Effect of patient and partner preconceptional nutraceutical supplementation on the onset of natural pregnancy: a retrospective study.

Infertility affects roughly 15% of couples worldwide. Although assisted reproductive technologies (ART) have advanced, treatment success remains suboptimal, prompting interest in non-invasive adjuncts such as lifestyle optimization and nutraceutical supplementation 1 . Preconception supplementation has been linked to higher pregnancy and live birth rates 2 , 3 , and nutrient-rich dietary patterns correlate with increased likelihood of live birth 4 . While individual micronutrients—including folic acid 5 , vitamin D, zinc 6 , selenium, and omega-3 fatty acids 7 —have been associated with fertility benefits, evidence on combined formulations in infertile or subfertile couples is still limited. The effect of multi-nutrient supplementation on time to pregnancy requires further investigation. Micronutrients may influence ovarian reserve markers, ovulation, endometrial receptivity, and luteal phase adequacy 8 , positioning nutritional support as a potentially accessible and cost-effective approach to enhance natural fertility and ART outcomes. Randomized trials highlight these benefits. Nouri et al. 3 reported that women receiving a multi-micronutrient supplement during ART produced more good-quality embryos (58%) than those using folic acid alone (36%), with a trend toward improved pregnancy rates. Similarly, adherence to a pro-fertility diet—rich in folate, vitamins B 12 and D, fruits and vegetables with low pesticide residues, whole grains, high-fat dairy, seafood, and soy—has been associated with higher live birth rates after ART 9 and reduced infertility risk 7 . B vitamins regulate homocysteine metabolism, and deficiencies may elevate inflammation and impair ovulation 7 . Additionally, Mediterranean-style patterns improve ART success, reduce insulin resistance, and lower ovulatory infertility risk 1 . Conversely, Western diets high in refined carbohydrates and trans fats promote inflammation and adversely affect oocyte and embryo quality 5 , 7 , and in men reduce sperm morphology and concentration 10 . Several micronutrients support reproductive physiology more broadly. Omega-3 fatty acids enhance steroidogenesis, reduce inflammation, improve semen quality, support oocyte development 7 , and may increase pregnancy rates and reproductive lifespan 7 , 11 . In a short-term intervention, Kermack et al. 12 found that omega-3 and vitamin D supplementation improved follicular fluid composition by increasing Eicosapentaenoic Acid/Docosahexaenoic Acid (EPA/DHA) and reducing omega-6 levels. Deficiencies in selenium, zinc, or copper have been linked to delayed conception and greater infertility risk 7 . Conditions characterized by oxidative stress—such as endometriosis and polycystic ovary syndrome (PCOS)—can impair oocyte quality 7 . Although evidence is limited, a Cochrane review suggested potential benefits of antioxidant supplementation, and coenzyme Q 10 may improve oocyte and embryo quality 13 . Folic acid supports Deoxyribonucleic Acid (DNA) synthesis and luteal progesterone production, reducing anovulatory cycles 5 . In men, folate deficiency increases sperm DNA damage, and combined folate–zinc therapy may enhance semen quality 14 . Additional compounds—such as glycyrrhizin—have shown reproductive benefits in PCOS models 15 . Few studies have evaluated simultaneous micronutrient intake in couples. Veselinović et al. 16 found that semen quality and serum micronutrient levels correlated with ART success. However, Arhin et al. 2 highlighted inconsistent evidence for antioxidant supplementation. A combined nutraceutical strategy may address oxidative stress, homocysteine metabolism, and hormonal balance through omega-3 fatty acids, coenzyme Q 10 , vitamin E, folic acid, selenium, catechins, glycyrrhizin, L-carnitine, L-arginine, zinc, and glutathione. These nutrients have been linked to enhanced embryo quality 3 , greater endometrial thickness 8 , and improved semen parameters 17 . This retrospective study evaluated whether simultaneous supplementation in both partners could improve fertility outcomes and shorten the time to conception.

This retrospective cohort study was conducted at the SGB Teofanović (Belgrade, Serbia) and the IMI Fertility Clinic (Vienna, Austria). Medical records from 213 sub-fertile couples treated between January 1, 2021, and January 31, 2022, were reviewed to compare outcomes between patients receiving nutraceutical supplementation and those receiving standard folic acid. Ethical approval was granted by the SGB Teofanović Ethics Committee (10/03/2025, EC-Nr. 49). Consent was waived due to the retrospective design, and all data were codified, anonymized, and securely stored. In the therapy group (n=119), both partners received the nutraceutical supplement; in the control group (n=94), women received folic acid 400 μg/day. Eligible women were aged 18–40, attempting natural conception while awaiting IVF treatment. Women aged 18–40 who were trying to conceive naturally while awaiting treatment at an IVF institute were eligible if they had unexplained subfertility or fertility-affecting conditions such as PCOS. Couples were excluded if medical records were incomplete, if the woman had premature ovarian insufficiency or bilateral tubal occlusion, if the male partner had severe infertility (e.g., azoospermia), or if either partner was taking other micronutrient supplements. Age, body mass index (BMI), parity, gravidity, duration of time to conceive, menstrual regularity, ovulation status or stimulation (including type), tubal patency, nicotine/alcohol consumption, medication, comorbidities, baseline anti-müllerian hormone (AMH), endometrial thickness before and after supplementation, and pregnancy onset (months 1–6). Age, BMI, nicotine status, urological/fertility history, and semen analysis. Clinical pregnancy confirmed by serum β-human chorionic gonadotropin and fetal cardiac activity. After confirmation, women transitioned to standard pregnancy supplements. Change in endometrial thickness (measured between cycle days 12–15 in the late follicular phase) before and after supplementation. Women in the therapy group received PROfertil Female ® , consisting of one soft capsule with 500 mg omega-3 fatty acids and one tablet containing 30 mg vitamin E, 30 mg coenzyme Q 10 , 800 μg folic acid, 70 μg selenium, 4 mg catechins, and 12 mg glycyrrhizin. Male partners received a formulation containing two capsules with 440 mg L-carnitine, 250 mg L-arginine, 15 mg coenzyme Q 10 , 120 mg vitamin E, 40 mg zinc, 800 μg folic acid, 80 mg glutathione, and 600 μg selenium (PROfertil Male ® ). Supplements were taken daily for 6 months or until pregnancy. Data were extracted by an independent reviewer (Dr. Johannes Barta) and analyzed using International Business Machines Statistical Package for the Social Sciences Statistics 30.0. Continuous variables were summarized as mean±standard deviation and ranges; categorical variables as absolute and relative frequencies. Normality was assessed using histograms, Q–Q plots, and the Kolmogorov-Smirnov test. Multivariate logistic regression evaluated the association between supplementation and pregnancy, adjusting for female age, BMI, smoking, alcohol intake, ovulation stimulation, AMH, and semen quality. Changes in endometrial thickness were analyzed with an independent samples t-test. Statistical significance was set at p<0.05.

Pregnancy onset was evaluated in 213 women: 119 received the nutraceutical supplement, and 94 took folic acid 400 μg/day. All therapy-group participants adhered to the protocol. Ovulation stimulation (Clomiphene or Letrozole) was used in 21% of the therapy group and 26.6% of controls. Therapy patients were treated at SGB Teofanović (56.3%) and the IMI Clinic (43.7%), while all controls were treated at IMI. Mean female age was 35.1±4 years (range 27–43) in the therapy group and 34.4±4 years (26–42) in controls, with BMI 24.5±2.5 versus 24.2±2.4. Previous pregnancies occurred in 27.7% of therapy patients (12.6% live births) and 30.9% of controls (13.8% live births). The average infertility duration was 12±6.8 months in both groups. Cycle regularity was reported in 69.7% of therapy patients (26.9% normal ovulation) versus 66% of controls (26.6%). Smoking and alcohol consumption were similar. Baseline endometrial thickness did not differ; after 6 months, supplemented women had significantly greater endometrial thickness (10.3±1.6 mm) than controls (9.5±1.6 mm; 95%CI −1.24 to −0.37) ( Table 1 ). Data is presented as mean±standard deviations (SD), ranges [minimum–maximum value], or frequencies n (%). AMH: anti-müllerian hormone. Comorbidities occurred in 26.9% of therapy patients and 22.3% of controls, including depression, type 2 diabetes, Hashimoto’s disease, insulin resistance, hypothyroidism, microadenoma, or PCOS; 24% of both groups used medications such as antidepressants, cabergoline, levothyroxine, inositol, or metformin. Fallopian tube obstruction was observed in 42.9% of therapy patients versus 62.8% of controls. Baseline AMH averaged 2.6±1 ng/mL in both groups. Endometrial thickness increased from 9.1±1.6 mm to 10.3±1.6 mm in therapy patients and from 9.4±1.6 mm to 9.5±1.6 mm in controls. Partner characteristics were comparable: therapy partners averaged 35.9±4.6 years and had a BMI of 26.4±2.1; 69.7% smoked, and 29.4% had abnormal semen analyses. Controls averaged 35.7±4.3 years, with a BMI of 26.4±1.3; 60.6% smoked, and 33% had abnormal semen analyses. Pregnancy within 6 months occurred in 66.4% of supplemented couples (monthly rates: 6.7, 16.8, 9.2, 18.5, 6.7, and 8.4%) versus 39.4% of controls (6.4, 6.4, 8.5, 9.6, 2.1, and 7.4%). One control patient conceived twice (months 1 and 3) ( Table 2 ). Multivariate logistic regression, adjusted for female age, BMI, smoking, alcohol, ovulation stimulation, AMH, and semen analysis, showed a significant model ( χ 2 [11, n=213]=44.14, p<0.001) with good fit (Hosmer-Lemeshow χ 2 [8]=8.27, p=0.408), explaining 25% of variance (Nagelkerke R 2 =0.25) and correctly classifying 73.2% of cases. Nutraceutical supplementation increased the odds of pregnancy 4.13-fold (95%CI 2.12–8.04, p<0.001). Maternal age (OR 0.87, p=0.002) and BMI (OR 0.86, p=0.02) decreased pregnancy likelihood, while higher AMH increased it (OR 1.45, p=0.043).

This study found that targeted nutraceutical supplementation significantly improved natural conception, with 66.4% of women achieving pregnancy within six months versus 39.4% of controls. These findings support prior evidence of improved conception rates with similar preparations 18 , highlighting the potential of nutraceutical strategies in fertility care. Supplementation also benefits semen quality. L-carnitine and vitamin E enhance sperm motility, concentration, and morphology, while L-carnitine counteracts reactive oxygen species. Long-term coenzyme Q 10 use improves progressive motility 19 . Selenium mitigates oxidative stress, supports DNA repair, and improves semen parameters 20 . Combined male supplementation with L-carnitine, L-arginine, coenzyme Q 10 , zinc, glutathione, selenium, and vitamins C and B 9 increases total and progressive motility, reduces DNA fragmentation, and enhances pregnancy rates 21 . ART studies show higher rates of good-quality embryos and trends toward improved pregnancy with female nutraceutical supplementation 3 ; male-partner antioxidant use also improves implantation and clinical pregnancy 22 . Adherence to pro-fertility or Mediterranean diets correlates with better ART outcomes and live births 23 , while in men, Western-style diets promote inflammation, oxidative stress, hormonal imbalance, and impaired semen parameters 10 . Mechanistically, folic acid and vitamins B 6 and B 12 regulate homocysteine metabolism; elevated homocysteine impairs ovulation, embryo quality, and increases miscarriage risk 24 . Omega-3 fatty acids and coenzyme Q 10 support steroidogenesis, oocyte quality, and reduce oxidative stress 25 . The evaluated supplement likely acts synergistically via these pathways. The proposed intervention is non-invasive, low-risk, and inexpensive, offering a safe adjunct to ART or natural conception. However, standardized recommendations for women attempting conception remain needed. Strengths of the study include standardized supplementation for both partners and clinically relevant outcomes. Limitations involve modest sample size, lack of dietary control beyond supplementation, reliance on self-reported adherence, absence of mechanistic biomarkers beyond AMH, and unavailable live birth data. To our knowledge, few studies have assessed simultaneous supplementation in both partners and its impact on natural conception. Large multicenter randomized trials are needed to identify mechanisms and responsive subgroups and explore combined male-female supplementation. In conclusion, nutraceutical supplementation may enhance fertility potential in both partners by modulating homocysteine metabolism, balancing oxidative stress, and improving semen quality and hormonal regulation. Clinically, it represents a safe, low-cost, non-invasive adjunct to natural conception and ART.