The mean age for women giving birth to their first child is increasing globally, with few therapeutic options to counteract an age-related decline in female fertility. This study aimed to investigate the effect of dietary micronutrient supplements on spontaneous pregnancy rates in women of advanced reproductive age with infertility of unknown etiology.
Materials & methodsThis was a retrospective, comparative study of 270 infertile women aged 35–40 years with non-pathological fertility work-up and normal male partner semen analysis attending a fertility clinic in Vienna, Austria. 146 women received an oral micronutrient preparation (omega-3 fatty acids, coenzyme Q10, vitamin E, folic acid, selenium, catechins and glycyrrhizin) daily for 6 months and subsequent monthly rates of spontaneous clinical pregnancy were compared to a control group of 124 women receiving only daily folic acid supplements. No other fertility-related interventions took place during the observation period.
ResultsThe total spontaneous pregnancy rate after 6 months was significantly higher in the study group, reaching 43.8%, compared to 29.8% in the control group (p=0.018). Moreover, the cumulative pregnancy rate in the study group taking micronutrient supplementation was 54.5%, and 34.1% in the control group.
ConclusionsThe findings of this study suggest that the intake of specific micronutrients might be associated with a higher occurrence of spontaneous pregnancies and thus improvement in female fertility among women of advanced reproductive age who experience unexplained infertility.
La edad media de las mujeres que dan a luz a su primer hijo está aumentando en todo el mundo, y existen pocas opciones terapéuticas para contrarrestar el descenso de la fertilidad femenina relacionado con la edad. El objetivo de este estudio fue investigar el efecto de los suplementos dietéticos de micronutrientes sobre las tasas de embarazo espontáneo en mujeres de edad reproductiva avanzada con infertilidad de etiología desconocida.
Materiales y métodosSe trata de un estudio retrospectivo y comparativo de 270 mujeres infértiles de 35-40 años con un estudio de fertilidad normal y un análisis de semen de la pareja masculina normal, que acudieron a una clínica de fertilidad de Viena, Austria. Ciento cuarenta y seis mujeres recibieron diariamente un preparado oral de micronutrientes (ácidos grasos omega-3, coenzima Q10, vitamina E, ácido fólico, selenio, catequinas y glicirricina) durante 6 meses y se compararon las tasas mensuales posteriores de embarazo clínico espontáneo con un grupo de control de 124 mujeres que solo recibieron suplementos diarios de ácido fólico. Durante el periodo de observación no se llevó a cabo ninguna otra intervención relacionada con la fertilidad.
ResultadosLa tasa total de embarazo espontáneo al cabo de 6 meses fue significativamente mayor en el grupo de estudio, alcanzando el 43,8 frente al 29,8% del grupo de control (p=0,018). Además, la tasa acumulada de embarazos en el grupo de estudio que tomó suplementos de micronutrientes fue del 54,5, y del 34,1% en el grupo de control.
ConclusionesLos resultados de este estudio sugieren que la ingesta de micronutrientes específicos puede estar asociada a una mayor ocurrencia de embarazos espontáneos y, por tanto, a una mejora de la fertilidad femenina entre las mujeres en edad reproductiva avanzada que experimentan infertilidad inexplicada.
Infertility is defined as the failure to achieve a clinical pregnancy after at least 12 months of regular unprotected sexual intercourse1 and is estimated to affect up to 48 million couples worldwide. Therefore, infertility is recognized as a global public health issue2 and has been defined as a disease by the World Health Organisation (WHO), emphasizing the right of elective treatment.3 In the last three decades, there has been a steady increase in the prevalence rate of infertility, with a more pronounced rise observed in females. Future predictions see this trend unlikely to reverse soon, as more and more women postpone having children to a later stage in life. As a result, the mean age for women giving birth is increasing globally.4–6 Higher maternal age is considered the most important and independent risk factor for female infertility and prolonged time to conception, attributed to the gradual decline in both the quantity and quality of remaining oocytes.7 Meanwhile, treatment options for delaying oocyte aging or possibly rejuvenating existing egg cells are limited. Couples with unexplained infertility (UI), meaning failure to conceive within 12 months despite evidence of female tubal patency, regular ovulation and normal male semen analysis, are considered most likely to conceive naturally compared to other infertility aetiologies. Optimization of life style factors is an important part of their initial fertility management plan.8,9 Studies have revealed that a considerable number of women experiencing infertility may display micronutrient deficiencies. Unhealthy dietary habits have been identified as a modifiable risk factor for subfertility and there is a prevailing suggestion of positive impacts on female fertility with periconceptional micronutrient intake.10
Despite this, nutritional status remains frequently neglected in reproductive work-up. Additionally, the effects of dietary supplements on the clinically significant outcome of pregnancy remains an under-researched topic, particularly in women of advanced age without obvious reproductive pathologies who are not using assisted reproductive techniques. Hence, the present study aims to investigate the association between the intake of a defined combination of micronutrients and pregnancy rates among women of higher reproductive age with unexplained infertility, relative to a control group that refrained from dietary supplementation other than folic acid.
Materials and methodsThis retrospective, comparative study includes 270 premenopausal women aged 35–40 years, who attended a fertility clinic in Vienna, Austria from January 2014 to December 2022 and had been trying for a child for at least 1 year. All data was retrieved retrospectively from the clinics electronic patient management system “4myhealth” from March until May 2023.
To be considered for inclusion, initial fertility work-up in the clinic had to be without any pathological or abnormal findings. The diagnostic tests of this work-up includes vaginal sonography, hysteroscopy, ovulation testing and fallopian tube patency exam as well as comprehensive serum blood tests including a complete blood count, hormonal status, thyroid function, infection screening (HIV, hepatitis, syphilis, cytomegalovirus, rubella, parvovirus), coagulation function, iron status and specific autoimmune parameters (Rheumatoid Factor and Connective Tissue Disease (CTD) screen). Moreover, inclusion criteria required the male partner's semen analysis to be normal, meaning his sperm density, motility, morphology and vitality parameters all being within current WHO reference values. Women were also excluded if they had previously undergone gonadotoxic treatment (chemotherapy or radiation), unilateral ovariectomy, or if they had currently been taking any additional micronutrient or vitamin supplements. As part of routine consultations, all infertile couples had received counseling and information on assisted reproductive technologies (ART) such as IVF/ICSI and IUI. Some had opted to persist in attempting spontaneous conception, while others had planned to pursue ART at a later stage. Patients who had decided to proceed with ART right away were excluded in this analysis. Moreover, folic acid supplementation is routinely recommended and prescribed to all women presenting with infertility issues. Simultaneously, micronutrient supplementation is advised as an optional therapy with potential benefits for fertility and the choice of supplements based on personal preference.
After initial evaluation, the study group of 146 women had only been taking a specific oral, prescription-free micronutrient preparation daily for 6 months, by their own choice and expense, while continuing with regular unprotected sexual intercourse. a soft capsule with omega-3 fatty acids (500mg) and a tablet containing coenzyme Q10 (30mg), vitamin E (30mg), folic acid (800mcg), selenium (70mcg), catechins from green tea extract (4mg) and glycyrrhizin from liquorice extract (12mg). The control group of 124 women had only taken 400mcg of folic acid tablets daily, also purchased at their own choice and expense, as this is the established standard therapy for the preconceptional and early pregnancy period, while also continuing with unprotected intercourse with their male partners for 6 months without the intake of other additional dietary supplements.11 To ensure adherence to the prescribed regimen, compliance regarding regular intake had been ascertained through direct questioning for both groups. Only women were included who stated that they had adhered to regular, daily intake of the respective oral supplements without taking any additional micronutrient preparations for at least 6 months or until pregnancy occurred.
As part of the initial fertility work-up, all women and their partners had also been counseled on ways to optimize life-style factors, including avoiding nicotine and alcohol consumption, reducing stress, getting enough sleep, and maintaining moderate physical activity levels. Additionally, patients were advised on adequate timing of sexual intercourse to maximize pregnancy chances. Apart from the intake of the oral micronutrient or folic acid preparations, no other fertility related interventions had taken place during the observational period.
Clinical pregnancy had been confirmed by ultrasound visualization of a gestational sac and corresponding human chorionic gonadotropin serum levels. The monthly pregnancy rates were calculated based on the remaining non-pregnant women at the beginning of the month, respectively, and compared in both groups within the first 6 months after starting the micronutrient or folic acid supplementation regimens. Additionally, both total and cumulative pregnancy rates for the entire observational period of 6 months were assessed and compared. Lastly, important parameters that affect female fertility were evaluated in both groups to identify possible biases, including age, body mass index (BMI) and reporting of regular smoking or alcohol use. Regular smoking was hereby defined as >5cigarettes per day and regular alcohol use as consumption of alcoholic beverages on at least 3 days per week.
Statistical analysis was performed using the Statistical Package for the Social Sciences version 21.0 (IBM SPSS, Armonk, NY, USA). Numerical parameters are presented as the mean plus/minus standard deviation and dichotomous categorical parameters as absolute and relative frequencies. For the comparison of continuous numerical data (BMI, age) Student t-test was applied. χ2-test test was used for comparison of categorical variables (pregnancy rate, nicotine and alcohol consumption, primary infertility). To evaluate the association of patient characteristics with pregnancy outcomes a multivariable logistic regression model was performed and odds ratios (OR) with 95% confidence intervals (95% CI) as well as Nagelkerke's R square for goodness of fit provided. For all analyses and p-values<0.05 were considered significant. The study was approved by the Local Review Board of the Landsteiner Institute. Informed consent was not obtained, due to the retrospective study design.
Results270 women were included in the analysis; 146 taking only a specific micronutrient preparation as described below daily (study group), and 124 taking only 400mcg folic acid daily (control group).
Both groups had a similar mean age range with 37.3 (±1.8) years the study group, and 37.4 (±1.7) years in the control group. Control and study group also showed comparable shares of primary infertile women (93.5% vs. 94.5%), daily smokers (17.4% vs. 18.6%) and regular alcohol consumers (11.3% vs. 11.6%). The mean BMI value of the control group was 21.8 (±4.1), which was significantly lower (p=0.000) than in the study group with 24.1 (±4.9), though within the healthy weight range of 18.5–25 for both groups (Table 1).
Basic patient characteristics.
| Control groupn=124 | Study groupn=146 | p-Value | |
|---|---|---|---|
| AGEa (years) | 37.4 (±1.7) | 37.3 (±1.8) | 0.703 |
| BMIa (kg/m2) | 21.8 (±4.1) | 24.1 (±4.9) | 0.000* |
| NICOTINE consumptionb | 20 (17.4) | 24 (18.6) | 0.945 |
| ALCOHOL intakeb | 13 (11.3) | 15 (11.6) | 0.955 |
| Primary infertilityb | 116 (93.5) | 138 (94.5) | 0.736 |
| Secondary infertilityb | 8 (6.5) | 8 (5.5) |
BMI=body mass index×weight in kg/(height in m)2.
To assess the predictive potential of basic patient characteristics on the pregnancy outcome a multivariable logistic regression model was conducted. It was found that neither the women's age, BMI, type of infertility nor regular nicotine or alcohol consumption were significantly predictive for clinical pregnancy (p>0.05) (Table 2). Accordingly, the goodness of fit of the model was low (Nagelkerke's R square=0.027).
Predictive factors for pregnancy outcome: a multivariable logistic regression model.
| Not pregnant(n=169) | Pregnant(n=101) | OR (95% CI) | p | |
|---|---|---|---|---|
| AGEa (years) | 37.4 (±1.7) | 37.3 (±1.8) | 0.981 (0.848;1.136) | 0.797 |
| BMIa (kg/m2) | 22.8 (±4.6) | 23.5 (±4.9) | 1.024 (0.971;1.081) | 0.383 |
| NICOTINE consumptionb | 24 (14.5) | 20 (19.8) | 1.487 (0.764;2.893) | 0.243 |
| ALCOHOL intakeb | 18 (10.8) | 10 (9.9) | 0.831 (0.361;1.913) | 0.664 |
| Primary infertilityb | 155 (93.4) | 99 (98.0) | 2.719 (0.736;10.044) | 0.134 |
After each of the 6 months under investigation pregnancy rates were higher in the study group (Fig. 1). In the first two months the differences in pregnancy rates were minimal, with only 1.1%- and 0.3%-point variations. The biggest difference was recorded in month 4, with a 6.7% higher pregnancy rate in the study group than in the control group, followed by month 6, where this difference was 6.3%. Overall, the cumulative pregnancy rate after 6 months was 54.5% in the group receiving micronutrient therapy compared to 34.1% in the women taking only folic acid. The total pregnancy rate of all women after the observation period was significantly higher with 43.8% in the study group as compared to 29.8% in the control group (p=0.018) (Table 3).
Cumulative, total, and monthly pregnancy rates. The graph illustrates the monthly pregnancy rates in percent during the 6 months of observation following initiation of micronutrient supplementation for the study group (dark gray) and folic acid supplementation for the control group (light gray.) Moreover, comparison of cumulative monthly pregnancy rates as well as total pregnancy rates after 6 months are displayed for both groups; * Statistical significance p<0.05.
Pregnancy outcomes.
| Control groupn=124 | Study groupn=146 | |||||
|---|---|---|---|---|---|---|
| Pregnanta | Not pregnantb | Preg.-ratec [%] | Pregnant | Not pregnant | Preg.-rate [%] | |
| Month 1 | 4 | 124 | 3.2 | 6 | 146 | 4.1 |
| Month 2 | 4 | 120 | 3.3 | 5 | 140 | 3.6 |
| Month 3 | 7 | 116 | 6.0 | 12 | 135 | 8.9 |
| Month 4 | 6 | 109 | 5.5 | 15 | 123 | 12.2 |
| Month 5 | 9 | 103 | 8.7 | 13 | 108 | 12.0 |
| Month 6 | 7 | 94 | 7.4 | 13 | 95 | 13.7 |
| Total | 37 | 87 | 29.8 | 64 | 82 | 43.8 |
The aim of this study was to analyze the impact of a specific oral micronutrient preparation on pregnancy rates in infertile women of advanced reproductive age, as compared to a control group taking only folic acid supplementation. Significantly higher total pregnancy rates were achieved in the study group who adhered to daily intake of micronutrient supplementation. As anticipated, the observed variations in pregnancy rates were only minimal and negligible during the initial 2 months, before potential effects of micronutrient therapy became increasingly evident.
These results suggest that the intake of certain micronutrients may enhance female fertility, though the detailed underlying mechanisms of action remain not fully understood. Recent estimates indicate that two-thirds of non-pregnant women of reproductive age worldwide are deficient in at least one micronutrient.12 Many micronutrients and vitamins have a crucial role in various stages of physiological processes involved in female reproduction, including oocyte development, maturation, fertilization, and implantation. Evidence suggests that adherence to diets characterized by higher intake of monounsaturated and n−3 polyunsaturated fatty acids, flavonoids, and reduced red and processed meat may improve fertility through mediation of anti-inflammatory pathways.13 Moreover, many females struggling to conceive seem to lack certain micronutrients and lower than recommended levels of some of these micronutrients seem to negatively impact chances for conception.10,14 Nevertheless, large trials on clinical effects of micronutrient supplementation on female fertility in humans remain scarce. Evidence from a small amount of studies suggests increased chances for spontaneous conception and shorter time to pregnancy in women taking certain nutritional supplementation.10 A 2020 Cochrane analysis states that antioxidant supplements may increase clinical pregnancy rates compared to placebo, however emphasizing that evidence is low-quality and many of the included studies displayed high risks of bias.15 Meanwhile, a recent analysis showed strong consensus amongst selected Egyptian obstetrics and gynecology experts for recommending supplements and antioxidants such as Vitamin E, Vitamin C, Vitamin D, zinc, and folic acid to optimize natural female fertility. Regarding unexplained infertility they largely agreed on the potentially beneficial effects of l-carnitine and acetyl l-carnitine, while highlighting that co-enzyme Q10's role is not fully understood, though it may improve ovarian response and pregnancy outcomes.16 Nevertheless, sufficient data providing robust evidence for general recommendations on periconceptional micronutrient intake beyond the prevention of neural tube defects with folic acid supplements is still lacking. Literature merely focussing on women of higher reproductive age and with unexplained infertility is especially limited regarding this issue.
One of the difficulties when investigating nutritional supplements in the context of reproductive medicine is that there are numerous different multivitamin and micronutrient preparations promoting fertility enhancement available on the market, all containing vastly different amounts and types of active ingredients. This makes research on the individual effects of single nutrients challenging and studies on their clinical effects difficult to compare. The standard micronutrient preparation used in this present study is a non-prescription nutraceutical, which has been obtainable on the international market for many years and proved to be well tolerable without notable side effects. A previous randomized, placebo-controlled study with this preparation has shown to improve embryo quality in the setting of assisted reproductive techniques (ART).17 Another retrospective analysis conducted in 2019 found that supplementation with these specific micronutrients resulted in a significant increase in serum AMH (Anti-Mullerian Hormone) levels among women attempting to conceive, and demonstrated positive effects on endometrial thickness, ovulation frequency, and luteal phase duration in women with infertility of unknown cause.18
The mechanisms how these vitamins and micronutrients may interact with the female reproductive system are complex and diverse. Firstly, periconceptional supplementation or increased dietary intake of omega-3-fatty has been shown to result in a significantly lower risk of anovulation, shorter time to pregnancy and higher probability of spontaneous conception in different cohorts women attempting pregnancy.19–21 Folate acid is well known to play a key role in DNA replication, folliculogenesis and regulation of homocysteine levels in the ovary.22 Various studies have shown that folate intake of doses well above 400μg, which is currently recommended for neural tube defect prevention, may result in improved female fecundability and higher chances of pregnancy when compared to women with no or less amounts of folate supplementation.11,23 Selene deficiency in women of reproductive age has been associated with a higher risk of luteal phase insufficiency, which can result in a thinner endometrium less receptive for implantation and therefore increase chances for infertility and/or early pregnancy loss.24 Moreover, selenium is an important co-factor for several antioxidative enzymes in the follicular environment and has been found to be decreased in the follicular fluid of women with unexplained infertility.25 Another important antioxidant is vitamin E, which can scavenger free radicals in the uterine and ovarian microenvironment, inhibit propagation of lipid peroxidation and thereby prevent cell damage. To demonstrate its impact on female fertility, one data analysis revealed a positive association between increased vitamin E intake and shorter time to pregnancy in women over 35 years of age, while another study showed higher pregnancy rates in women with a thin endometrium after treatment with vitamin E in combination with pentoxifylline.26,27 Catechins are the most important physiologically active component in green tea, exhibiting anti-inflammatory, antioxidant and possibly vasodilative effects in female reproductive organs.28 Glycyrrhizin from the root of the liquorice plant has been shown to interact with the physiological steroid metabolism, possibly improving hyperandrogenaemia and normalizing irregular menstrual cycles in women.29 Finally, co-enzyme Q10 (Co10) is a key protein for ATP production in the mitochondria, which is the most abundant cell organelle in oocytes. Mitochondrial function appears to play an important role in oocyte aging and some data suggests that Co10 supplementation may enhance mitochondrial activity in the ovary, though larger studies and investigations on the impact of co-enzyme Q10 intake on female fertility are still lacking.30
Considering the fact that oocyte quality and quantity rapidly diminishes with age, periconceptional micronutrient supplementation might be especially beneficial to women at a later stage of their reproductive lifespan.6 The age-related deterioration of female fertility gradually begins in her late 1920s, followed by an exponential decline of ovarian reserve from 35 years old and, with fertility ceasing completely at the onset of menopause between ages 45 and 55.31,32 Therefore, the age range of 35–40 years was chosen for the patient population of this analysis. Considering improved fertility outcomes of the study group, certain nutritional supplements might have a minor role in counteracting or slowing down the ovarian aging process, though this has yet to be proven in more research. Ovarian aging is characterized by a gradual decrease in both the number and quality of egg cells. Evidently, in assisted reproductive technologies (ART) older women using oocytes donated from younger women seem to achieve similar pregnancy success rates as their younger counterparts.7 To this day no reliable tests or biomarkers have been established that allow for a direct assessment of oocyte quality in clinical routine prior to fertilization. Meanwhile, information on follicle quantity and residual ovarian reserve can obtained by measuring serum levels of AMH or Follicle-Stimulating Hormone, or by counting ovarian antral follicles via ultrasound.33 The mechanisms involved in ovarian aging are very complex, multifactorial and still poorly understood. Studies have shown that aneuploidy rates and mitochondrial damage in oocytes increase with a woman's age, which can result in lower fertilization rates and impaired embryonic development. More frequent occurrence of such pathologies in aging egg cells has been associated with higher oxidative stress (OS=) in and around the ovary.34 Without adequate antioxidant response OS leads to more free radicals as well as reactive oxygen species (ROS) within the ovarian microenvironment. Those highly reactive molecules can cause mitochondrial DNA mutations and other intracellular damage, possibly leading to meiotic arrest or early apoptosis of oocytes. This explains why OS is considered a key factor in accelerating ovarian aging.35 Moreover, the number mitochondria were found to be significantly lower in oocytes of older women.36
These findings explain the current intense research interest in interventions involving either reduction of oxidative stress or improvement of mitochondrial function to delay oocyte aging or possibly rejuvenate oocytes in older women.34,36 So far, antioxidant supplementation showed to reduce excess OS in the ovary and enhance ovarian function.35 Continuing research of therapeutic options for ovarian aging is essential, as the median age of women giving birth to their first child has been rising worldwide over the past decades – a trend predicted to continue in the foreseeable future.5,6 In most OECD countries the mean age of women giving birth to their first child is now at 30 years or above.6 Despite the tremendous technical advances that reproductive medicine has seen over the past years, ARTs and other innovative therapeutic options cannot completely overcome the burden of age-related decrease of female fecundity. Without the use of donor oocytes, IVF pregnancy success rates significantly decline in women older than 35 years and remain at a very low level for females over 40 years of age.5,7 Moreover, invasive and lengthy ART regimens often put women under severe psychological and physical stress, present a financial burden and frequently require multiple treatment cycles to achieve clinical pregnancy.37
It is noteworthy that all couples included in this retrospective analysis were affected by what is known as unexplained infertility (UI), without any known reproductive pathology in both partners. Estimates suggest that unexplained infertility is affecting up to 30% of infertile men and women. Unsurprisingly, according an international consensus development study from 2021, amongst the top 10 important questions for future infertility research is whether age-related infertility can be prevented, and what causes unexplained infertility.38 Regarding treatment guidelines for UI, a 2019 Cochrane review found insufficient evidence for differences in live births between expectant management and fertility interventions including ovarian stimulation, intrauterine insemination (IUI), in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Hence, the authors conclude that there is a good chance of achieving pregnancy without extensive fertility treatment in couples without a known cause for their infertility.39 By default, management will be mostly empiric. However, rates of natural conception in couples with UI show considerable variations in the literature, depending on the specific patient populations under investigation. One notable multicentre study conducted by Brandes et al. revealed a spontaneous conception rate of 55.5% (206/407) in couples diagnosed with UI following expectant management. Compared to our analysis, this study reported a lower mean female age, a smaller percentage of primary infertility cases, and a longer follow-up period, which may elucidate the disparities with our results of 43.8% and 29.8% for the study and control group, respectively.40 Such clinical heterogeneity inherent with diverse fertility prognoses poses a challenge when directly comparing outcomes with other studies on this topic.
There is a strong recommendation to counsel all fertility patients, but especially those with UI, on the optimization of certain life style factors before or alongside considering more invasive and costly treatment options for further management.9 Improving factors such as nutrition and exercise, and limiting harmful environmental exposures prior to conception is should always be part of the early fertility management, regardless if ART procedures might follow or not.23,24
The results of this study should be considered within the context of certain limitations, primarily stemming from its retrospective study design and a relatively small sample size. Furthermore, several other potential variables known to impact pregnancy outcomes were not subjected to control, including exercise, pre-existing medical conditions in both the male and female partners, which may potentially influence fertility, and socioeconomic status. The latter may be important considering potential economic bias of the study, as micronutrient preparations are generally more expensive than simple folic acid supplements, which may have affected the choice of which to purchase. Moreover, the study may be subject to selection bias, as it excluded couples with potentially poorer fertility prognoses who opted for ART immediately. Another limitation worth highlighting is that the nutritional status prior to the administration of micronutrient supplementation was not evaluated, leading to a lack of information regarding potential disparities in specific nutrient levels between the study group and the control group. Since this study investigated a multi-component supplement, it also challenging to draw specific conclusions about the effect of individual nutrients on clinical outcomes. The potentially beneficial effects on female fertility are likely synergistic, and more research is needed to determine the exact impact and extent of which of each may nutrient contribute.
Nonetheless, the study maintained rigorous inclusion criteria, notably excluding females who were already consuming micronutrient preparations before their participation in the study. Furthermore, it is important to underscore the scarcity of prior research endeavors focused on investigating the implications of micronutrient supplementation within this specific cohort of patients.
To conclude, preconceptional micronutrient supplementation in women at a later stage of their reproductive years struggling to conceive might correct underlying nutritional deficiencies and potentially improve chances for pregnancy. It seems that oral intake of certain micronutrients might optimize nutritional status and reduce oxidative stress in the environment of reproductive organs. Therefore, it could be a simple and non-invasive, yet effective way to positively impact female fertility in women of higher reproductive age with unexplained infertility, especially when there is no strong indication that calls for immediate ART. To validate these results there is a need for larger, prospective and randomized trials.
Ethical disclosuresProtection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this study.
Confidentiality of dataThe authors declare that they have followed the protocols of their work center on the publication of patient data.
Right to privacy and informed consentThe authors declare that no patient data appear in this article.
FinancingThe authors declare that they have no funding.
Patient consentComplete patient anonymity was preserved throughout retrospective data analysis and no research involving identifiable human data or material was conducted, following privacy protocols of the Karl Landsteiner Institute on the publication of patient data. All data analyzed was collected as part of routine diagnosis or treatment and not set up as a study or research project at the time of collection.
Conflict of interestThis study was no subject to any financial grants and other funding by any institution or company. All authors declare that they have no competing interests or conflict of interest to disclose.
