuncture for irritable bowel syndrome.⁷⁰ Significant reductions in depression scores and cortisol levels were also reported in two studies utilizing EA,^71,72 and in one performing auricular acupuncture.⁷³

In contrast, Cabıoğlu et al. reported acupuncture increased cortisol and adrenocorticotropic hormone levels, and weight loss in overweight patients.^66,74 Similarly, the cumulative effect of acupuncture for acute pain and stress resulted in increased cortisol concentrations, that correlated with self-reported improvements in stress and pain scores over time (English abstract only).⁷⁵ Magarelli et al. likewise reported acupuncture for in vitro fertilization resulted in significantly higher cortisol and prolactin levels, reflecting “a trend toward more normal fertile cycle dynamics” (p. 1870).⁷⁶ We found no evaluation of acupuncture impacts on OT concentrations; however, 18 studies provided possible indirect effects on synthetic OT requirement during labor (see Discussion section).

This study aimed to assess whether acupuncture could exert regulatory impacts on neuroendocrine functioning in women experiencing antenatal depression. Specifically, the aim was to determine whether acupuncture recipients experienced postintervention alterations to cortisol: dehydroepiandrosterone (DHEA) ratios, and OT concentrations, compared to a progressive muscle relaxation (PMR) comparator and treatment as usual (TAU) groups. This article reports the biomarker findings from the randomized controlled trial (RCT) component of a mixed-methods study. Qualitative^23,77 and quantitative³⁷ components have previously been reported.

Methods

The RCT protocol is published, and methods detailed.⁷⁸ Study approval was granted by Western Sydney University (WSU) and South-Western Sydney Local Health District (SWSLHD) HREC committees, approval numbers H10993 and 14/LPOOL/400, respectively. The Australian New Zealand Clinical Trials Registry Number is 12615000250538. Key features are summarized in Table 1. Fifty-seven women at gestation (G) week 24, with Edinburgh Postnatal Depression Scale (EPDS) scores ≥13 were randomized to semistandardized depression-specific acupuncture (n = 19), attention comparator PMR (n = 19), or TAU (n = 19). Weekly 1-h sessions were commenced at G 24, for 8 weeks, or until all treatments were completed.

Table 1.

Details of Employed Randomized Controlled Trial Methodologies

RCT method	Description of procedure
Recruitment	Recruitment period: February 2015 to August 2016. Women detected at the first antenatal hospital appointment with elevated EPDS scores, and/or risk factors for MH disturbances were provided with study details. Posters advertising the study were also displayed in the antenatal clinic. Before enrolment, signed consent forms were collected from participants.
Sample size	Fifty-seven eligible women were enrolled in this study.
Randomization	An independent researcher computer generated the randomization schedule of random “blocks of three,” at a ratio of 1:1:1 (acupuncture, PMR, TAU), n = 19 per group.
Concealment	The independent researcher provided randomized group allocations in concealed envelopes.
Blinding	Blinding of participants and the administrator was not possible due to the nature of both interventions.
Interventions	Semistandardized depression-specific acupuncture or attention comparator PMR.
Interventions	All sessions were provided in a one-to-one format, for 1 h duration, by the first author, a qualified acupuncturist with, at that time, 14 years of clinical experience.
Acupuncture protocol	Adapted from previously published depression-specific protocols for depressed general and antenatal populations, with additional incorporations from high = profile traditional East Asian medicine practitioners and scholars. CONSORT and STRICTA guidelines were followed, and checklists published with reported RCT findings.^a
PMR protocol	Adapted from a previously published protocol developed by the third author (C.A.S.).^b

Ormsby et al.³⁷

Smith et al.¹³⁸

CONSORT, Consolidated Standards of Reporting Trials; EPDS, Edinburgh Postnatal Depression Scale; MH, mental health; PMR, progressive muscle relaxation; RCT, randomized controlled trial; STRICTA, Standards for Reporting Interventions in Clinical Trials of Acupuncture; TAU, treatment as usual.

Saliva collection

Saliva was chosen due to noninvasiveness and ease of sample collection, as well as validity of methods.^79,80 Preintervention samples and enrolment data were collected from all groups immediately before randomization at G 24, and before commencement of the first session (acupuncture or PMR). Postintervention samples were collected at the end of intervention data collection point at G 31. For acupuncture and PMR groups, sample collection occurred immediately after the completion of the eighth treatment (at G31+, if a session had been missed).

To minimize the impacts of cortisol^81,82 and DHEA circadian rhythms,⁸³ as well as pulsatile releases of OT,⁸⁴ each individual's postintervention samples were collected as close as possible to the time of day that the preintervention sample had been collected (by S.M.O.), without causing unnecessary inconvenience to the participant. Participants deposited 4 mL of saliva using the passive drool technique into prechilled sample tubes (15 mL sterile CELLSTAR polypropylene tubes, Cat. No. 188271; Greiner Bio-One, Frickenhausen, Germany), resting tubes on ice in between deposits. Collected samples were stored at −20°C.

Hormone assays

The Enzo Life Sciences assay method incorporating a concentration step was selected for reliable OT detection.⁸⁰ Salimetrics protocols were utilized for cortisol and DHEA determination.^85,86 We assessed cortisol and DHEA in reference to each other,⁸⁷ as cortisol and DHEA are antagonistic,⁵³ and the ratio more reliably detects HPA system dysregulation.^87
–89 In addition, ratios calculated at each time point are independent of the effects of time, thereby neutralizing the impacts of within-individual preintervention and postintervention sample collection time variation.

The OT concentration step was performed utilizing Waters Corporation Sep-Pak C 18 200 mg reversed-phase resin columns (Cat. No. WAT 054945; Waters Corporation, Milford, MA). OT analysis was conducted according to the Enzo Life Sciences protocol manual “Oxytocin ELISA 96 Well Kit” (Cat. No. ADI-900-153A-0001, Farmingdale, NY). Plates were read using a spectrophotometer (POLARstar Omega; BMG LABTECH, Offenburg, Germany) at 405 nm. Minor protocol modifications are detailed in Supplementary Table S1.

Supernatant volumes remaining after OT assessment were thawed on ice before cortisol and DHEA assays. The Salimetrics protocol manuals “Salivary Cortisol Enzyme Immunoassay Kit” (Cat. No. 1-3002) and “Salivary DHEA Enzyme Immunoassay Kit” (Cat. No. 1-1202) were followed as recommended.^85,86 Plates were read using a spectrophotometer (POLARstar Omega; BMG LABTECH) at 450 nm. Samples were plated in duplicate to provide mean concentrations for each assay.

Statistical analysis

Analyses were performed utilizing SPSS software (version 24.0). Ranges and means of sample collection characteristics were explored using descriptive statistics. Data were log transformed to provide normal distributions (Supplementary Figs. S1–S8). The generalized linear model was chosen to test whether mean postintervention cortisol: DHEA ratios were predicted by mean preintervention cortisol: DHEA ratios, or group allocation. The mean postintervention cortisol: DHEA ratio was the dependent variable compared to group allocation as a factor (BY), and preintervention cortisol: DHEA ratios as a covariate (WITH). Into this model, group allocation, preintervention cortisol: DHEA ratios, and the intercept were also incorporated.

Two adjustments were included, one for the presence of a male fetus, as higher maternal cortisol concentrations were reported in women carrying males in one study (< G 30),⁹⁰ although this finding was not replicated in another.⁹¹ Second, as cortisol levels reportedly increase,^81,90,91 and DHEA declines^92,93 with gestational age, an adjustment for the number of days in the intervention was included, as completion gestational ages varied. The model was adjusted for the presence of a male fetus as a factor (BY), and the number of days in the intervention as a covariate (WITH). Into the model, group allocation, preintervention cortisol: DHEA ratio, presence of a male fetus, the intercept, and the number of days in the intervention were included. Posthoc exploratory analyses were performed if findings neared significance.

While OT release is reportedly not subject to diurnal variation,^94,95 some reports do suggest OT concentrations increase with gestational age^95,96; hence, an identical analysis was performed to determine between-group postintervention to preintervention OT concentration differences.

Results

Analysis of variation in time of participants' preintervention and postintervention sample collections

Forty-six women completed the intervention, 17 in acupuncture, 11 in PMR, and 18 in TAU. While postintervention samples were collected as close as possible to the same time of the day that an individual's preintervention sample had been taken, this was not always possible. In majority of cases however, participants' preintervention and postintervention samples were collected within 1 h of each other (mean 0.7174 ± standard deviation 0.49), as well as at similar times of the day (12.35 ± 2.584 and 1.07 ± 2.265 pm, respectively), which was typically several hours after the greatest diurnal flux of cortisol and DHEA.^85,86 The longest time difference between preintervention and postintervention sample collection for any individual was 8 h; however, both samples were collected after peak diurnal releases. In addition, as previously mentioned, the calculation of cortisol/DHEA ratios at each time point negates the potential impacts of variation in time collection.

Group preintervention and postintervention biomarker ranges

Within-individual, within-group, and between-group variations in preintervention and postintervention hormone levels were broad ranging (Table 2). Preintervention OT detection ranged from 11.15 to 203.87 pg/mL, with similar postintervention ranges being observed (12.43–284.24 pg/mL). Wide ranges were also seen for precortisol and postcortisol (0.14–0.77 and 0.05–0.89 μg/dL), and DHEA concentrations (14.91–315.52 and 16.82–277.13 pg/mL), respectively. Directions of change for individual's postintervention to preintervention cortisol, DHEA, and OT concentrations were also highly variable, with increases, decreases, and relatively stable levels being observed (Supplementary Tables S2 and S3).

Table 2.

Participant Preintervention and Postintervention Biomarker Concentration Ranges

Concentration (lowest to highest)	PMR (n = 11)	Acupuncture (n = 17)	TAU (n = 18)
Precortisol (μg/dL)	0.18–0.37	0.14–0.76	0.14–0.77
Postcortisol (μg/dL)	0.21–0.49	0.05–0.61	0.14–0.89
Pre-DHEA (pg/mL)	54.51–315.52	14.91–303. 01	19.67–203.60
Post-DHEA (pg/mL)	30.98–277.13	16.82–138.12	19.34–205.63
Pre-OT (pg/mL)	38.53–175.14	33.89–155.14	11.15–203.87
Post-OT (pg/mL)	23.60–119.59	23.47–284.24	12.43–149.22

DHEA, dehydroepiandrosterone; OT, oxytocin; PMR, progressive muscle relaxation; TAU, treatment as usual.

Examination of group postintervention to preintervention cortisol: DHEA ratio differences

Logged transformed cortisol: DHEA ratios were calculated for each individual at both the preintervention and postintervention time points (n = 46). Changes in postintervention to preintervention cortisol: DHEA ratio means by group allocation were then calculated and plotted as a histogram in Figure 1. As can be seen, mean postintervention cortisol: DHEA ratios increased in both the acupuncture and PMR groups, with a more noticeable increase being seen in the acupuncture group, whereas TAU group mean postintervention cortisol: DHEA ratios decreased.

FIG. 1.

Histogram of group preintervention to postintervention cortisol: DHEA ratio means. DHEA, dehydroepiandrosterone.

Analysis of between-group postintervention to preintervention cortisol: DHEA ratio changes

Findings for both the unadjusted and adjusted models are presented in Table 3. In the unadjusted model, logged preintervention cortisol: DHEA ratios were significantly predictive of logged postintervention cortisol: DHEA ratios (p = 0.000), whereas randomized group allocation approached significance (p = 0.065). In the adjusted model, logged preintervention cortisol: DHEA ratios were also significantly predictive of logged postintervention cortisol: DHEA ratios (p = 0.000); however, the presence of a male fetus (p = 0.211) and number of days in the intervention (p = 0.617) were not. Group allocation again approached significance (p = 0.068). In both models, the intercept was found to be significant (p = 0.000).

Table 3.

Model of Effects Prediction of Postntervention Cortisol: Dehydroepiandrosterone Ratio Changes by Variable

Variable	Unadjusted model	Adjusted model
Logged preintervention cortisol: DHEA ratio	0.000	0.000
Group allocation	0.065	0.068
Intercept	0.002	0.029
Presence of a male fetus	N/A	0.211
Days in the intervention	N/A	0.617

Dependent variable logged postintervention cortisol: DHEA ratio; alpha levels were set at p ≤ 0.05.

DHEA, dehydroepiandrosterone; N/A, not applicable.

As logged postintervention to preintervention cortisol: DHEA ratio changes by group allocation approached significance, a posthoc exploratory analysis was performed by removing one group at a time, to enable two-group comparisons (Table 4).

Table 4.

Model of Effects Dual Group Prediction of Logged Postintervention Cortisol: Dehydroepiandrosterone Ratio Changes by Variable (Unadjusted Model)

Variable	ACU vs. UC	ACU vs. PMR	PMR vs. UC
Logged preintervention cortisol: DHEA ratio	0.000	0.000	0.000
Group allocation	0.039	0.179	0.421
Intercept	0.000	0.022	0.060

Dependent variable logged postintervention cortisol: DHEA ratio; alpha levels were set at p ≤ 0.05.

DHEA, dehydroepiandrosterone; PMR, progressive muscle relaxation.

A significant difference in postintervention to preintervention cortisol: DHEA ratios was observed between the acupuncture and TAU groups (p = 0.039), whereas not between acupuncture and PMR (p = 0.179), or PMR and TAU (p = 0.421). In all three cases, preintervention cortisol: DHEA ratios were significantly predictive of those obtained at postintervention (p = 0.000); however, the intercept was significant in the acupuncture to TAU (p = 0.000) and acupuncture to PMR group comparisons (p = 0.022), and not for TAU to PMR (p = 0.060). As the presence of a male fetus and the number of days in the intervention did not significantly impact upon postintervention cortisol: DHEA ratios in the three-group comparison adjusted model, two-group comparisons were conducted in the unadjusted model only.

Examination of group postintervention to preintervention OT concentration differences

Logged transformed mean OT concentrations were calculated for each individual at both the preintervention and postintervention time points (n = 46). Changes in postintervention to preintervention OT concentration means by group allocation were calculated and plotted as a histogram (Fig. 2), to determine if any impact of the intervention could be seen. It was observed that between-group postintervention to preintervention OT changes appeared to be minimal.

FIG. 2.

Histogram of group logged preintervention to postintervention OT means. OT, oxytocin.

Analysis of between-group postintervention to preintervention OT changes

Findings for both the unadjusted and adjusted models are presented in Table 5. In the unadjusted model, preintervention OT concentrations were significantly predictive of postintervention OT concentrations (p = 0.004), whereas randomized group allocation was not (p = 0.321). In the adjusted model, preintervention OT concentration was also significantly predictive of postintervention OT concentration (p = 0.002); however, group allocation (p = 0.271), presence of a male fetus (p = 0.159), and the number of days in the intervention (p = 0.439) were not significantly predictive of postintervention OT concentration. In the unadjusted model, the intercept was significant (p < 0.000), whereas in the adjusted model, this was no longer the case (p = 0.076).

Table 5.

Model of Effects Prediction of Logged Postintervention Oxytocin Hormone Concentration Changes by Variable

Variable	Unadjusted model	Adjusted model
Preintervention OT concentration	0.004	0.002
Group allocation	0.321	0.271
Intercept	0.000	0.076
Presence of a male fetus	N/A	0.159
Days in the intervention	N/A	0.439

Dependent variable logged postintervention OT concentrations; alpha levels were set at p ≤ 0.05.

OT, oxytocin.

Correlational analysis between mood scores and biomarkers of depression and stress

As the main RCT findings demonstrated statistically significant reductions to depression (EPDS), stress (Depression, Anxiety, Stress Scale-21), and distress (Kessler 6) scores when acupuncture was compared to PMR and TAU³⁷ (data not shown), a correlational analysis was also conducted to explore associations between preintervention and postintervention mood questionnaire scores and biomarker findings; however, no significant association was noted (Supplementary Table S4).⁹⁷

Limitations

Significantly increased postintervention cortisol: DHEA ratios in the acupuncture group compared to TAU should be cautiously interpreted, due to the small sample size and posthoc analysis. Attrition from the PMR group was high at 42%, and loss of data may have compromised the effectiveness of the comparison.⁹⁸

Collection of samples at the same time of day was attempted, however, dependent upon participants' availability. In addition, weekly acupuncture and PMR sessions were scheduled however on occasion a treatment was unable to be conducted, due to participants' competing commitments; nonetheless, such occurrences emulate normal clinical practice, and if flexibility had not been incorporated, further drop out may have ensued.

Discussion

This is the first acupuncture RCT incorporating an antenatal assessment of changes to cortisol: DHEA ratios, and OT concentrations in women exhibiting depressive symptomologies. We observed wide-ranging within-individual, group, and between-group variability in both preintervention and postintervention cortisol, DHEA, and OT concentrations.

When postintervention to preintervention differences were assessed, significant differences in cortisol: DHEA ratios were observed when acupuncture was compared to TAU (p = 0.039). Specifically, ratios were seen to increase, possibly reflecting a homeostatic normalization of a potentially disrupted neuroendocrine system, due to the “general adaptation syndrome” (GAS) response.⁹⁹ According to Selye, the body's first response to stressors is the initial acute “alarm,” followed by a “resistance or adaptation phase” if stressors continue, and an “exhaustion” phase if prolonged. HPA axis hyperreactivity may therefore reflect more recent stress responses, whereas hyposecretion/blunted activity may indicate ongoing and/or significant exposures.^46,100

It has been suggested that different disorders may, in addition, result in distinct HPA responses,^46,101 for example, post-traumatic stress disorder being associated with hypocortisolemia.⁴⁶ Furthermore, if multiple MH morbidities are present, bidirectional responses may ensue, making findings difficult to interpret.^46,102 With respect to this cohort, we hypothesize that most women were in the “exhaustion” phase of the GAS, due to chronic stress exposure. Participants provided details in support of this position, namely: early life adversity exposure; depressive episodes being chronic in nature;^23,97 stressors being ongoing;³⁷ and previous personal and/or family histories of MH disturbances.⁹⁷ The broad range in cortisol and DHEA concentrations observed in this population may therefore reflect participants' different genetic predispositions, stages in the GAS response, and MH complexities/co-morbidities, all of which can contribute to altered HPA axis reactivity.^102

–105

Two other studies have assessed cortisol: DHEA ratio responses to therapeutic interventions in populations experiencing MH disturbances. In the first, postintervention cortisol: DHEA ratios elevated in schizophrenic patients responding to medication,¹⁰⁶ a finding in alignment with this study. In the second, elevated cortisol: DHEA ratios in patients with major depressive disorder were unchanged after cognitive therapy,¹⁰⁷ possibly reflecting treatment-resistant depression, blunted HPA axis responsiveness for a chronic condition, MH complexity, or study design impacts.

With respect to acupuncture impacts on HPA axis activity in perinatal populations, we identified two small studies assessing differing outcomes. In the first, twice-daily auricular acupressure for 4 consecutive days postbirth (at shen men), significantly reduced cortisol levels, heart rate, anxiety symptoms, and fatigue in women recovering from caesarean section.¹⁰⁸ The findings in this study may similarly reflect a homeostatic restoration toward normal HPA axis functioning, as suggested to have occurred in our intervention.

In the other, retained auricular acupuncture press tacks (at shen men, muscle relaxation, tension, anxiety 1 and 2) did not result in statistical between-group differences in State-Trait Anxiety Inventory-State anxiety scores or cortisol levels in lactating mothers who birthed preterm infants with very low birth weights. However the control comprising tooth prick pressure being applied to the same points, before the taping on of a noninserting modified sham tack,¹⁰⁹ likely elicited an acupressure response, and thus was not “inert,”^110,111 thereby possibly confounding findings.

The wide variability in OT concentrations observed in this cohort undoubtedly also reflected the complexity of oxytocinergic system effects during pregnancy, as well as under the influence of varied environmental and co-morbid physical and MH disturbances. In addition, OT exerts broad influences to many physiological functions other than those relating to reproduction, connection, and socialization, such as the growth and function of the neocortex, autonomic nervous system and vagal nerve regulation, and anti-inflammatory and antioxidant effects.¹¹² This intricacy potentially contributed to why no postintervention between-group differences in OT concentrations was identifiable in this study population.

Other authors have also reported intraindividual variability in OT concentrations in perinatal populations. Galbally et al., for example, described considerable variability in OT concentrations among individuals across the perinatal period.⁶³ Likewise, Prevost et al. reported broad individual antenatal concentrations ranging from 50 pg/mL to over 2000 pg/mL, with an overall increase in concentrations being seen by the third trimester for most women.⁹⁶ Levine et al. additionally demonstrated wide intraindividual prenatal and early postpartum OT levels among healthy women; however, stable, increasing, decreasing, and both increasing and decreasing levels were seen.¹¹³ Galbally et al. similarly suggested such varied OT findings are not surprising, considering the complex, and interinfluencing relationships between endocrine systems and external environments.⁶³

No other mechanistic evaluation of acupuncture for regulation of the oxytocinergic system in perinatal populations with MH disturbances was identified. However, 18 clinical studies assessing acupuncture, transcutaneous electrical nerve stimulation (TENS), or acupressure influences to the onset/processes of labor were identified. Of these, nine reported significantly reduced numbers of synthetic OT units used and/or numbers of women needing OT induction/augmentation,^{114

–122} possibly reflecting upregulation of endogenous OT expression after acupuncture.^66,123,124

Others described differing outcomes, including significantly superior labor enhancement when acupuncture plus intravenous OT was compared to intravenous OT alone,¹²⁵ nonsignificantly reduced OT units being required,¹²⁶ no difference in OT requirement,^{127

–132} and acupuncture increasing OT requirement.¹³³ Findings are cautiously interpreted due to methodological issues, including small/moderate sample sizes, lack of study detail (abstracts only in two cases), nonrandomization in five studies, overall study design heterogeneity, and minimalistic acupuncture point prescriptions and provider training. Indeed, nonclassically indicated acupuncture points for labor enhancement were selected in some studies,¹³⁴ possibly reflecting inadequate training and nonconsultation with acupuncturists.^98,135

With respect to the attention comparator, PMR, much like “sham” acupuncture, may also not be truly “inert.”⁹⁸ Reports of PMR effectiveness are mixed; however, some suggest benefits to antenatal stress, disturbed mood, and perinatal outcomes,¹³⁶ as well as depression in general populations. Suggested benefits include increased production of endorphins, and enhanced calmness, coping, and sense of self-control.¹³⁷ Despite these possible benefits, attrition from the PMR group was high. Reasons provided for dropout differing from those described across all groups (child minding difficulties and conflicting time constraints) was a short-lasting benefit that did not outweigh the level of commitment required.⁹⁷ An alternative attention comparator could therefore be considered; however, if also minimally effective, the same reasons provided for dropout may occur. A larger sample size factoring in high attrition potential may nonetheless overcome this issue.

The findings of the main RCT have been reported elsewhere,³⁷ along with a qualitative evaluation of women's experiences of receiving acupuncture for antenatal mood disturbances.²³ Briefly, statistically significant reductions to depression, stress, and distress scores were observed when acupuncture was compared to PMR and TAU. These findings aligned with acupuncture recipients' reports of feeling more relaxed, experiencing improved MH symptomologies, and having greater resilience to life stressors after treatment.²³ Taken together, along with the potential rectification of a blunted HPA axis response, it is possible that the acupuncture provided in this study resulted in a homeostatic restoration toward balance, by reducing and/or buffering the effects of stress, which resulted in improved overall psychological well-being and depression severity.

Conclusion

In this study, acupuncture appeared to increase cortisol: DHEA ratios, possibly reflecting homeostatic upregulation of a disrupted HPA axis system, due to prolonged stress exposure in this population. Findings are cautiously interpreted due to the small sample size. Further explorations appear warranted.

Availability of Data and Materials

Participant preintervention and postintervention biomarker concentrations are provided in Supplementary Tables S2 and S3. Raw enzyme-linked immunosorbent assay (ELISA) plate data can be provided by the corresponding author upon request.

Footnotes

Acknowledgments

The authors with to thank the late Dr. Joanne Lind, and Christine Chiu for assistance with the molecular biology aspects of this project; WSU and SWSLHD ethics committees; Campbelltown and Camden hospital midwives and administration staff for assistance with the study; Sharon Ellis, antenatal services manager, for her key role in the running of the trial; Helio Supply Co. for the kind donation of acupuncture equipment; Drs. Paul Fahey and Kingsley Agho, for assistance with statistical analyses; WSU, NICM, and the Australian Government for funding sources; and Prof. Richard Harris for publication suggestions.

Authors' Contributions

S.M.O. designed the study, obtained ethics approval, conducted the RCT and laboratory techniques, analyzed the data, and wrote the article. H.G.D. and C.A.S. assisted with all aspects of the design and running of the study and provided direction and critical appraisal of the writing of the article.

Author Disclosure Statement

S.M.O. is a private practicing acupuncturist. S.M.O. and C.A.S. declare that, as a medical research institute, NICM Health Research Institute receives research grants and donations from foundations, universities, government agencies, individuals, and industry. Sponsors and donors provide untied funding for work to advance the vision and mission of the Institute. The project that is the subject of this article was not undertaken as part of a contractual relationship with any organization, other than the funding declared in the “Funding Information” section. It should also be noted that NICM Health Research Institute conducts clinical trials relevant to this topic area, for which further details can be provided on request. H.G.D. declares no competing interests.

Funding Information

S.M.O. obtained funding for this study in the format of a WSU School of Science and Health Research and Training Scheme, Australian Postgraduate Award, and NICM Health Research Institute Top-Up Scholarship from a private donor.

Supplementary Material

Supplementary Figure S1

Supplementary Figure S2

Supplementary Figure S3

Supplementary Figure S4

Supplementary Figure S5

Supplementary Figure S6

Supplementary Figure S7

Supplementary Figure S8

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

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