Effects of combined preconception and prenatal myo-inositol, probiotics, and trace element supplementation on the outcomes of depressed mothers

Abstract

BACKGROUND

Perinatal depression affects 10%-20% of pregnant women and subsequently influences maternal health and fetal development. Concerns over the safety of antidepressants during pregnancy have prompted the exploration of nutritional interventions as adjunct therapies. This study evaluated the impact of combining preconception and prenatal supplementation with myo-inositol, probiotics, and trace elements on mood, quality of life, and fetal development in depressed mothers.

AIM

To identify a novel therapeutic approach to reduce pregnancy complications and improve maternal-fetal health outcomes.

METHODS

This retrospective cohort study included 314 pregnant women who were diagnosed with mild to moderate depression, as determined by a Zung self-rating depression scale score of less than 69. The participants were divided into an intervention group (n = 161) receiving myo-inositol, probiotics, and trace elements and a control group (n = 153) without supplementation. Supplementation commenced 3 months before conception and continued through pregnancy. Psychiatric symptoms and quality of life were evaluated using the positive and negative affect schedule-now, state-trait anxiety inventory, Patient Health Questionnaire-8, and World Health Organization Quality of life Assessment: Brief Version scales preconception and postpartum. Fetal development metrics were assessed via ultrasound, and neonatal outcomes were recorded.

RESULTS

The intervention group presented significant reductions in gestational diabetes mellitus (13.04% vs 23.53%, P = 0.016) and gestational hypertension (3.73% vs 9.15%, P = 0.049). Higher levels of inositol, iron, zinc, and probiotics were observed near term in the intervention group. Postpartum mood assessments indicated lower anxiety and depression scores for the intervention group, with significant improvements in the positive and negative affect schedule-now (P = 0.002), trait anxiety (P = 0.002), and Patient Health Questionnaire-8 (P = 0.018) scores. The World Health Organization Quality of life Assessment: Brief Version scores improved in the psychological (P = 0.041) and environmental (P = 0.009) domains postpartum. Fetal biparietal diameter and femoral length were greater in the intervention group alongside better neonatal body length and reduced neonatal unit admissions (2.48% vs 7.84%, P = 0.031).

CONCLUSION

Combined supplementation with myo-inositol, probiotics, and trace elements from preconception through pregnancy may reduce pregnancy-related complications, enhance mood and quality of life, and improve fetal growth metrics.

Key Words: Myo-inositol; Probiotics; Perinatal depression; Fetal development; Nutritional supplementation; Pregnancy outcomes

Core Tip: This study assessed the effects of combined myo-inositol, probiotics, and trace elements on maternal and fetal health. Results showed reduced gestational diabetes mellitus and hypertension rates, improved postpartum mood, and enhanced quality of life scores. Fetal growth parameters and neonatal outcomes also improved. These findings highlight a promising strategy to reduce complications and improve maternal-fetal health.

INTRODUCTION

The incidence of perinatal depression is a growing public health concern, affecting approximately 10%-20% of women during pregnancy and the postpartum period[1]. This condition not only affects maternal mental and emotional health but also poses significant risks to fetal development and birth outcomes[2]. In recent years research has focused on the potential role of nutritional interventions as adjunct therapies for managing perinatal depression[3]. Although pharmacotherapy remains a primary treatment strategy, concerns about the safety and efficacy of antidepressant use during pregnancy have led to increased interest in alternative or complementary approaches[4].

Myo-inositol, a naturally occurring compound in the vitamin B complex, has gained attention for its potential benefits in modulating mood and metabolic parameters[5]. As a structural component of cell membranes and a precursor to inositol phosphates and other biomolecules, myo-inositol is involved in several biological processes, including insulin signal transduction, cellular osmoregulation, and neurotransmitter regulation[6]. Its role in improving insulin sensitivity and reducing the incidence of gestational diabetes mellitus (GDM) makes it a promising candidate for prenatal supplementation[7]. Research indicates that myo-inositol may alleviate depressive symptoms by modulating neurotransmitter pathways[8].

In addition, the gut–brain axis is increasingly recognized as a pivotal factor in mental health, with probiotics playing a crucial role in this connection[9]. Probiotic supplementation, particularly with strains such as Lactobacillus rhamnosus, has demonstrated efficacy in influencing the gut microbiome, which can affect mood by modulating inflammatory responses and neurotransmitter production[10]. Probiotics may contribute to maintaining a balanced gut microbiota, enhancing the production of neuroactive compounds such as serotonin, thereby exerting potential anxiolytic and antidepressant effects[11].

Trace elements such as zinc and iron are essential for numerous biological functions, including the immune response and oxygen transport, which are vital during pregnancy for maternal health and fetal development[12]. Deficiencies in these micronutrients have been associated with adverse pregnancy outcomes and a heightened risk of mood disorders[13]. Consequently, supplementation with zinc and iron is not only beneficial for preventing deficiencies but also holds promise for alleviating mood disturbances associated with perinatal depression[14].

The integration of myo-inositol, probiotics, and trace elements into a combined supplementation strategy offers a novel, holistic approach to enhancing maternal mood, quality of life, and fetal development[15]. However, the evidence supporting this approach remains limited, and comprehensive studies evaluating the synergistic effects of such a regimen are sparse. Our retrospective cohort study aimed to address this gap by examining the impact of combined preconception and prenatal supplementation on a cohort of pregnant women diagnosed with mild to moderate depression. The purpose of this study was to evaluate the effects of combined preconception and prenatal supplementation with myo-inositol, probiotics, and trace elements on mood, quality of life, and fetal development among depressed mothers.

MATERIALS AND METHODS

Study design

We conducted a retrospective analysis of 314 pregnant women who were diagnosed with depression and treated at our hospital between January 2019 and December 2021. Patient data were obtained from the medical recording system. The participants were divided into two groups on the basis of whether they received combined supplementation with myo-inositol, probiotics, or trace elements before pregnancy. The intervention group comprised 161 women who received the supplements, whereas the control group included 153 women who did not.

The Institutional Review Board and Ethics Committee of the Second Children and Women’s Healthcare of Jinan City approved this study. Given that the research was retrospective and exclusively utilized de-identified patient data, which did not affect patient care or pose any harm, informed consent was unnecessary. This waiver of consent was granted following the regulatory and ethical guidelines governing retrospective research studies.

Eligibility and grouping criteria

Inclusion criteria: Participants were eligible if they were over 18 years old, delivered at our hospital between 2019 and 2021, and had a diagnosis of mild or moderate perinatal depression, as indicated by a Zung self-rating depression scale score of less than 69 (Cronbach’s α = 0.8727)[16]. Additionally, participants had to have received psychological therapy, could read and understand independently, demonstrated good compliance by consuming at least 60% of the prescribed formulations, and had complete case records.

Exclusion criteria: Participants were excluded if they had severe depression requiring medication, were lost to follow-up within 2 years postpartum, had a lifetime diagnosis of bipolar disorder, or currently suffered from alcohol or substance dependence. Other exclusions included cognitive impairment; receiving treatment for HIV, hepatitis B, or hepatitis C; and having an educational level of elementary school or lower.

Procedure

Three months prior to planning conception, participants began taking the supplements, which continued until the end of pregnancy. Both the intervention and control formulations were packaged identically and stored at temperatures between 2-6 °C. These compounds were administered twice daily and presented similar sensory characteristics. Both formulations contained common ingredients: Folic acid (400 μg/day, lot number H12020215, Tianjin Lisheng Pharmaceutical Co., Ltd., China), vitamin D (10 μg/day, lot number H35021450, Sinopharm Holding Xingsha Pharmaceutical (Xiamen) Co., Ltd., China), vitamin B2 (1.8 mg/day, lot number H42020612, Central China Pharmaceutical Co., Ltd.), vitamin B6 (2.6 mg/day, lot number H42020613, Central China Pharmaceutical Co., Ltd.), and vitamin B12 (5.2 μg/day, lot number H14023321, Shanxi Yunpeng Pharmaceutical Co., Ltd.). The intervention formulation also included myo-inositol (4 g/day, lot number H32026275, Jiangsu Suhua Pharmaceutical Group Co., Ltd.), calcium iron zinc tablets (1 g/day, lot number SC10736098210111, Jiangxi Shangshang Industrial Co., Ltd.), and probiotics [Lactobacillus rhamnosus NCC 4007 (CGMCC 1.3724), with a dosage of 5 × 10⁹ CFU/day]. This dosage was chosen based on previous studies indicating that a dose of 5 × 10⁹ CFU/day is effective in improving gut health and modulating the gut-brain axis[17]. The average viable count of refrigerated probiotic products remained within the target range throughout their shelf life. Prenatal, perinatal, and neonatal outcomes were assessed via medical records, and compliance with the trial formulation was monitored by counting the remaining sachets.

Biomarker collection

Maternal biomarkers were assessed at two key timepoints: At the time of planning pregnancy (prior to intervention) and1 week before delivery. After 8 h of fasting, 4 mL of venous blood was collected from each participant. Blood samples were immediately centrifuged at 3000 rpm for 10 min at 4 °C to separate plasma, which was then stored at -80 °C until analysis. The plasma concentrations of folate, homocysteine (indicative of 1-carbon status and other physiological conditions and deficiencies in folate and B-vitamins), riboflavin, flavin mononucleotide (FMN) (indicative of riboflavin status), and myo-inositol were measured in the control and intervention groups via a targeted method based on liquid chromatography-tandem mass spectrometry provided by Bevital, Bergen, Norway. Additionally, blood concentrations of calcium, iron, and zinc were determined via an atomic absorption spectrophotometer (AA800, Jingke Ruida Technology Co., Ltd., Beijing, China). Fecal samples were collected in sterile containers and immediately frozen at -80 °C to preserve microbial DNA integrity. These samples were later used to amplify the genetic sequences of the probiotics via an Applied Biosystems Polymerase Chain Reaction instrument (Thermo Fisher Scientific, United States), and the probiotics were counted.

Mood scale data collection

At the time of planning pregnancy (prior to intervention) and 2 days postpartum, women completed a questionnaire designed to collect data on maternal mood. This process followed an explanation provided by a physician. Two physicians recorded and statistically analyzed the collected data. The positive affect (PA) and negative affect (NA) schedule was employed to evaluate participants’ current mood, achieving an interclass correlation of 0.93[18]. The scores for PA and NA were calculated on a scale of 20 to 80, with higher scores indicating greater levels of PA or NA.

The participants also completed the state-trait anxiety inventory, which includes 40 items and has a Cronbach’s α of 0.837[19]. The state-trait anxiety inventory addresses “state” anxiety (SA), which refers to the presence and severity of current anxiety symptoms, through 20 items. All the items were rated on a four-point Likert scale. Responses for SA items ranged from “not at all” to “very much so”, reflecting participants’ feelings at that moment. For “trait” anxiety (TA) items, responses ranged from “almost never” to “almost always”, indicating the frequency of feelings in general. Items were appropriately reverse-coded and summed to yield SA and TA scores, each ranging from 20 to 80. Higher SA and TA scores indicated higher SA and TA levels, respectively.

The Patient Health Questionnaire-8 (PHQ-8), which has a Cronbach’s alpha of 0.922[20], was used to assess depressive symptoms. The PHQ-8 includes eight items corresponding to the Diagnostic and Statistical Manual criteria for depression, excluding suicidal ideation. The participants rated the frequency of being bothered by each item over the prior 2 weeks via a four-point Likert scale, with responses ranging from “0: Not at all” to “3: Nearly every day”. An overall score was calculated by summing the responses across all the items, resulting in a total score ranging from 0 to 24. Cutoff scores were used to categorize the severity of depressive symptoms: Scores of 5 indicated mild depression; 10 indicated moderate depression; 15 indicated moderately severe depression; and 20 or more indicated severe depression.

Quality of life data collection

At the time of planning pregnancy (prior to intervention) and 2 days postpartum, participants completed the World Health Organization Quality of life Assessment: Brief Version questionnaire, which has a Cronbach’s alpha of 0.90[21]. This questionnaire includes one item from each of the 24 facets of the World Health Organization Quality of life-100 that pertain to perceived quality of life. These facets cover areas such as energy, fatigue, sleep, rest, body image, self-esteem, personal relationships, social support, financial resources, health and social care, and the home environment, along with two additional items addressing overall quality of life and general health.

The questionnaire items were rated on five-point Likert scales, where “1” denotes “very poor; very dissatisfied; not at all; and never” and “5” represents “very good; very satisfied; an extreme amount; extremely; completely; and always”. The items were summed and standardized across four domains: Physical health; psychological; social relationships; and environment. Higher scores indicated greater perceptions of quality or aptitude within each domain.

Fetal development data collection

Ultrasound measurements of fetal biparietal diameter (BPD), femoral length (FL), transverse abdominal diameter, anterior-posterior abdominal diameter, and abdominal circumference (AC) were collected and recorded within 1 week prior to delivery. These measurements were conducted and analyzed by professional ultrasound technicians to ensure data quality.

The BPD was assessed from the outer edge of the parietal bone nearest the probe to the inner edge of the parietal bone on the opposite side via a cross-section of the fetal brain that included key anatomical landmarks such as the hyaline membrane cavity, thalamus, third ventricle, and accumbens compartment. Head circumference was measured on the same plane as the BPD via the ellipse function of the ultrasonic instrument. The AC was obtained perpendicular to the fetal umbilical plexus level, encompassing the spine, gastric vesicles, liver, umbilical vein, skin, and subcutaneous fat. The FL was measured from the greater trochanter to the lateral condyle, ensuring clear visibility of the bones at both ends during the scan.

After birth, two physicians recorded various neonatal data, including gestational age at birth, the number of admissions to the neonatal ward, cases of sepsis, placental weight, placental area, and umbilical cord length. Neonatal length, weight, and head circumference were measured via a neonatal measurement device (Holtain Ltd., Crymych, United Kingdom), with a precision of 0.01 cm.

Statistical analysis

The data were analyzed via SPSS 29.0 statistical software (SPSS Inc., Chicago, IL, United States). For categorical data, n (%) was used for representation. For continuous data with a normal distribution, the mean ± SD format was adopted. P < 0.05 was considered statistically significant.

RESULTS

Demographic and basic data

This retrospective cohort study compared the effects of preconception and prenatal supplementation with myo-inositol, probiotics, and trace elements on mood, quality of life, and fetal development among depressed mothers. Table 1 shows highly similar baseline characteristics between the control group (n = 153) and the intervention group (n = 161). Age, body mass index, marital status, educational level, smoking status, household income, compliance, parity, infant sex, breastfeeding rates, incidence of preterm deliveries, preterm premature rupture of membranes, major postpartum hemorrhage, severe nausea and vomiting, preeclampsia, chronic hypertension with superimposed preeclampsia, and scores on the Zung self-rating depression scale did not significantly differ between the groups (P > 0.05). However, significant differences were observed in the prevalence of GDM, which was lower in the intervention group than in the control group (13.04% vs 23.53%, P = 0.016), and in the occurrence of gestational hypertension, which was also lower in the intervention group (3.73% vs 9.15%, P = 0.049). These results suggest that the intervention regimen may have beneficial effects on reducing certain pregnancy-related complications.

Table 1 Baseline characteristics.

Parameters	Control group (n = 153)	Intervention group (n = 161)	t/χ2	P value
Age (year), mean ± SD	27.25 ± 2.17	27.36 ± 2.61	0.416	0.678
BMI (kg/m2), mean ± SD	23.68 ± 2.74	23.71 ± 2.83	0.084	0.933
Marital status (married/other)	149 (97.39)/4 (2.61)	151 (93.79)/10 (6.21)	2.382	0.123
Educational level			0.555	0.758
Junior high school	51 (33.33)	48 (29.81)
High school and vocational school	42 (27.45)	49 (30.43)
College and above	60 (39.22)	64 (39.75)
Smoker	6 (3.92)	8 (4.97)	0.202	0.653
Household income (monthly)			0.071	0.965
< 10000 RMB	38 (24.84)	39 (24.22)
10000-20000 RMB	78 (50.98)	81 (50.31)
> 20000 RMB	37 (24.18)	41 (25.47)
Compliance	122 (79.74)	133 (82.61)	0.424	0.515
Nulliparous	105 (68.63)	115 (71.43)	0.293	0.588
Infant sex (male/female)	70 (45.75)	77 (47.83)	0.136	0.713
Any breastfeeding	146 (95.42)	157 (97.52)	1.014	0.314
All preterm deliveries (< 37 weeks)	13 (8.50)	9 (5.59)	1.017	0.313
PPROM	9 (5.88)	4 (2.48)	2.282	0.131
Major postpartum hemorrhage	8 (5.23)	4 (2.48)	1.607	0.205
GDM	36 (23.53)	21 (13.04)	5.806	0.016
Severe nausea and vomiting	24 (15.69)	19 (11.80)	1.002	0.317
Gestational hypertension	14 (9.15)	6 (3.73)	3.869	0.049
Preeclampsia	6 (3.92)	4 (2.48)	0.163	0.687
Chronic hypertension with superimposed preeclampsia	5 (3.27)	2 (1.24)	0.694	0.405
Zung self-rating depression scale	45.75 ± 4.26	45.37 ± 4.65	0.75	0.454

Data are presented as n (%). BMI: Body mass index; PPROM: Preterm premature rupture of membranes; GDM: Gestational diabetes mellitus; SD: Standard deviation.

Biomarkers

Table 2 shows comparable values between the two groups in terms of the levels of folate (25.37 ± 3.12 nmol/L vs 24.79 ± 3.46 nmol/L, P = 0.12), homocysteine (7.31 ± 1.17 μmol/L vs 7.28 ± 1.34 μmol/L, P = 0.865), riboflavin (8.78 ± 2.04 nmol/L vs 8.52 ± 1.97 nmol/L, P = 0.241), FMN (12.08 ± 2.57 nmol/L vs 12.41 ± 2.39 nmol/L, P = 0.245), inositol (16.27 ± 3.24 μmol/L vs 15.98 ± 3.61 μmol/L, P = 0.449), calcium (9.12 ± 1.06 mg/dL vs 9.23 ± 1.12 mg/dL, P = 0.352), iron (92.17 ± 10.25 μg/dL vs 93.74 ± 9.76 μg/dL, P = 0.165), zinc (86.33 ± 6.19 μg/dL vs 86.04 ± 7.18 μg/dL, P = 0.706), and probiotics measured as colony-forming units (92.37 ± 16.15 CFU × 10⁸/g vs 93.25 ± 17.24 CFU × 10⁸/g, P = 0.642). These findings indicate that both cohorts were similar with respect to biomarkers prior to the beginning of the supplementation intervention.

Table 2 Comparison of baseline biomarkers before intervention between the two groups.

Variable	Control group (n = 153)	Intervention group (n = 161)	t	P value
Folate (nmol/L)	25.37 ± 3.12	24.79 ± 3.46	1.558	0.12
Homocysteine (μmol/L)	7.31 ± 1.17	7.28 ± 1.34	0.170	0.865
Riboflavin (nmol/L)	8.78 ± 2.04	8.52 ± 1.97	1.176	0.241
FMN (nmol/L)	12.08 ± 2.57	12.41 ± 2.39	1.164	0.245
Inositol (μmol/L)	16.27 ± 3.24	15.98 ± 3.61	0.757	0.449
Calcium (mg/dL)	9.12 ± 1.06	9.23 ± 1.12	0.932	0.352
Iron (μg/dL)	92.17 ± 10.25	93.74 ± 9.76	1.391	0.165
Zinc (μg/dL)	86.33 ± 6.19	86.04 ± 7.18	0.378	0.706
Probiotics (CFU × 108/g)	92.37 ± 16.15	93.25 ± 17.24	0.465	0.642

Data are presented as mean ± SD. FMN: Flavin mononucleotide.

Table 3 shows that compared with the control group, the intervention group had higher levels of inositol (22.37 ± 3.45 μmol/L vs 21.28 ± 4.71 μmol/L, P = 0.021), iron (111.35 ± 10.28 μg/dL vs 107.34 ± 12.28 μg/dL, P = 0.002), zinc (95.34 ± 10.81 μg/dL vs 91.74 ± 9.34 μg/dL, P = 0.002), and probiotics. These indices were measured as colony-forming units (99.64 ± 16.27 CFU × 10⁸/g vs 95.34 ± 15.27 CFU × 10⁸/g, P = 0.016). For biomarkers such as calcium levels, which were marginally greater in the intervention group (10.15 ± 2.27 mg/dL vs 9.66 ± 2.14 mg/dL, P = 0.051), although these differences did not reach statistical significance, they may still hold clinical relevance. The observed trend suggests a potential benefit of supplementation on maternal calcium metabolism, which warrants further investigation in larger studies. The effect size for this comparison was small (Cohen’s d = 0.22), indicating a minor but potentially meaningful difference. Other variables, including folate, homocysteine, riboflavin, and FMN, did not differ significantly between the groups (P > 0.05). These significant differences suggest that the supplementation regimen positively influenced certain biomarkers in the intervention group.

Table 3 Comparison of biomarkers between the two groups 1 week before delivery.

Variable	Control group (n = 153)	Intervention group (n = 161)	t	P value
Folate (nmol/L)	42.28 ± 5.37	42.69 ± 3.46	0.801	0.424
Homocysteine (μmol/L)	3.95 ± 1.03	3.94 ± 1.14	0.063	0.95
Riboflavin (nmol/L)	16.31 ± 3.67	17.08 ± 4.28	1.709	0.088
FMN (nmol/L)	10.35 ± 2.07	10.39 ± 2.34	0.154	0.877
Inositol (μmol/L)	21.28 ± 4.71	22.37 ± 3.45	2.326	0.021
Calcium (mg/dL)	9.66 ± 2.14	10.15 ± 2.27	1.962	0.051
Iron (μg/dL)	107.34 ± 12.28	111.35 ± 10.28	3.130	0.002
Zinc (μg/dL)	91.74 ± 9.34	95.34 ± 10.81	3.156	0.002
Probiotics (CFU × 108/g)	95.34 ± 15.27	99.64 ± 16.27	2.413	0.016

Data are presented as mean ± SD. FMN: Flavin mononucleotide.

Maternal mood

Table 4 shows comparable scores between the two groups in terms of PA (27.36 ± 3.15 vs 27.42 ± 3.62, P = 0.866), NA (67.65 ± 10.25 vs 69.47 ± 9.71, P = 0.107), SA (9.44 ± 2.88 vs 9.52 ± 3.01, P = 0.806), TA (12.35 ± 2.36 vs 12.64 ± 2.61, P = 0.302), and PHQ-8 (27.36 ± 3.15 vs 27.42 ± 3.62, P = 0.866). These findings indicate that the participants had similar mood-related characteristics at baseline in both cohorts.

Table 4 Comparison of baseline mood scale scores before the intervention between the two groups.

Variable	Control group (n = 153)	Intervention group (n = 161)	t	P value
PANAS-NOW
PA	12.35 ± 2.36	12.64 ± 2.61	1.048	0.296
NA	27.36 ± 3.15	27.42 ± 3.62	0.166	0.868
STAI
State anxiety	67.65 ± 10.25	69.47 ± 9.71	1.614	0.108
Trait anxiety	71.34 ± 8.18	72.35 ± 8.02	1.112	0.267
PHQ-8	9.44 ± 2.88	9.52 ± 3.01	0.241	0.81

Data are presented as mean ± SD. PANAS-NOW: Positive and negative affect schedule-now; PA: Positive affect; NA: Negative affect; STAI: State-trait anxiety inventory; PHQ-8: Patient Health Questionnaire-8.

The intervention group presented higher scores for TA (16.34 ± 3.14 vs 15.26 ± 3.02, P = 0.002), suggesting improved mood states (Figure 1). Conversely, the intervention group presented lower scores for PA (25.57 ± 3.12 vs 26.33 ± 2.55, P = 0.018), NA (58.22 ± 6.82 vs 60.21 ± 6.37, P = 0.008), SA (7.56 ± 2.53 vs 8.24 ± 2.62, P = 0.02), and PHQ-8 scores (25.57 ± 3.12 vs 26.33 ± 2.55, P = 0.018), indicating lower anxiety and depressive symptoms in the intervention group than in the control group. These results further suggest that the supplementation regimen may contribute positively to mood and anxiety levels in postpartum individuals.

Figure 1 Comparison of scale scores between the two groups 2 days after delivery. ^aP < 0.05; ^bP < 0.01. Statistical methods: Independent samples t-test; n = 314 (control group: n = 153; intervention group: n = 161). PA: Positive affect; NA: Negative affect; SA: State anxiety; TA: Trait anxiety; PHQ-8: Patient Health Questionnaire-8.

Quality of life score

Table 5 shows comparable scores between the two groups in terms of physical health scores (45.68 ± 6.84 vs 46.12 ± 6.72, P = 0.57), psychological scores (33.13 ± 6.77 vs 33.65 ± 7.11, P = 0.509), social relationship scores (42.25 ± 7.12 vs 41.98 ± 7.62, P = 0.748), and environment scores (43.66 ± 7.87 vs 42.97 ± 8.12, P = 0.446). These findings indicate that participants in both groups had similar quality-of-life profiles at baseline prior to any intervention.

Table 5 Comparison of baseline World Health Organization Quality of life Assessment: Brief Version scores before intervention between the two groups.

Variable	Control group (n = 153)	Intervention group (n = 161)	t	P value
Physical health	45.68 ± 6.84	46.12 ± 6.72	0.569	0.570
Psychological	33.13 ± 6.77	33.65 ± 7.11	0.661	0.509
Social relationships	42.25 ± 7.12	41.98 ± 7.62	0.322	0.748
Environment	43.66 ± 7.87	42.97 ± 8.12	0.762	0.446

Data are presented as mean ± SD.

The intervention group had significantly higher scores in the psychological domain (38.75 ± 7.36 vs 37.26 ± 5.34, P = 0.041) and the environment domain (47.31 ± 6.21 vs 45.22 ± 7.65, P = 0.009), suggesting improvements in psychological well-being and environmental perception with supplementation (Figure 2). Although the physical health scores were higher in the intervention group (22.36 ± 6.07 vs 21.25 ± 5.32), this difference did not reach statistical significance (P = 0.086). The scores for social relationships were not significantly different between the groups (47.65 ± 6.41 vs 46.62 ± 7.64, P = 0.199). These findings suggest a potential benefit of supplementation in enhancing the psychological and environmental aspects of quality of life in postpartum mothers.

Figure 2 Comparison of World Health Organization Quality of life Assessment: Brief Version scores between the two groups 2 days after delivery. ^aP < 0.05; ^bP < 0.01. Statistical methods: Independent sample t-test; n = 314 (control group: n = 153; intervention group: n = 161).

Fetal development

Ultrasound examination conducted 1 week before delivery revealed a significantly greater BPD of 9.38 ± 1.13 cm in the intervention group than in the control group (9.12 ± 1.05 cm; P = 0.042) and a longer FL of 8.24 ± 0.79 cm vs 8.04 ± 0.87 cm (P = 0.036) (Figure 3). Other parameters, including the abdominal anteroposterior diameter, thoracic anteroposterior diameter, and AC, were not significantly different between the groups, with P values of 0.205, 0.622, and 0.501, respectively. These findings suggest that combined preconception and prenatal supplementation may positively influence certain aspects of fetal growth.

Figure 3 Comparison of ultrasound examination findings 1 week before delivery between the two groups. A: Biparietal diameter; B: Femoral length; C: Abdominal anteroposterior diameter; D: Thoracic anteroposterior diameter; E: Abdominal circumference. ^aP < 0.05; ^bP < 0.01. Statistical methods: Independent sample t-test; n = 314 (control group: n = 153; intervention group: n = 161). All measurements are in centimeters (cm). BPD: Biparietal diameter; FL: Femoral length; APAD: Abdominal anteroposterior diameter; TAD: Thoracic anteroposterior diameter; AC: Abdominal circumference.

Table 6 shows the assessment scores for basic neonatal conditions at birth. The neonates in the intervention group were born at a slightly earlier gestational age (39.15 ± 1.09 weeks vs 39.42 ± 1.23 weeks, P = 0.036) and had a significantly greater body length at birth (49.71 ± 1.56 cm vs 49.25 ± 1.35 cm, P = 0.005). Although the birth weight was greater in the intervention group (3.28 ± 0.52 kg vs 3.18 ± 0.51 kg), this difference did not reach statistical significance (P = 0.088; Cohen’s d = 0.20). Despite the lack of statistical significance, the moderate effect size suggests potential clinical relevance. The head circumference was also slightly smaller in the intervention group (34.57 ± 2.81 cm vs 35.14 ± 2.36 cm, P = 0.053; Cohen’s d = 0.21), which is close to reaching statistical significance and may warrant further investigation. Placental weight, placental area, and umbilical cord length were not significantly different between the groups (P > 0.05 for all variables). Notably, the rate of admission to the neonatal unit was significantly lower in the intervention group (2.48% vs 7.84%, P = 0.031). The incidence of neonatal septicemia was not significantly different between the groups (P = 0.456). These findings suggest that the supplementation regimen may contribute to positive neonatal outcomes, including reduced neonatal unit admissions.

Table 6 Comparison of basic neonatal conditions at birth between the two groups.

Variable	Control group (n = 153)	Intervention group (n = 161)	t/χ2	P value
Gestational age at birth	39.42 ± 1.23	39.15 ± 1.09	2.111	0.036
Birth weight (kg)	3.18 ± 0.51	3.28 ± 0.52	1.714	0.088
Body length (cm)	49.25 ± 1.35	49.71 ± 1.56	2.820	0.005
Head circumference	35.14 ± 2.36	34.57 ± 2.81	1.945	0.053
Placental weight (g)	541.55 ± 15.82	540.19 ± 17.52	0.721	0.472
Placental area (cm2)	175.69 ± 17.64	174.74 ± 16.78	0.492	0.623
Umbilical cord length (cm)	55.12 ± 17.85	57.36 ± 18.94	1.074	0.284
Admission to neonatal unit, n (%)	12 (7.84)	4 (2.48)	4.658	0.031
Neonatal septicemia, n (%)	2 (1.31)	0 (0)	0.556	0.456

Data are presented as mean ± SD.

DISCUSSION

The selection of biomarkers in this study was guided by their established roles in perinatal health and potential interactions with the administered supplements. Myo-inositol has been shown to enhance insulin sensitivity and improve glucose metabolism, crucial for preventing GDM. Elevated levels of myo-inositol have also been linked to improved neuroplasticity and neurotransmitter signaling, potentially alleviating depressive symptoms. Zinc, an essential trace element, plays a vital role in immune function and oxidative stress reduction, both important for maternal and fetal well-being. Additionally, probiotics such as Lactobacillus rhamnosus have been associated with reduced inflammation and improved gut-brain axis communication, contributing to mood stabilization.

This retrospective cohort study examined the effects of combined preconception and prenatal supplementation with myo-inositol, probiotics, and trace elements on mood, quality of life, and fetal development among pregnant women diagnosed with mild to moderate depression. One of the most intriguing insights from this study is the significant reduction in pregnancy-related complications observed in the intervention group, specifically the lower prevalence of GDM and gestational hypertension. The inclusion of myo-inositol, which has been implicated in improved insulin signaling and carbohydrate metabolism, likely contributed to these findings[22]. Myo-inositol plays a key role as a precursor to inositol phosphates that mediate insulin action, and its supplementation has been demonstrated to modulate insulin resistance during pregnancy, which could explain the reduced incidence of GDM in our study cohort[23]. Additionally, the trace element zinc could contribute to improved insulin function and the regulation of blood pressure, helping mitigate the risks associated with gestational hypertension[24].

The observed increase in certain blood indices in the intervention group provides further insights into the biological underpinnings of these outcomes. The elevated levels of inositol, iron, and zinc, along with increased probiotic concentrations observed near term, are worth mentioning. The role of myo-inositol in cellular signaling and osmoregulation may positively affect fetal and maternal tissue responses to stress and nutrient transfer[7,22]. Furthermore, elevated iron and zinc levels can ensure optimal oxygen transport and immune function for both mothers and fetuses[25,26]. Probiotics, specifically Lactobacillus rhamnosus, may contribute to maintaining a healthy gut microbiome, inhibiting pathogenic bacteria, and potentially lowering inflammation, a factor linked to depressive symptoms[27,28].

In terms of maternal mood, the results indicated a notable improvement among those receiving the supplementation, as evidenced by lower anxiety and depression scores postpartum than in the controls. The reduction in the NA and TA scores emphasized the potential mood-stabilizing benefits of this supplement combination[29]. This could be partially attributed to the role of probiotics in the gut-brain axis where they have been postulated to synthesize or influence neurotransmitters such as serotonin and gamma-aminobutyric acid, which are crucial for mood regulation[30,31]. Additionally, normalizing inositol levels could improve neuroplasticity and neurotransmitter signaling, thereby reducing depressive symptoms[5]. The enriched nutritional environment, supported by optimized mineral and vitamin status, likely facilitates biochemical processes essential for neurotransmitter function, potentially reducing mood disturbances associated with depression[32].

The quality of life enhancements in the psychological and environmental domains observed in the intervention group could be attributed to interconnected improvements in mood and physiological well-being[33]. A robust relationship between mood and quality of life in postpartum women has been noted previously. In our study supplementation likely strengthened resilience against stress and promoted a positive maternal psychological state[34]. Probiotics, which modulate the gut microbiota, might reduce systemic inflammation, a contributor to mood disorders and a diminished quality of life[35]. Furthermore, maternal empowerment from improved metabolic and nutritional status during pregnancy could promote self-esteem and environmental control, contributing to perceived improvements in quality of life[36].

Assessments of fetal development indicated that the intervention group exhibited favorable outcomes, such as increased BPD and FL measured by ultrasound, along with increased neonatal body length at birth. These outcomes may be directly influenced by the role of myo-inositol in cell growth and differentiation, trace element contributions to fetal development, and probiotics ensuring maternal health and lowering adverse outcomes[37,38]. Myo-inositol might support placental function and fetal growth; furthermore, zinc and iron ensure critical cellular proliferation and hemoglobin synthesis[7]. Such nutritional enrichment can create a conducive intrauterine environment, promoting optimal fetal development[6]. The significant reduction in neonatal unit admissions from 7.84% in the control group to 2.48% in the intervention group (P = 0.031) represents a 68.4% relative risk reduction. This decrease suggests fewer infants needing immediate postnatal care, potentially lowering healthcare costs and improving long-term outcomes for both infants and their families.

Recent randomized controlled trials on myo-inositol during pregnancy have shown benefits in reducing GDM and other complications[39]. However, our study extended these findings by demonstrating additional benefits, including improved maternal mood, quality of life, and reduced neonatal morbidity. The inclusion of probiotics and trace elements alongside myo-inositol is a novel approach that addresses multiple aspects of maternal and fetal health. Compared with previous studies, our research provided a more comprehensive evaluation of the synergistic effects of combined supplementation. For example, while Santamaria et al[40] focused on GDM reduction, our findings indicated that adding probiotics and trace elements can also mitigate gestational hypertension and neonatal unit admissions. These results highlight the potential of a holistic nutritional strategy to optimize both maternal and neonatal outcomes.

Although certain variables such as calcium levels, neonatal birth weight, and head circumference did not reach traditional statistical significance, they exhibited small to moderate effect sizes, suggesting potential clinical relevance. Specifically, despite the non-significant difference in calcium levels, considering the increased demand for calcium during pregnancy and its importance for fetal bone development, these trends warrant further exploration. Additionally, changes in neonatal birth weight and head circumference may reflect the impact of the intervention on fetal growth. Future studies should aim to verify these trends through larger sample sizes or extended follow-up periods to determine if these variables indeed hold clinical significance.

This study revealed multiple practical implications and important directions for future research. Although retrospective analyses cannot confirm causality, the observed correlations encourage further exploration of combining nutritional supplements with traditional therapies for pregnant women with mild to moderate depression. Particularly, in situations where pharmacological interventions face challenges, supplement regimens can serve as an adjunctive strategy to promote maternal and neonatal health. For instance, tailoring supplement formulations based on regional dietary habits, genetic backgrounds, and socioeconomic statuses may enhance their efficacy and applicability.

However, this study had certain limitations, such as potential selection bias and inherent constraints from the retrospective design. These issues should be addressed in future prospective and randomized controlled trials. Expanding the socioeconomic backgrounds, geographic locations, and cultural differences of study participants can validate the generalizability and external validity of the findings. Extending the follow-up period can help assess the impact on postnatal development and maternal mental health, particularly at different stages of child growth (e.g., preschool, adolescence), to comprehensively understand the long-term benefits of interventions.

Future studies should optimize sample selection and increase sample sizes to include populations from diverse socioeconomic backgrounds and regions, ensuring broad applicability of the findings. Measurement indicators should incorporate new biomarkers reflecting maternal-fetal health or use advanced imaging techniques to monitor fetal growth, thereby obtaining more comprehensive data support. Adjusting supplement dosages and combinations based on individual differences is crucial. Genetic testing can identify which populations benefit most from specific supplements, and micronutrient ratios can be adjusted based on regional dietary habits to maximize intervention effects and minimize adverse reactions. Conducting multicenter collaborative studies will further enhance the representativeness and reliability of the data, providing scientific evidence for developing personalized nutritional interventions.

CONCLUSION

Our study suggested that combined preconception and prenatal supplementation with myo-inositol, probiotics, and trace elements may confer significant benefits in improving pregnancy outcomes, mood, and quality of life in depressed mothers. The findings underscored the value of such nutritional interventions, providing an integrative approach to address complex physiological and psychological demands during pregnancy. As research progresses, these insights can shape guidelines for enhancing prenatal care, contributing to healthier pregnancies and neonatal development.