research paper on in vitro fertilization

• Open access
• Published: 18 January 2022

Female dietary patterns and outcomes of in vitro fertilization (IVF): a systematic literature review

• Elizabeth A. Sanderman   ORCID: orcid.org/0000-0001-8895-0972 1 ,
• Sydney K. Willis 2 &
• Lauren A. Wise 2  

Nutrition Journal volume  21 , Article number:  5 ( 2022 ) Cite this article

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Infertility affects up to 15% of couples. In vitro fertilization (IVF) treatment has modest success rates and some factors associated with infertility and poor treatment outcomes are not modifiable. Several studies have assessed the association between female dietary patterns, a modifiable factor, and IVF outcomes with conflicting results. We performed a systematic literature review to identify female dietary patterns associated with IVF outcomes, evaluate the body of evidence for potential sources of heterogeneity and methodological challenges, and offer suggestions to minimize heterogeneity and bias in future studies.

We performed systematic literature searches in EMBASE, PubMed, CINAHL, and Cochrane Central Register of Controlled Trials for studies with a publication date up to March 2020. We excluded studies limited to women who were overweight or diagnosed with PCOS. We included studies that evaluated the outcome of pregnancy or live birth. We conducted an initial bias assessment using the SIGN 50 Methodology Checklist 3.

We reviewed 3280 titles and/or titles and abstracts. Seven prospective cohort studies investigating nine dietary patterns fit the inclusion criteria. Higher adherence to the Mediterranean diet, a ‘profertility’ diet, or a Dutch ‘preconception’ diet was associated with pregnancy or live birth after IVF treatment in at least one study. However, causation cannot be assumed. Studies were potentially hindered by methodological challenges (misclassification of the exposure, left truncation, and lack of comprehensive control for confounding) with an associated risk of bias. Studies of the Mediterranean diet were highly heterogenous in findings, study population, and methods. Remaining dietary patterns have only been examined in single and relatively small studies.

Conclusions

Future studies with rigorous and more uniform methodologies are needed to assess the association between female dietary patterns and IVF outcomes. At the clinical level, findings from this review do not support recommending any single dietary pattern for the purpose of improving pregnancy or live birth rates in women undergoing IVF treatment.

Peer Review reports

Approximately 15% of couples in the United States and one in four couples in developing countries are affected by infertility, defined as the inability to become pregnant after 12 months of regular unprotected intercourse [ 1 , 2 ]. The World Health Organization recognizes infertility treatment and the examination of factors associated with fertility as essential to the promotion of reproductive health [ 1 , 3 ].

Though in vitro fertilization (IVF) is one of the most effective treatments for infertility [ 4 ], much of the success of IVF relies on women undergoing multiple embryo transfers and oocyte retrievals. However, multiple embryo transfers and oocyte retrievals can be cost prohibitive and emotionally and physically burdensome resulting in reported treatment attrition rates of up to 35–50% [ 5 , 6 ]. While some factors associated with lower success of IVF treatment, such as advanced female age, are not modifiable, there is growing interest in the impact of modifiable factors, such as diet, on treatment outcomes.

Diet currently accounts for nearly a tenth of the global burden of disease [ 7 , 8 ] and epidemiological studies have linked female and male diet to reproductive outcomes. Studies on the general impact of diet on female fertility have focused largely on the examination of specific dietary nutrients and food groups, such as dairy, fats, and antioxidants, and point to several different potential pathways of effect. Animal and in vitro human cell studies indicate possible associations with mechanisms that underlie fertility including hormone levels, ovarian insufficiency, diminished ovarian reserve, and embryonic development [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Human studies link dietary factors to longer time to pregnancy and the risk of developing reproductive disorders which may impact fertility such as anovulatory infertility, endometriosis, and uterine leiomyomata [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. However, despite uncovering possible links with fertility and fecundity, studies of associations between individual female dietary factors and infertility in both animals and humans are largely equivocal.

Much of what is known about the impact of individual female dietary factors specifically on IVF outcomes derives from a single observational study, the study of Environment And Reproductive Health (EARTH), described in detail elsewhere [ 30 , 31 , 32 ]. Within the context of IVF, female dietary patterns have been more widely studied. This reflects a trend toward viewing diet holistically in an effort to limit confounding from individual dietary items, capturing the effects resulting from the complex interactions between food groups, and providing results that are more interpretable and translatable to individuals [ 33 , 34 , 35 ].

To date, studies on associations between female dietary patterns and IVF outcomes have relied on observational designs. While randomized controlled trials are the gold standard for research methods, observational designs can be appropriate when the exposure is a dietary pattern; blinding may not be possible, ensuring adherence can be difficult, and participants may need to remain in a trial for long periods of time to observe the effect [ 36 ]. However, observational studies are often hindered by methodological challenges that carry the risk for bias, such as exposure misclassification, confounding control, and cohort selection. Further, observational studies are often carried out in populations and employ methods that are considerably different, necessitating careful consideration of heterogeneity across studies when comparing findings or pooling results [ 37 , 38 ].

Given the importance of understanding the associations between diet, including dietary patterns, and IVF outcomes, the observational nature of existing studies, and the need to compare and conduct well-designed epidemiologic studies, we performed a systematic literature review with the following aims: to identify female dietary patterns associated with the outcomes of IVF treatment, to evaluate the body of evidence for sources of heterogeneity and methodological challenges, and to offer suggestions for minimizing heterogeneity and potential sources of bias in future studies.

This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 39 ] (Supplemental Table  1 ).

Search strategy

Articles were identified through computerized literature searches undertaken March–April 2020. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL for English language publications. In EMBASE we utilized key words and EMTREE terms: ‘infertility’ OR (‘ in vitro fertilization’ OR ‘infertility therapy’ OR ‘IVF’) AND (‘dietary intake’ OR ‘diet’ OR ‘dietary pattern’). In PubMed we utilized MeSH terms and keywords: (‘IVF’ OR ‘ in vitro fertilization’) OR (‘reproductive techniques, assisted’ OR ‘assisted reproductive technology’) and (‘food OR diet’). Finally, we performed a manual search of the reference lists from the final included articles.

Selection criteria

Inclusion criteria were based on the PICO framework (Population, Intervention, Comparison, Outcome) [ 39 ]. P: women undergoing IVF or IVF with intracytoplasmic sperm injection (ICSI). Weight loss potentially improves outcomes during IVF treatment among women who are overweight (body mass index > = 25 kg/m2) or diagnosed with polycystic ovarian syndrome (PCOS) [ 40 ]; thus, we excluded studies restricted to women who are overweight or diagnosed with PCOS. I: dietary pattern with clearly delineated component food items. C: comparison group that differed in adherence to the dietary pattern. Early outcomes, such as embryo quality and yield, may not predict overall IVF treatment success [ 41 , 42 , 43 ]. Thus O: biochemical pregnancy (pregnancy diagnosed only by the detection of beta human chorionic gonadotrophin (βhCG) in serum or urine), clinical pregnancy (pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy), or live birth (the birth of a live fetus after 22 completed weeks of gestational age) [ 44 ].

We included peer reviewed original research articles with a publication date up to March 1, 2020. Review articles, editorials, conference abstracts, opinions, and case reports were excluded.

Assessment of study quality

The SIGN 50 Methodology Checklist 3 [ 45 ], a checklist specific to observational studies, was utilized to assess study quality. Studies were rated as “high quality” if the majority of criteria in the checklist were met and there is little risk of bias, “acceptable” if most criteria were met with some flaws and an associated risk of bias and “low quality” if either most criteria were not met or if there were significant flaws in the study design. One of the aims of this review is to explore methodological challenges in some depth. However, an initial assessment of studies was conducted to eliminate studies that did not receive a rating of “acceptable” or higher.

Data extraction

One author extracted data from the included studies and another subsequently confirmed or disconfirmed the data. Investigators from five studies were contacted for clarification. We extracted study characteristics: first author, year of publication, location, study duration, study design (observational vs. interventional; and cross-sectional, case-control, cohort), and analytical sample size. We extracted sample characteristics: age, major exclusions, infertility diagnosis, type of ART (IVF vs IVF/ICSI), prior ART treatment, number of prior failed pregnancy attempts, and ‘duration of infertility’. We extracted data on the exposure (dietary pattern, exposure window), methods (questionnaire used for assessing exposure, timing of recruitment and exposure assessment, covariates, study end points, follow up period), and how outcomes were defined (Supplemental Table  2 ).

Search results

The search of databases identified 5308 English language references (Fig.  1 ). After removal of duplicates, 3280 articles remained. We screened remaining references by reading titles and/or titles and abstracts; 3215 articles were deemed not relevant. We scanned the full texts of the remaining 65 articles and identified 56 for exclusion: 12 were reviews, opinions, or conference abstracts and 2 could not be located. 42 did not meet PICO criteria. Nine articles, representing nine independent research studies reporting on female dietary patterns and IVF outcomes, remained. No additional articles were identified after scanning reference lists.

PRISMA flow diagram

Nine studies underwent the initial quality assessment and two studies were omitted; one lacked sufficient information to make an assessment [ 46 ] and one contained a measure of association for clinical pregnancy that fell outside the confidence interval (OR 0.14, 95% CI: 0.3–0.7) [ 47 ]. Study authors could not be reached to correct this error [ 47 ] (Table 1 ). Seven studies were rated as “acceptable” quality and were included in the review. In included studies, potential selection bias and reliability of exposure assessment were the most common inadequately addressed items (items 1.2, 1.3, 1.4, 1.5, 1.6, 1.12, Table 1 ).

Dietary patterns associated with IVF outcomes

Nine dietary patterns were examined for an association with IVF outcomes in seven observational cohort studies: the MedDiet (Mediterranean diet and a ‘Mediterranean style’ dietary pattern), a Dutch ‘preconception’ diet, a ‘profertility’ diet, the ‘Fertility Diet’, the alternate Healthy Eating Index 2010 (aHEI-2010) diet, and the ‘health-conscious low processed’, ‘vegetable and seafood’, ‘Western’, and ‘rice and miso soup’ dietary patterns (Table 2 ).

Mediterranean diet

The MedDiet is generally comprised of high intake of whole grains, vegetables, fruits, nuts, legumes and/or pulses, and olive oil; moderate intake of nonfat or low-fat dairy products, seafood, and wine; and low consumption of poultry and red meat [ 55 , 56 , 57 ] (Table 2 ). In all five studies examining the MedDiet, participants were recruited from IVF treatment centers, had their diet assessed using a questionnaire at a point prior to embryo transfer, and followed prospectively.

Four studies examined the outcome biochemical pregnancy (Table  3 ). In a study of 161 couples in the Netherlands, Vujkovic (2010) reported a positive association between a positive urine pregnancy test 15 days after oocyte retrieval, and a couple’s increased adherence to a ‘Mediterranean style’ dietary pattern (adjusted OR 1.4, 95% CI: 1.0–1.9). Study participants were assigned an individual diet adherence score based on their responses to a food frequency questionnaire (FFQ). The scores from both members of the couple were then averaged and used as the exposure. No analysis was conducted to decipher associations of female or male diet alone with biochemical pregnancy. Biochemical pregnancy was the only examined pregnancy related outcome in this study and no appreciable association with biochemical pregnancy was found in any other study of the MedDiet [ 48 , 49 , 52 ].

Four studies examined associations with clinical pregnancy [ 48 , 49 , 50 , 52 ] (Table 3 ). In a study conducted in a Greek population with 244 women, Karayiannis (2018) reported a positive association between high adherence to the MedDiet (as a continuous variable) and clinical pregnancy in women under the age of 35 (adjusted RR 1.2, 95% CI: 1.05–1.43). Findings were not consistent among older women (adjusted RR 1.00, 95% CI: 0.92–1.09). In a study of 474 Italian women, Ricci (2019) found an association between lower adherence to the MedDiet and risk of not achieving a clinical pregnancy however, contrary to Karayiannis (2018), the association was only present among older women aged ≥35 years. Further, among older women, the association was found only in the intermediate versus lower MedDiet adherence categories (adjusted RR 0.84, 95% CI: 0.71–1.01) and not present in the highest versus lower adherence categories (adjusted RR 0.94, 95% CI: 0.78–1.13). No other study found an appreciable association with clinical pregnancy [ 48 , 52 ].

Three studies examined associations between the MedDiet and live birth [ 48 , 49 , 50 ] (Table 3 ). Gaskins and colleagues (2019) reported a positive association between the MedDiet and the probability of live birth in a sample of 357 U.S. women. There was not a dose-response association and the association was only present when comparing the lowest level of adherence to an intermediate level of adherence (probability of live birth as an adjusted proportion (95% CI) in increasing quartiles of adherence = 0.31 (0.25–0.39), 0.47 (0.39–0.55), 0.44 (0.36–0.49), 0.41 (0.34–0.49). Karayiannis (2018) found a positive association between increased adherence to the MedDiet (as a continuous variable) and live birth. Mirroring the study’s results for clinical pregnancy, the association was only among women under age 35 years (adjusted RR 1.25, 95% CI: 1.07–1.45). Ricci and colleagues (2019) reported no association with live birth in any age or dietary adherence group.

In a study conducted in China, Sun (2019) observed that clinical pregnancy rates in a high versus low adherence group was 42.62% vs. 50.94% and biochemical pregnancy rate 27.97% versus 31.75% respectively (Table 3 ). However, out of 590 participants, only 61 women in the high adherence group and 106 in the low adherence group had an embryo transfer by study completion. Reasons for the abbreviated follow up are not given. Results for biochemical pregnancy and clinical pregnancy were only adjusted for endometrial thickness on embryo transfer day and number of embryos transferred.

‘Profertility’ diet

The ‘profertility’ diet was examined alongside the MedDiet in Gaskins 2019. The ‘profertility’ diet is based on findings from the EARTH study and comprises higher intake of supplemental folic acid, vitamin B12, vitamin D, low-pesticide fruits and vegetables, whole grains, seafood, dairy, and soy foods; and lower intake of high pesticide fruits and vegetables [ 32 , 48 ] (Table 2 ). Higher adherence to the ‘profertility’ diet was positively associated with biochemical pregnancy, clinical pregnancy, and probability of live birth (probability of live birth as an adjusted proportion Q1 vs Q4 (95% CI) = 0.33 (0.26–0.40), 0.56 (0.47–0.64) (Gaskins, 2019) (Table  4 ). Findings were largely attributed to intake of micronutrients and pesticide residues on fruits and vegetables, however an indirect approximated measure of pesticide intake was used to assess exposure [ 48 ]. The sample included 357 women participating in the EARTH study and the ‘profertility’ diet has not been tested in an independent cohort [ 32 , 48 ]. Gaskins (2019) followed women for multiple cycles (maximum of 6 ‘cycles’) and included all ‘in study cycles’ in the main analysis. The sample contained a relatively low number of frozen embryo transfer cycles (14%) versus fresh embryo transfer cycles (82%) when compared with recent (2016) U.S. wide treatment trends (33% frozen embryo transfer cycles versus 33% fresh embryo transfer cycles [ 58 ]).

A Dutch ‘preconception’ diet

In a study of 199 Dutch women undergoing IVF treatment, Twigt (2012) found a positive association between increasing adherence to a Dutch ‘preconception’ diet and ongoing pregnancy at 10 weeks (adjusted OR 1.65, 95% CI: 1.08–2.52) [ 53 ] (Table 4 ). The Dutch ‘preconception’ diet is comprised of: high daily intake of whole grains, vegetables, and fruit; weekly intake of at least three servings of meat or meat replacers and one serving of fish; and use of monounsaturated or polyunsaturated oils [ 53 ] (Table 2 ). The study occurred within the context of a preconception intervention in which women attending an outpatient OB/GYN clinic could opt into counseling to improve their lifestyle, including diet. The analytic population comprised women who opted into the intervention and subsequently underwent an IVF treatment. Findings may have different implications from other findings in this review. Participants were given a preconception dietary risk score (PDR) with the highest score corresponding to dietary intake that meets the basic requirements of a preconception diet. Thus, lower PDRs likely represent inadequate dietary intake and any increase in PDR score, a step toward adequacy. Conversely, it is not clear if lower levels of adherence to most other dietary patterns in this review correspond to an inadequate, or merely different, dietary pattern. Exposure was reassessed in 46% of participants at a voluntary follow up session, however only baseline exposure was used in the analysis.

Dietary patterns with largely null associations with IVF outcomes

The ahei-2010 diet and ‘fertility diet’.

The aHEI-2010 diet and ‘Fertility Diet’ were examined alongside the MedDiet and ‘profertility’ diet in Gaskins, 2019. Higher adherence to the aHEI-2010 diet or the ‘Fertility Diet’ was not appreciably associated with biochemical pregnancy, clinical pregnancy, or live birth (aHEI-2010 diet probability of live birth as an adjusted proportion Q1 vs Q4 (95%CI) = 0.44 (0.36–0.52), 0.37 (0.29–0.45)) (‘Fertility Diet’ probability of live birth as an adjusted proportion Q1 vs Q4 (95%CI) = 0.37 (0.30–0.45), 0.43 (0.34–0.52)) [ 48 ] (Table 4 ). The ‘Fertility Diet’ is comprised of higher intake of monounsaturated fatty acids to trans-fat, vegetable protein, high-fat dairy, iron, and multivitamins; lower intake of animal protein and low-fat dairy; and lower glycemic load. The aHEI-2010 diet is comprised of higher intake of vegetables (excluding potatoes), fruit, whole grains, nuts and legumes, long chain omega-3 fats, polyunsaturated fat, and alcohol; and lower intake of sugar-sweetened beverages, fruit juice, red and processed meat, trans-fat, and sodium [ 48 ] (Table 2 ).

‘Vegetable and seafood’, ‘Western’ and ‘rice and miso soup’ dietary patterns

Like Twigt (2012), Sagawa (2018) examined the association between adherence to a ‘healthier’ dietary pattern, defined as ‘high intake of fruit and vegetables and abundant nutrients’, and IVF outcomes [ 51 ]. Sagawa identified three patterns of dietary intake in a cohort of 140 infertile Japanese women: a ‘healthier’ pattern called ‘vegetable and seafood’ with a high intake of vegetable, seafood, soy, and chicken; and two likely less healthy dietary patterns, ‘Western’ with a high intake of oil, meat, and chicken; and ‘rice and miso soup’ with a high intake of rice and miso soup (Table 2 ). Contrary to Twigt (2012), Sugawa (2018) found no association between higher adherence to a ‘healthier’ pattern and clinical pregnancy, confirmed by ultra sound 21 days after egg retrieval (vegetable and seafood adjusted O R per 1 category increase in adherence = 0.85 95% CI (0.67–1.39)) (‘Western’ = 0.92 95% CI (0.63–1.36))(rice and miso soup = 0.94 95% CI (0.63–1.40)) (Table 4 ).

‘Health-conscious low processed’ dietary pattern

Vujkovik [ 54 ] examined a ‘Mediterranean style’ and ‘health-conscious low processed’ dietary pattern, within the same cohort of 161 couples. The ‘health-conscious low processed’ dietary pattern is defined as containing high intakes of fruits, vegetables, whole grains, fish, and legumes, but low intake of mayonnaise, snacks, and meat products (Table 2 ). Contrary to findings for the ‘Mediterranean style’ dietary pattern, a couple’s higher adherence to a ‘health-conscious low processed’ dietary pattern was associated with reduced odds of biochemical pregnancy (adjusted OR 0.8 (95% CI: 0.6–1.0) (Table 4 ). Vujkovik [ 54 ] attributes the difference in findings to higher intake of linoleic acid, a component found in vegetable oil, and higher levels of vitamin B6 found in the serum and follicular fluid of women with higher adherence to a ‘Mediterranean style’ dietary pattern.

Study characteristics likely leading to increased heterogeneity

Study population and exclusion criteria.

Studies were conducted in six countries: China, Japan, Greece, Italy, the Netherlands ( n  = 2), and U.S. (Supplement Table  2 ). Three studies excluded women based on underlying medical and/or reproductive conditions including; hypertension, endometriosis, or tubal factor infertility [ 49 , 51 , 54 ]. Two excluded older women (over 40 or 41) [ 49 , 52 ], two excluded women based on treatment protocol [ 49 , 52 ], and three studies contained a higher percentage of participants with male versus female factor infertility [ 49 , 53 , 54 ]. By exclusion criteria, one study each excluded women who did not undergo an ART treatment [ 48 ], did not undergo an embryo transfer [ 53 ], or became pregnant before treatment started [ 54 ].

Dietary patterns and components

Across studies, the exposure under investigation (dietary pattern) was selected using two different methods (Supplemental Table  2 ). In two studies, an α-posteriori approach was utilized [ 51 , 54 ]. Results from participant questionnaires or FFQ were examined and the exposure was derived based on which dietary pattern best fit the data. In the remaining studies, investigators used a hypothesis driven α-priori approach. An exposure was chosen before dietary intake information was obtained and a FFQ or questionnaire appropriate for the respective pattern administered.

No two studies included the same dietary components in their definitions of the MedDiet (Table 2 ). All MedDiet definitions included higher intake of seafood, legumes, fruits, and vegetables. Most included low consumption of meat [ 48 , 49 , 50 , 52 ] and low to moderate (versus no or high) intake of alcohol [ 48 , 49 , 50 , 54 ]. Definitions inconsistently included; whole grains, type of fats and oils, dairy, nuts, poultry, and potatoes (Table 2 ).

Time period of exposure assessment

All studies reporting the exposure window period asked participants about relatively recent dietary intake with exposure windows ranging from four weeks [ 54 ] to twelve months prior to exposure assessment [ 48 , 49 , 50 , 52 ] (Supplemental Table 2 ). In Sugawa (2018), participants reported their current dietary intake during the month leading up to oocyte retrieval, and in Twigt (2012) the exposure window is not stated. In two studies, women were asked whether they had changed their diet during the exposure window and were excluded if they had made a change [ 49 , 52 ]. In the remaining studies, diet change during the exposure window was not reported [ 48 , 50 , 51 , 53 , 54 ].

Study end points and follow-up

Study length varied from one month [ 51 ] to ten years [ 48 ] (Supplemental Table 2 ). Participants were followed until the occurrence of at least one of the following events: biochemical pregnancy, clinical pregnancy, or live birth; completion of a maximum of six medical stimulation ‘cycles’ or treatment cessation [ 48 ], one oocyte retrieval and the transfer of resulting fresh and/or frozen embryos (only cycle with ‘best’ outcome included in analysis) [ 50 ], one oocyte retrieval and transfer of only the first fresh embryo(s) [ 49 , 51 , 53 , 54 ], or until study end date [ 52 ]. The maximum time period between the exposure assessment and reproductive outcome was not explicitly stated across studies, however likely ranged from weeks and months [ 48 , 49 , 50 , 51 , 52 , 53 , 54 ] to years [ 48 , 50 ], and in the case of Gaskins and colleagues (2019), potentially up to ten years.

Outcome definitions

Outcomes were defined somewhat inconsistently (Supplemental Table  2 ). Four studies reported on biochemical pregnancy defined as a rise in serum βhCG 14–21 days after oocyte retrieval [ 48 , 49 ], urine test 15 days after oocyte retrieval [ 54 ], and undefined in one [ 52 ]. Six studies reported on clinical pregnancy confirmed by ultrasound at 6–10 weeks [ 48 , 49 , 50 , 51 , 53 ], and undefined in one study [ 52 ]. Three studies reported the outcome of live birth, which was defined as birth of a neonate after 24 weeks in two studies [ 48 , 49 ] and not defined in the third study [ 50 ].

Study characteristics likely leading to methodological challenges

Exposure assessment.

All studies utilized questionnaires to assess exposure, with most utilizing a validated self-administered semi-quantitative FFQ (number of items ranging from 6 to 131) [ 48 , 49 , 51 , 54 ] (Supplemental Table  2 ). No questionnaire was validated prospectively in a population of women experiencing infertility and/or undergoing IVF treatment. In all studies, for exposure classification, participants were grouped into categories of adherence (e.g., low, intermediate, high) to the dietary pattern under investigation in relation to other participants’ adherence based on questionnaire responses. In all studies, exposure used for analyses and covariates were assessed once at baseline and not reassessed during the follow up period for changes. Studies including participants who utilized cryopreserved embryos or oocytes did not assess exposure at both the time of cryopreservation and the time of attempted use/transfer into a uterus [ 48 , 50 ].

Timing of recruitment and exposure data collection

It is unclear if studies included baseline data on the duration of the current pregnancy attempt. A portion of participants in three studies had undergone at least one prior IVF treatment cycle during the current pregnancy attempt at the time of recruitment [ 48 , 50 , 54 ] while no participant had a previous IVF treatment in two studies [ 49 , 51 ] (Supplemental Table  2 ). Four studies collected information on participants’ ‘duration of infertility’ at the time of baseline data collection [ 49 , 52 , 53 , 54 ]. In the two studies in which a range of data was provided, participants had a mean duration of 3 years [ 49 , 52 ]. Six studies collected exposure data subsequent to initial consultation for infertility; three at treatment initiation [ 48 , 51 , 52 ], two at the time of oocyte retrieval [ 49 , 50 ] and one at the time of embryo transfer [ 54 ].

Covariates collected for assessment of confounding

Female age and body mass index (BMI) were the only covariates controlled for in all studies (Supplemental Table  2 ). All but one study controlled for energy intake and smoking [ 52 ]. ‘Duration of infertility’, previous use of ART, infertility diagnosis (male, female, unexplained), education, income, treatment protocol and use of ICSI, parity, physical activity, vitamin/supplement use, alcohol and caffeine intake, paternal covariates, and covariates related to mental health were inconsistently controlled for [ 48 , 49 , 50 , 51 , 52 , 53 , 54 ].

Associations between dietary patterns and IVF outcomes

Nine different dietary patterns from seven observational studies were examined among participants. Higher adherence to the MedDiet, a Dutch ‘preconception’ diet, and a ‘profertility’ diet were associated with improvements in biochemical pregnancy, clinical pregnancy, or live birth in at least one study. Amongst studies of the MedDiet, findings were inconsistent and dose-response associations were only found in one study. Within the study, associations were modified by age and present only among women age < 35 and only for the outcomes of clinical pregnancy and live birth. Although examined in one relatively small population, increased adherence to a ‘profertility’ diet was associated with improvements in biochemical pregnancy, clinical pregnancy, and live birth. Likewise, higher adherence to a Dutch ‘preconception diet’ was associated with improvements in clinical pregnancy in a single small study. The aHEI-2010 diet, ‘Fertility Diet’, ‘health-conscious low processed’ dietary pattern, ‘vegetable and seafood’ dietary pattern, ‘Western’ dietary pattern, and ‘rice and miso soup’ dietary pattern were not materially associated with improved IVF outcomes. Explanations for differences in findings across and within studies on the MedDiet put forth by study authors include the escalating and overshadowing influence of age on fertility [ 49 ], lack of accounting for dietary supplements [ 50 ], and insufficient statistical power [ 51 ]. Likewise, authors of studies investigating remaining dietary patterns hypothesize that differences may be attributed to intake of substances such as pesticides [ 48 ] and linoleic acid [ 54 ]. However, causative conclusions are difficult to draw due to the high degree of heterogeneity across studies and potential bias resulting from methodological issues which may mask true associations.

Heterogeneity across studies

Sources of heterogeneity included different study populations, dates, and length; selection of participants and dietary pattern under investigation; exposure window and assessment relative to the outcome; outcomes investigated and definitions; and control for potential confounders. However, differences in how the MedDiet was defined, geographic locations, and study end points make comparing studies especially difficult.

The MedDiet has over 34 definitions across the broader literature differing by a number of factors including constituent dietary components [ 59 , 60 ]. In this review, five different MedDiet definitions were used, one determined α posteriori, and some included and/or excluded individual dietary components that have been independently associated with reproductive outcomes [ 31 ]. Moderate intake (0.5–2 glasses per day) of alcohol is a common yet controversial component of the MedDiet [ 61 , 62 , 63 ]. There is uncertainty around the safety of women’s alcohol consumption during conception and pregnancy [ 64 , 65 , 66 ], however alcohol was incorporated into almost all definitions of the MedDiet in this review. Due to the low number of studies using any one MedDiet definition, we cannot speculate on the extent to which definitional differences may have affected findings across studies. However, in future studies, it may be informative to compare analyses within a given population using different existing definitions of the MedDiet and prudent to consider excluding alcohol from future dietary pattern definitions used in studies on this topic.

Geographic location of studies may contribute to heterogeneity and affect observed associations across studies [ 67 , 68 ]. Studies examining the MedDiet were conducted in five different countries, two in Mediterranean regions. As studies on the MedDiet generally contain internal comparison groups and the range of adherence differs across geographic regions, it is difficult to appreciate how the same categories of dietary intake correlate across studies. Similarly, different populations may not contain enough heterogeneity in dietary intake to fully test some hypotheses [ 37 , 69 ]. In future studies, it may be useful to provide a population mean and range or clinically based cut points (when available), so that it is easier to understand how results may apply in different populations.

Lastly, study end points were heterogenous across studies. Ideally, in a study on IVF treatment, women would be followed for all pregnancy attempts until they achieved the outcome of interest or stopped treatment. Most studies on the MedDiet followed women for one fresh embryo transfer. While abbreviating the follow-up period simplifies the data collection and analysis, this strategy can oversimplify associations [ 70 ] and limit comparability. For instance, associations between exposure and the results from a single first fresh embryo transfer versus multiple embryo transfers or transfers with cryopreserved embryos, may differ. When placing findings into context, it may be helpful to limit comparisons to studies with similar end points so that women and clinicians can better interpret results.

Methodological challenges

Three key methodological challenges of existing studies include the inaccurate assessment of exposure, enrollment of women with previous pregnancy attempts, and lack of comprehensive control for confounding.

Collecting accurate exposure information

Information about the potential impact of diet, healthy eating and weight loss on fertility is widely available [ 71 , 72 , 73 ]. Studies have reported that some women change their habits in response to unsuccessful pregnancy attempts [ 74 , 75 , 76 , 77 , 78 , 79 ] and that populations of women undergoing IVF treatment have a higher prevalence of disordered eating when compared with the general population [ 80 , 81 , 82 , 83 , 84 ].

Exposure in all studies was based on information from a single questionnaire or FFQ. However, the accuracy of FFQs and questionnaires can vary across populations [ 85 , 86 ]. No study questionnaire was prospectively validated among women experiencing infertility and/or undergoing IVF treatment before use, potentially resulting in exposure misclassification. Exposure misclassification would likely attenuate associations toward the null as the outcomes was not known at the time of assessment. Even with a validated FFQ, collecting accurate information on exposure is difficult as FFQs are designed to approximate intake over a period of time. Few studies assessed if women changed their diet during the exposure window [ 49 , 52 ] increasing risk for heterogeneity within categories of exposure. Future studies would benefit from FFQs prospectively validated in populations of women undergoing IVF and collecting data on any dietary changes during the exposure window.

Enrollment of women with previous pregnancy attempts

All studies recruited women seeking IVF treatment and it’s unclear if studies collected data on number of previous pregnancy attempts. Women seek and receive IVF treatment after a different number of pregnancy attempts and two studies included women with prior IVF attempts [ 87 , 88 ]. Thus, cohorts likely contained samples with a heterogenous number of prior pregnancy attempts at baseline. If the dietary pattern under study is a cause of improved fertility, then women with higher adherence to the dietary pattern will have higher underlying fertility and will be less likely to be included in the study, resulting in a selection bias (left truncation) that could attenuate associations toward the null [ 89 , 90 ]. To minimize (but not eliminate) bias from left truncation, future studies examining associations between dietary patterns and IVF outcomes could, at the very least, enroll and follow women from their initial consult at an infertility treatment center.

If infertility or a previous unsuccessful IVF cycle caused a change in diet, then reverse causation could be a potential source of bias in studies that enroll infertile couples utilizing IVF treatment. Reverse causation usually occurs in studies when participants’ knowledge of the outcome influences their exposure [ 91 ]. Although all exposure data was collected prior to the outcome, there is the potential for reverse causation if participants had related outcomes and believe their exposure may be related to these outcomes [ 23 , 92 , 93 ]. Women have reported using diet to enhance IVF treatment success since as early as 2001 [ 73 , 75 , 94 , 95 ] and no data was collected in any study in this review regarding participants’ knowledge of the associations between diet and reproductive outcomes. The potential for reverse causation could be assessed in future studies by collecting data on participants’ knowledge of the potential associations between diet, fertility, and IVF outcomes, and if any change in diet was related to their knowledge.

Controlling for confounding

While all studies in this review collected data on potential confounders, it is difficult to anticipate and collect data on every possible confounder related to diet. Most authors acknowledge the potential for residual confounding. However, potentially important sources of residual confounding not addressed in most studies include male diet, which often mirrors female diet [ 96 , 97 , 98 , 99 ]; complementary and ‘add-on’ therapies, which may be used by women in conjunction with diet to enhance fertility [ 78 , 100 , 101 , 102 , 103 , 104 , 105 ]; and weight loss [ 106 , 107 ]. At a minimum, all studies should collect a broad range of data on potential confounders including demographic factors (e.g., race, ethnicity, age, and country of origin), socioeconomic position (e.g., education, occupation, income, and marital status), behavioral factors, lifestyle, anthropometrics, multivitamin use, medication use, and medical, and reproductive history. In addition, all studies should control for total energy intake to adjust for confounding, reduce measurement error, and account for differences in basal metabolic rate and body size.

Limitations

Limitations to our systematic review should be noted when considering its findings. Across the literature, no study investigated long-term dietary patterns, therefore results only reflect recent intake. We included only English language publications in our search and excluded studies with samples restricted to women who were overweight and/or diagnosed with PCOS. A prospective registration was not undertaken and a single author conducted the literature search and screen. A meta-analysis was not conducted due to the high degree of heterogeneity across studies and the low number of studies examining any one dietary pattern and any one outcome. We did not discuss potential limitations of different statistical approaches and some findings from included studies may be spurious. Conversely, strengths of our review include the systematic approach and focus on sources of heterogeneity and bias. Likewise, our review included all study dates during the literature search and all identified dietary patterns that fit the review criteria.

The literature on associations between female diet and fertility is rapidly expanding. This review adds to the current knowledge by highlighting: female dietary patterns that have been investigated for associations with IVF outcomes, ways in which studies differ, methodological challenges, and strategies that could be employed in future studies. Although some studies reported positive associations between female dietary patterns and IVF outcomes, causation cannot be assumed. Studies were potentially hindered by methodological challenges (misclassification of exposure, left truncation, and lack of comprehensive control for confounding) with an associated risk of bias. In particular, studies of the MedDiet were highly heterogenous in study population, methods, and findings, and remaining dietary patterns have each only been examined in single and relatively small populations of women. Future studies with rigorous and more uniform methodologies are needed to determine the association between female dietary patterns and IVF outcomes. At the clinical level, findings from this review do not support recommending any single dietary pattern for the purpose of improving pregnancy or live birth rates in women undergoing IVF treatment.

Availability of data and materials

Not applicable.

Abbreviations

in vitro fertilization

Assisted Reproductive Technology

Intracytoplasmic Sperm Injection

beta Human Chorionic Gonadotrophin

Polycystic Ovarian Syndrome

the study of Environmental and Reproductive Health

Mediterranean Diet and ‘Mediterranean style’ Dietary pattern

alternate healthy eating index 2010

Food Frequency Questionnaire

Preconception Dietary Risk Score

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Acknowledgements

We would like to thank Wanda Anderson for her assistance with the literature search and Susan Kelly-Weeder for providing feedback on an early draft.

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Sanderman, E.A., Willis, S.K. & Wise, L.A. Female dietary patterns and outcomes of in vitro fertilization (IVF): a systematic literature review. Nutr J 21 , 5 (2022). https://doi.org/10.1186/s12937-021-00757-7

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In Vitro Fertilization Research is Translational Research

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In vitro fertilization (IVF) is the perfect example of translational research. Changes in IVF and the IVF laboratory have been transmitted to clinical care, showing dramatic improvements in health outcomes, including notable increases in the cumulative pregnancy rate. Current research in the laboratory focusing on culture media, embryo selection criteria, and implementation of genetic testing and manipulation promises to translate to further improvements in our ability to assist human reproduction. The field of IVF and ART remains a large source for clinical and scientific discovery and development, and will require the proper interested and invested personnel, occupational structuring, and funding for continued success.

Keywords: ART; IVF; assisted reproductive technologies; evidence-based medicine; in vitro fertilization; translational research.

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In vitro fertilization (IVF) and aneuploidy

Fetal aneuploidy can lead to developmental abnormalities as well as implantation failure after in vitro fertilization. Preimplantation genetic testing for aneuploidy (PGT-A) is designed to minimize these risks. 

PGT-A encompasses a range of methods, including comparative genomic hybridization, single nucleotide polymorphism array, quantitative PCR, and next-generation sequencing, using either a blastomere or trophectoderm cells from the blastocyst. These methods vary in their ability to detect partial aneuploidy (where one chromosomal portion is duplicated or absent in all cells), mosaicism, and partial mosaicism (where one cell line is euploid and the other is partial aneuploid). While advances in biopsy, screening, and embryo culture techniques have improved the efficacy and accessibility of PGT-A, there remains some debate over the evidence supporting its widespread use. 

This Collection will highlight original research on all aspects of IVF and aneuploidy, including current approaches in preimplantation genetic testing and the clinical implications of preimplantation aneuploidy and mosaicism.  

Yasushi Hirota, MD, PhD

Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tokyo, Japan

Michał Kunicki, MD, PhD

Medical University of Warsaw, Poland INVICTA Fertility Clinic, Warsaw, Poland

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In Vitro Fertilization: A Method Facilitating the Production of Hybrid Embryos and Plants

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In vitro pollination techniques facilitate detailed studies on fertilization, and embryo, and endosperm development in controlled environment including the effects of various physical and chemical factors on the processes. The term in vitro pollination includes: 1/ direct pollination of ovules followed by their culture together with the placenta and parts of the calyx, on a suitable medium; this is referred to as placental pollination, and 2/ pollination of stigmas of the pistils which are then cultured along with a part of the pedicel and calyx. There can be various modifications of the above mentioned procedures depending on the type of experimental material. For example, in Solanaceae, the whole ovary wall is removed, while in Brassicaceae only the upper part of the ovary is cut off in order to make an opening for the deposition of pollen grains.

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Douglas, G.C., Connolly, V. Self-fertilization and seed set in Trifolium repens L. by in situ and in vitro pollination. Theor. Appl. Genet. 77: 71 – 75; 1989.

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Murashige, T., Skoog, F. A revised medium for rapid growth and bioassay with tobacco tissue cultures. Physiol. Plant. 15: 473 – 497; 1962.

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Shulz, O. Cruciferae. In: Engler A. (ed.). Die Naturlichen Pflanzenfamilien. Wilhelm Engelmann, Leipzig, 17b: 1–799; 1936.

Stewart, J. McD. In vitro fertilization and embryo rescue. Environmental and Experimental Botany 21: 301–315; 1981.

Zenkteler, M. In vitro fertilization and wide hybridization in higher plants. Crit. Rev. Plant Sci. 9: 267–279; 1990.

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Zenkteler, M. (1992). In Vitro Fertilization: A Method Facilitating the Production of Hybrid Embryos and Plants. In: Ottaviano, E., Gorla, M.S., Mulcahy, D.L., Mulcahy, G.B. (eds) Angiosperm Pollen and Ovules. Springer, New York, NY. https://doi.org/10.1007/978-1-4612-2958-2_53

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• In vitro fertilization (IVF)

• In vitro fertilization

During in vitro fertilization, eggs are removed from sacs called follicles within an ovary (A). An egg is fertilized by injecting a single sperm into the egg or mixing the egg with sperm in a petri dish (B). The fertilized egg, called an embryo, is transferred into the uterus (C).

In vitro fertilization, also called IVF, is a complex series of procedures that can lead to a pregnancy. It's a treatment for infertility, a condition in which you can't get pregnant after at least a year of trying for most couples. IVF also can be used to prevent passing on genetic problems to a child.

During in vitro fertilization, mature eggs are collected from ovaries and fertilized by sperm in a lab. Then a procedure is done to place one or more of the fertilized eggs, called embryos, in a uterus, which is where babies develop. One full cycle of IVF takes about 2 to 3 weeks. Sometimes these steps are split into different parts and the process can take longer.

In vitro fertilization is the most effective type of fertility treatment that involves the handling of eggs or embryos and sperm. Together, this group of treatments is called assisted reproductive technology.

IVF can be done using a couple's own eggs and sperm. Or it may involve eggs, sperm or embryos from a known or unknown donor. In some cases, a gestational carrier — someone who has an embryo implanted in the uterus — might be used.

Your chances of having a healthy baby using IVF depend on many factors, such as your age and the cause of infertility. What's more, IVF involves getting procedures that can be time-consuming, expensive and invasive. If more than one embryo is placed in the uterus, it can result in a pregnancy with more than one baby. This is called a multiple pregnancy.

Your health care team can help you understand how IVF works, what the risks are and whether it's right for you.

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Why it's done

In vitro fertilization is a treatment for infertility or genetic problems. Before you have IVF to treat infertility, you and your partner might be able to try other treatment options that involve fewer or no procedures that enter the body. For example, fertility drugs can help the ovaries make more eggs. And a procedure called intrauterine insemination places sperm directly in the uterus near the time when an ovary releases an egg, called ovulation.

Sometimes, IVF is offered as a main treatment for infertility in people over the age of 40. It also can be done if you have certain health conditions. For example, IVF may be an option if you or your partner has:

• Fallopian tube damage or blockage. Eggs move from the ovaries to the uterus through the fallopian tubes. If both tubes get damaged or blocked, that makes it hard for an egg to be fertilized or for an embryo to travel to the uterus.
• Ovulation disorders. If ovulation doesn't happen or doesn't occur often, fewer eggs are available to be fertilized by sperm.
• Endometriosis. This condition happens when tissue that's like the lining of the uterus grows outside of the uterus. Endometriosis often affects the ovaries, uterus and fallopian tubes.
• Uterine fibroids. Fibroids are tumors in the uterus. Most often, they're not cancer. They're common in people in their 30s and 40s. Fibroids can cause a fertilized egg to have trouble attaching to the lining of the uterus.
• Previous surgery to prevent pregnancy. An operation called tubal ligation involves having the fallopian tubes cut or blocked to prevent pregnancy for good. If you wish to conceive after tubal ligation, IVF may help. It might be an option if you don't want or can't get surgery to reverse tubal ligation.
• Issues with sperm. A low number of sperm or unusual changes in their movement, size or shape can make it hard for sperm to fertilize an egg. If medical tests find issues with sperm, a visit to an infertility specialist might be needed to see if there are treatable problems or other health concerns.
• Unexplained infertility. This is when tests can't find the reason for someone's infertility.
• A genetic disorder. If you or your partner is at risk of passing on a genetic disorder to your child, your health care team might recommend getting a procedure that involves IVF . It's called preimplantation genetic testing. After the eggs are harvested and fertilized, they're checked for certain genetic problems. Still, not all of these disorders can be found. Embryos that don't appear to contain a genetic problem can be placed in the uterus.

A desire to preserve fertility due to cancer or other health conditions. Cancer treatments such as radiation or chemotherapy can harm fertility. If you're about to start treatment for cancer, IVF could be a way to still have a baby in the future. Eggs can be harvested from their ovaries and frozen for later use. Or the eggs can be fertilized and frozen as embryos for future use.

People who don't have a working uterus or for whom pregnancy poses a serious health risk might choose IVF using another person to carry the pregnancy. The person is called a gestational carrier. In this case, your eggs are fertilized with sperm, but the embryos that result are placed in the gestational carrier's uterus.

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IVF raises the chances of certain health problems. From short term to longer term, these risks include:

• Stress. IVF can be draining for the body, mind and finances. Support from counselors, family and friends can help you and your partner through the ups and downs of infertility treatment.
• Complications from the procedure to retrieve eggs. After you take medicines to spur the growth of sacs in the ovaries that each contain an egg, a procedure is done to collect the eggs. This is called egg retrieval. Ultrasound images are used to guide a long, thin needle through the vagina and into the sacs, also called follicles, to harvest the eggs. The needle could cause bleeding, infection or damage to the bowel, bladder or a blood vessel. Risks are also linked with medicines that can help you sleep and prevent pain during the procedure, called anesthesia.

Ovarian hyperstimulation syndrome. This is a condition in which the ovaries become swollen and painful. It can be caused by receiving shots of fertility medicines, such as human chorionic gonadotropin (HCG), to trigger ovulation.

Symptoms often last up to a week. They include mild belly pain, bloating, upset stomach, vomiting and diarrhea. If you become pregnant, your symptoms might last a few weeks. Rarely, some people get a worse form of ovarian hyperstimulation syndrome that also can cause rapid weight gain and shortness of breath.

• Miscarriage. The rate of miscarriage for people who conceive using IVF with fresh embryos is similar to that of people who conceive naturally — about 15% for pregnant people in their 20s to over 50% for those in their 40s. The rate rises with the pregnant person's age.
• Ectopic pregnancy. This is a condition in which a fertilized egg attaches to tissue outside the uterus, often in a fallopian tube. The embryo can't survive outside the uterus, and there's no way to continue the pregnancy. A small percentage of people who use IVF will have an ectopic pregnancy.
• Multiple pregnancy. IVF raises the risk of having more than one baby. Becoming pregnant with multiple babies carries higher risks of pregnancy-related high blood pressure and diabetes, early labor and delivery, low birth weight, and birth defects than does pregnancy with a single baby.
• Birth defects. The age of the mother is the main risk factor for birth defects, no matter how the child is conceived. But assisted reproductive technologies such as IVF are linked with a slightly higher risk of a baby being born with heart issues, digestive problems or other conditions. More research is needed to find out if it's IVF that causes this raised risk or something else.
• Premature delivery and low birth weight. Research suggests that IVF slightly raises the risk that the baby will be born early or with a low birth weight.
• Cancer. Some early studies suggested that certain medicines used to stimulate egg growth might be linked with getting a specific type of ovarian tumor. But more-recent studies do not support these findings. There doesn't seem to be a significantly higher risk of breast, endometrial, cervical or ovarian cancer after IVF .

How you prepare

To get started, you'll want to find a reputable fertility clinic. If you live in the United States, the Centers for Disease Control and Prevention and the Society for Assisted Reproductive Technology provide information online about clinics' individual pregnancy and live birth rates.

A fertility clinic's success rate depends on many things. These include the ages and medical issues of people they treat, as well as the clinic's treatment approaches. When you talk with a representative at a clinic, also ask for detailed information about the costs of each step of the procedure.

Before you start a cycle of IVF using your own eggs and sperm, you and your partner will likely need various screening tests. These include:

• Ovarian reserve testing. This involves getting blood tests to find out how many eggs are available in the body. This is also called egg supply. The results of the blood tests, often used together with an ultrasound of the ovaries, can help predict how your ovaries will respond to fertility medicines.
• Semen analysis. Semen is the fluid that contains sperm. An analysis of it can check the amount of sperm, their shape and how they move. This testing may be part of an initial fertility evaluation. Or it might be done shortly before the start of an IVF treatment cycle.
• Infectious disease screening. You and your partner will both be screened for diseases such as HIV .
• Practice embryo transfer. This test doesn't place a real embryo in the uterus. It may be done to figure out the depth of your uterus. It also helps determine the technique that's most likely to work well when one or more actual embryos are inserted.
• Uterine exam. The inside lining of the uterus is checked before you start IVF . This might involve getting a test called sonohysterography. Fluid is sent through the cervix into the uterus using a thin plastic tube. The fluid helps make more-detailed ultrasound images of the uterine lining. Or the uterine exam might include a test called hysteroscopy. A thin, flexible, lighted telescope is inserted through the vagina and cervix into the uterus to see inside it.

Before you begin a cycle of IVF , think about some key questions, including:

How many embryos will be transferred? The number of embryos placed in the uterus often is based on age and the number of eggs collected. Since the rate of fertilized eggs attaching to the lining of uterus is lower for older people, usually more embryos are transferred — except for people who use donor eggs from a young person, genetically tested embryos or in certain other cases.

Most health care professionals follow specific guidelines to prevent a multiple pregnancy with triplets or more. In some countries, legislation limits the number of embryos that can be transferred. Make sure you and your care team agree on the number of embryos that will be placed in the uterus before the transfer procedure.

What will you do with any extra embryos? Extra embryos can be frozen and stored for future use for many years. Not all embryos will survive the freezing and thawing process, but most will.

Having frozen embryos can make future cycles of IVF less expensive and less invasive. Or you might be able to donate unused frozen embryos to another couple or a research facility. You also might choose to discard unused embryos. Make sure you feel comfortable making decisions about extra embryos before they are created.

• How will you handle a multiple pregnancy? If more than one embryo is placed in your uterus, IVF can cause you to have a multiple pregnancy. This poses health risks for you and your babies. In some cases, a surgery called fetal reduction can be used to help a person deliver fewer babies with lower health risks. Getting fetal reduction is a major decision with ethical, emotional and mental risks.
• Have you thought through the risks linked with using donor eggs, sperm or embryos, or a gestational carrier? A trained counselor with expertise in donor issues can help you understand the concerns, such as the legal rights of the donor. You also may need an attorney to file court papers to help you become legal parents of an embryo that's developing in the uterus.

What you can expect

After the preparations are completed, one cycle of IVF can take about 2 to 3 weeks. More than one cycle may be needed. The steps in a cycle go as follows:

Treatment to make mature eggs

The start of an IVF cycle begins by using lab-made hormones to help the ovaries to make eggs — rather than the single egg that usually develops each month. Multiple eggs are needed because some eggs won't fertilize or develop correctly after they're combined with sperm.

Certain medicines may be used to:

• Stimulate the ovaries. You might receive shots of hormones that help more than one egg develop at a time. The shot may contain a follicle-stimulating hormone (FSH), a luteinizing hormone (LH) or both.
• Help eggs mature. A hormone called human chorionic gonadotropin (HCG), or other medicines, can help the eggs ripen and get ready to be released from their sacs, called follicles, in the ovaries.
• Delay ovulation. These medicines prevent the body from releasing the developing eggs too soon.
• Prepare the lining of the uterus. You might start to take supplements of the hormone progesterone on the day of the procedure to collect your eggs. Or you might take these supplements around the time an embryo is placed in the uterus. They improve the odds that a fertilized egg attaches to the lining of your uterus.

Your doctor decides which medicines to use and when to use them.

Most often, you'll need 1 to 2 weeks of ovarian stimulation before your eggs are ready to be collected with the egg retrieval procedure. To figure out when the eggs are ready, you may need:

• Vaginal ultrasound, an imaging exam of the ovaries to track the developing follicles. Those are the fluid-filled sacs in the ovaries where eggs mature.
• Blood tests, to check on how you respond to ovarian stimulation medicines. Estrogen levels often rise as follicles develop. Progesterone levels remain low until after ovulation.

Sometimes, IVF cycles need to be canceled before the eggs are collected. Reasons for this include:

• Not enough follicles develop.
• Ovulation happens too soon.
• Too many follicles develop, raising the risk of ovarian hyperstimulation syndrome.
• Other medical issues happen.

If your cycle is canceled, your care team might recommend changing medicines or the amounts you take, called doses. This might lead to a better response during future IVF cycles. Or you may be advised that you need an egg donor.

Egg retrieval

This is the procedure to collect the eggs from one or both ovaries. It takes place in your doctor's office or a clinic. The procedure is done 34 to 36 hours after the final shot of fertility medicine and before ovulation.

• Before egg retrieval, you'll be given medicine to help you relax and keep you from feeling pain.
• An ultrasound device is placed into the vagina to find follicles. Those are the sacs in the ovaries that each contain an egg. Then a thin needle is inserted into an ultrasound guide to go through the vagina and into the follicles to collect the eggs. This process is called transvaginal ultrasound aspiration.
• If your ovaries can't be reached through the vagina this way, an ultrasound of the stomach area may be used to guide the needle through the stomach and into the ovaries.
• The eggs are removed from the follicles through a needle connected to a suction device. Multiple eggs can be removed in about 20 minutes.
• After the procedure, you may have cramping and feelings of fullness or pressure.
• Mature eggs are placed in a liquid that helps them develop. Eggs that appear healthy and mature will be mixed with sperm to attempt to create embryos. But not all eggs are able to be fertilized with success.

Sperm retrieval

If you're using your partner's sperm, a semen sample needs to be collected at your doctor's office or clinic the morning of egg retrieval. Or sperm can be collected ahead of time and frozen.

Most often, the semen sample is collected through masturbation. Other methods can be used if a person can't ejaculate or has no sperm in the semen. For example, a procedure called testicular aspiration uses a needle or surgery to collect sperm directly from the testicle. Sperm from a donor also can be used. Sperm are separated from the semen fluid in the lab.

Fertilization

Two common methods can be used to try to fertilize eggs with sperm:

• Conventional insemination. Healthy sperm and mature eggs are mixed and kept in a controlled environment called an incubator.
• Intracytoplasmic sperm injection (ICSI). A single healthy sperm is injected right into each mature egg. Often, ICSI is used when semen quality or number is an issue. Or it might be used if fertilization attempts during prior IVF cycles didn't work.

In certain situations, other procedures may be recommended before embryos are placed in the uterus. These include:

Assisted hatching. About 5 to 6 days after fertilization, an embryo "hatches" from the thin layer that surrounds it, called a membrane. This lets the embryo attach to the lining of the uterus.

If you're older and you want to get pregnant, or if you have had past IVF attempts that didn't work, a technique called assisted hatching might be recommended. With this procedure, a hole is made in the embryo's membrane just before the embryo is placed in the uterus. This helps the embryo hatch and attach to the lining of the uterus. Assisted hatching is also useful for eggs or embryos that were frozen, as that process can harden the membrane.

Preimplantation genetic testing. Embryos are allowed to develop in the incubator until they reach a stage where a small sample can be removed. The sample is tested for certain genetic diseases or the correct number of threadlike structures of DNA, called chromosomes. There are usually 46 chromosomes in each cell. Embryos that don't contain affected genes or chromosomes can be transferred to the uterus.

Preimplantation genetic testing can lower the chances that a parent will pass on a genetic problem. It can't get rid of the risk completely. Prenatal testing may still be recommended during pregnancy.

Embryo transfer

Egg-retrieval technique

Typically, transvaginal ultrasound aspiration is used to retrieve eggs. During this procedure, an ultrasound probe is inserted into the vagina to identify follicles. A needle is guided through the vagina and into the follicles. The eggs are removed from the follicles through the needle, which is connected to a suction device.

In intracytoplasmic sperm injection (ICSI), a single healthy sperm is injected directly into each mature egg. ICSI often is used when semen quality or number is a problem or if fertilization attempts during prior in vitro fertilization cycles failed.

Three days after fertilization, a healthy embryo will contain about 6 to 10 cells. By the fifth or sixth day, the fertilized egg is known as a blastocyst — a rapidly dividing ball of cells. The inner group of cells will become the embryo. The outer group will become the cells that nourish and protect it.

The procedure to place one or more embryos in the uterus is done at your doctor's office or a clinic. It often takes place 2 to 6 days after eggs are collected.

• You might be given a mild sedative to help you relax. The procedure is often painless, but you might have mild cramping.
• A long, thin, flexible tube called a catheter is placed into the vagina, through the cervix and into the uterus.
• A syringe that contains one or more embryos in a small amount of fluid is attached to the end of the catheter.
• Using the syringe, the embryo or embryos are placed into the uterus.

If the procedure works, an embryo will attach to the lining of your uterus about 6 to 10 days after egg retrieval.

After the procedure

After the embryo transfer, you can get back to your usual daily routine. Your ovaries may still be enlarged, so vigorous activities or sex might cause discomfort. Ask your care team how long you should stay away from these.

Typical side effects include:

• Passing a small amount of clear or bloody fluid shortly after the procedure. This is due to the swabbing of the cervix before the embryo transfer.
• Breast tenderness due to high estrogen levels.
• Mild bloating.
• Mild cramping.
• Constipation.

Call your care team if you have moderate or severe pain, or heavy bleeding from the vagina after the embryo transfer. You'll likely to need to get checked for complications such as infection, twisting of an ovary and ovarian hyperstimulation syndrome.

At least 12 days after egg retrieval, you get a blood test to find out whether you're pregnant.

• If you're pregnant, you'll likely be referred to an obstetrician or other pregnancy specialist for prenatal care.
• If you're not pregnant, you'll stop taking progesterone and likely get your period within a week. Call your care team if you don't get your period or if you have unusual bleeding. If you'd like to try another cycle of IVF , your care team might suggest steps you can take to improve your chances of getting pregnant next time.

The chances of giving birth to a healthy baby after using IVF depend on various factors, including:

• Maternal age. The younger you are, the more likely you are to get pregnant and give birth to a healthy baby using your own eggs during IVF . Often, people 40 and older are counseled to think about using donor eggs during IVF to boost the chances of success.
• Embryo status. Transfer of embryos that are more developed is linked with higher pregnancy rates compared with less-developed embryos. But not all embryos survive the development process. Talk with your care team about your specific situation.
• Reproductive history. People who've given birth before are more likely to be able to get pregnant using IVF than are people who've never given birth. Success rates are lower for people who've already tried IVF multiple times but didn't get pregnant.
• Cause of infertility. Having an average supply of eggs raises your chances of being able to get pregnant using IVF . People who have severe endometriosis are less likely to be able to get pregnant using IVF than are those who have infertility without a clear cause.
• Lifestyle factors. Smoking can lower the chance of success with IVF . Often, people who smoke have fewer eggs retrieved during IVF and may miscarry more often. Obesity also can lower the chances of getting pregnant and having a baby. Use of alcohol, drugs, too much caffeine and certain medicines also can be harmful.

Talk with your care team about any factors that apply to you and how they may affect your chances of a successful pregnancy.

Clinical trials

Explore Mayo Clinic studies of tests and procedures to help prevent, detect, treat or manage conditions.

• FAQs: Treating infertility. American College of Obstetricians and Gynecologists. http://www.acog.org/Patients/FAQs/Treating-Infertility. Accessed Feb. 23, 2023.
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• ART: Step-by-step guide. American Society for Reproductive Medicine. https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/general-information/art-step-by-step-guide/. Accessed Feb. 27, 2023.
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• Ovarian hyperstimulation. Society for Assisted Reproductive Technology. https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/stimulation/ovarian-hyperstimulation-syndrome/. Accessed Feb. 23, 2023.
• Guidance on the limits to the number of embryos to transfer: A committee opinion. Practice Committee of the American Society for Reproductive Medicine and the Practice Committee for the Society for Assisted Reproductive Technologies. https://www.asrm.org/news-and-publications/practice-committee-documents/. Accessed March 1, 2023.
• In vitro fertilization (IVF): What are the risks? American Society for Reproductive Medicine. https://www.sart.org/patients/risks-of-ivf/ Accessed Feb. 2, 2024.
• Preparing for IVF: Emotional considerations. Society for Assisted Reproductive Technology. https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/general-information/preparing-for-ivf-emotional-considerations/. Accessed March 1, 2023.
• Micromanipulation. Society for Assisted Reproductive Technology. https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/general-information/micromanipulation/. Accessed March 1, 2023.
• Preparing for in vitro fertilization (IVF): Lifestyle factors. Society for Assisted Reproductive Technology. https://www.sart.org/patients/fyi-videos/preparing-for-in-vitro-fertilization-ivf-lifestyle-factors/. Accessed March 1, 2023.
• Ubaldi FM, et al. Advanced maternal age in IVF: Still a challenge? The present and the future of its treatment. Frontiers in Endocrinology. 2019;10:94.
• Can I freeze my eggs to use later if I'm not sick? American Society for Reproductive Medicine. https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/can-i-freeze-my-eggs-to-use-later-if-im-not-sick/. Accessed Feb. 24, 2023.
• Medications for inducing ovulation: A guide for patients. American Society for Reproductive Medicine. https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/medications-for-inducing-ovulation-booklet/. Accessed Feb. 24, 2023.
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• Commonly asked questions about the US national ART surveillance system. Centers for Disease Control and Prevention. https://www.cdc.gov/art/reports/2019/commonly-asked-questions.html. Accessed Feb. 27, 2023.
• Evaluation before IVF. Society for Assisted Reproductive Technology. https://www.sart.org/patients/sart-patient-evaluation/. Accessed Feb. 27, 2023.
• Multifetal pregnancy reduction. The American College of Obstetricians and Gynecologists. https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/09/multifetal-pregnancy-reduction. Accessed Feb. 27, 2023.
• Third party reproduction. Society for Assisted Reproductive Technology. https://www.sart.org/patients/third-party-reproduction/. Accessed Feb. 27, 2023.
• Ho J. In vitro fertilization: Overview of clinical issues and questions. https://www.uptodate.com/contents/search. Accessed Feb. 27, 2023.
• American Society for Reproductive Medicine. Fertility drugs and cancer: A guideline. Fertility and Sterility. 2016; doi:10.1016/j.fertnstert.2016.08.035.
• Bart CJM. Overview of ovulation induction. https://www.uptodate.com/contents/search. Accessed March 2, 2023.
• Gershenson DM, et al. In vitro fertilization. In: Comprehensive Gynecology. 8th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed March 2, 2023.
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• Hornstein MD, et al. Endometriosis: Treatment of infertility in females. https://www.uptodate.com/contents/search. Accessed March 2, 2023.
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• v.14(10); 2022 Oct

Recent Advancements in In Vitro Fertilisation

Kadambari singh.

1 Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences, Wardha, IND

Deepika Dewani

2 Obstetrics and Gynaecology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences, Wardha, IND

The field of assisted reproductive technologies has witnessed many new developments over the past 10 years. This review examines new stimulation techniques that might increase the number of fully developed oocytes derived during the in vitro fertilisation (IVF) cycle in addition to strategies for enhancing oocyte quality in older women.

Before moving on to several fresh methods for determining endometrial receptivity, we talk about how preimplantation genetic screening (PGS) is currently being utilised. The main goal of this review is to highlight technological fields that might be debatable or are still sufficiently novel to require rigorous controlled trials for recognition. The use of IVF has been on the rise recently, mostly as a result of deferred childbearing, and there is no reason to believe that this trend will alter. Infertility therapies have advanced significantly thanks to the methods and techniques that were established via studies on animals and, more recently, people. Some technical discoveries in reproductive medicine have had a significant impact on innovations and treatment choices in other fields of medicine as well. The objective of this succinct review article is to quickly summarise and explain the advancements made in this intriguing area of medicine over the past 40 years.

Introduction and background

A higher yield of mature oocytes during an in vitro fertilisation (IVF) cycle may be obtained by using novel stimulation techniques. Additionally, we are interested in devising techniques to raise oocyte quality, particularly in older women. In fact, according to recent projections, assisted reproductive technologies (ART) may keep 400 million people (3% of the world's population) alive by the year 2100 [ 1 ]. Treatments must be both secure and efficient as a result. IVF research will face new challenges in the future. The main difficulties are as follows: how to deal with the inevitable issues of egg ageing and female infertility, how to understand implantation problems and subsequently create remedies, and how to advance therapies for male infertility. Given the compelling motivations for caretakers, researchers, and most critically, infertile couples, only time will tell what chances and avenues the ensuing 40 years will offer for assisted reproduction. Since the world's first IVF baby was born around 40 years ago, it is estimated that over eight million infants have been born as a result of IVF infertility therapy. Before delving into some problematic new techniques for determining endometrial receptivity, we first explore the current debate around preimplantation genetic screening (PGS) [ 1 ]. Due to sociodemographic shifts and advances in technology, the demand for IVF has increased, changing how a significant portion of the population reproduces. The goal of this analysis is to emphasise the social and demographic factors that are fueling an increase in the demand for IVF on a global scale, in addition to providing an overview of emerging technologies that have the potential to considerably enhance IVF usage and lower its cost.

Improving oocyte quality: role of mitochondria

A woman's procreative capacity dramatically declines in the fourth decade of her life, which is directly tied to an ageing-related decline in oocyte quality and quantity [ 2 ]. After the age of 32, fecundity gradually decreases, and after the age of 38, it decreases fast [ 3 ]. Since the frequency of live births following oocyte donation in older women is proportional to the donor's age, oocyte quality is most likely the key factor causing a decrease in fecundity with age. Although greater DNA damage brought on by a less active DNA repair mechanism is a potential contributor to oocyte loss, the pathways leading to an increase in ovarian follicle loss in "aged" ovaries are yet unknown [ 4 ]. Chromosome aneuploidy increases in frequency when oocyte quality declines, primarily as a result of meiotic mistakes made during oocyte maturation. The oocyte must undergo nuclear, cytoplasmic, and epigenetic alterations in order to develop. These modifications all need energy, which the mitochondria provide by oxidative phosphorylation (OXPHOS) [ 5 ]. Mitochondria play an integral role in maintaining the quality of oocytes, the dysfunction of which is depicted in the flow chart given below [ 6 ] (Figure ​ (Figure1 1 ).

Mitochondria play an integral role in maintaining oocyte quality [ 6 ]

Coenzyme Q10 supplementation

Adenosine triphosphate (ATP) is made through an approach called OXPHOS, which involves five complexes that are positioned on the inner mitochondrial membrane [ 2 ].

The antioxidant properties of ubiquinone, also known as coenzyme Q10 (CoQ10), along with its capacity to control cellular redox and having an impact on several signalling pathways make it crucial in this process [ 7 , 8 ]. After the age of 30 in humans, the majority of their tissues have lower CoQ10 concentrations [ 9 , 10 ]. Due to its association with a decline in fertility and an increase in aneuploidies, CoQ10 loss may hasten the ageing process. In an elderly animal model, Ben-Meir et al. (2015) showed that supplementing with CoQ10 prevented the loss of ovarian reserve, enhanced mitochondrial function, and markedly decreased oocyte aneuploidy. In comparison to older animals on a placebo, these elderly mice stimulated produced more offspring and had more oocytes [ 2 ]. Afterwards, it was found that isolated CoQ deficiency brought on by conditional deletion of the PDSS-2 gene in young animal oocytes resulted in phenotypic changes resembling oocyte mitochondrial dysfunction linked to ageing [ 2 ]. If the animals received CoQ10, these alterations might be undone. It is reasonable to assume that CoQ10 supplementation would be beneficial to older women in a manner similar to how CoQ10 administration has been shown to improve reproductive outcomes in elderly animals [ 2 ]. Currently, a great deal of research is being conducted in this field. The ageing process is very different between mice and women because of the enormous differences in lifespan, despite the animal model's apparent promise. Given that giving CoQ10 to mice for 12-16 weeks is likely equivalent to years of human use, more clinical research is necessary [ 2 ]. Ultimately, we can say that CoQ10 is advantageous in IVF as it improves the oocyte quality with regard to ageing. The only disadvantages of this method are the side effects of CoQ10, which are very rare and include heartburn, nausea, diarrhoea, abdominal pain, fatigue, and dizziness. This procedure of supplementing CoQ10 can be accomplished by two methods: in vivo (Figure ​ (Figure2) 2 ) and in vitro (Figure ​ (Figure3). 3 ). In in vivo method, oral treatment methods are employed to enhance the oocyte quality. Whereas, in in vitro method, the culture media is supplemented with the enzyme, which can further be either standard culture or in vitro maturation culture [ 6 ].

CoQ10 is directly administered to the patient in the form of oral tablets [ 6 ]

CoQ10: coenzyme Q10

CoQ10 is supplied to the culture media containing oocytes [ 6 ]

Mitochondrial transfer

To combat ooplasmic ageing, subcellular oocyte modification has been used in other programmes. Cohen et al. performed ooplasmic transfers into mature oocytes of patients whose numerous IVF cycles had failed due to insufficient embryo development using donor oocytes. The findings indicated that the infants were alive and in good health [ 11 ]. Given that mitochondria are found in the cytoplasm, donor ooplasm's mitochondria were also present in recipient eggs, which was thought to be the primary factor influencing better development. Ooplasm donation is no longer practised because heteroplasmy testing on several healthy children revealed that their mitochondrial DNA (mtDNA) was derived from both the mother and the cytoplasm donor, indicating that the heteroplasmy was present in the oocytes [ 12 ]. But later research using autologous mitochondrial transfer has enhanced the earlier work with ooplasm transfer. The mitochondria are taken out of the patient's ovary's oocyte precursor cells in the superficial epithelial layer and injected into their oocytes during fertilisation in this cutting-edge procedure. It has been demonstrated that mitochondrial injection enhances embryo growth and aids in live births in women who had previously experienced poor embryo development [ 13 ]. There are some unethical demerits regarding the above-mentioned technique, such as germlines being modified during mitochondrial donation which leads to the passing down of such modifications to upcoming generations. This method also has the potential of psychological and emotional impact on the offspring leading to an effect on an individual's sense of identity. The efficacy of this method, like the existence of oocyte precursor cells, needs to be confirmed through appropriate randomised controlled trials.

Medical advancements

To enhance the production of oocytes available for IVF, controlled ovarian hyperstimulation, or COH is used. Numerous gonadotropin injections, visits to the fertility clinic, and transvaginal ultrasound examinations are required for COH. As a result, it takes a lot of time and effort to perform COH. The utilisation of transportable facilities and perhaps self-contained endovaginal telemonitoring might further simplify follicular and endometrial monitoring in light of recent improvements in portable, less expensive ultrasound systems [ 14 ]. Combining such methods would hasten and reduce COH intrusion. This method of treatment is known to have several demerits such as emotional stress, high economical costs, and lastly ovarian hyperstimulation syndrome (OHSS), which manifests as abdominal pain, nausea, vomiting, bloating, tenderness over the area of ovaries, diarrhea, and shortness of breath. Evaluation of patients for psychological issues during IVF is one therapy that may help lessen the burden of treatment even further, in addition to counselling and coping mechanisms like e-therapy [ 15 , 16 ]. As per a randomised controlled trial conducted by van Dongen et al., internet-based interventions carry great potential in relieving psychological distress, particularly when care is personalised to patients' personal risk profiles [ 17 ].

Technological advancements

One could argue that automation and the miniaturisation of IVF laboratories are the two most promising technological advancements that have the potential to democratise access to IVF in the near future. An IVF facility's exorbitant costs, unequal access, and inconsistent operations are primarily the result of its manual hiring, construction, and operation.

The fundamental steps conducted in the IVF laboratory are as follows. Firstly, there is determination and segregation of sperm and oocytes, followed by fertilisation and embryo culture. Next, we select embryo for transfer, and lastly, cryopreservation of surplus embryos and gametes is done.

Significant progress has already been made toward automating each of these various stages with the help of novel techniques. However, the majority of the IVF process is still carried out manually. The revolutionary new IVF lab-on-a-chip concept has the potential to transform in vitro fertilisation by automating nearly all necessary steps in a single system [ 15 , 16 , 17 ]. In the multidisciplinary field of microfluidics, fluid dynamics is precisely controlled and manipulated under the influence of minute geometrical constraints that favour surface forces over volumetric counterparts. Earlier IVF laboratory procedures used macroscale methodologies to microscale cellular biological activities, despite their historical success [ 18 ].

At least four benefits that could result from integrating microfluidics into the IVF laboratory have been predicted. Firstly, fluidic gamete/embryo manipulations that are precisely controlled. The second involves creating biomimetic culture environments, while the third entails making microscale genetic and molecular bioassays easier. The last benefit involves allowing for miniaturisation and automation. On the contrary, it is difficult to standardise and scale up, which require external pumps and tubing, as well as connectors and valves to operate. Automated sperm analysers and microfluidic sperm-sorting equipment are frequently used in IVF procedures [ 19 , 20 , 21 ]. Using microfluidics, sperm and sperm-bearing tissue have been removed from testicular biopsies [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Even though the vast majority of IVF patients are candidates for conventional fertilisation, microfluidic in vitro insemination has been shown to be successful [ 29 ]. Potentially, intracytoplasmic sperm injection (ICSI) will not be necessary in the future thanks to microfluidic devices. ICSI has established itself as the de facto technique of insemination in human clinical IVF, demonstrating the significance of precise microfluidic push/pull cumulus-oocyte-complex cumulus cell removal in creating good visibility of the oocyte cytoplasm/orientation [ 30 ]. Despite its technological difficulties, the ICSI phase of fertilisation may be carried out effectively on a commercial scale [ 30 ]. In the future, automated ICSI is likely to be integrated with microfluidics, robotics, and high-tech optics [ 31 , 32 ].

Scientific advancements 

Our understanding of the mechanisms that control folliculogenesis has continually improved as a result of research on fertility preservation [ 33 ]. The interactions between the oocytes and the somatic cells surrounding them, as well as the vital hormones and growth factors, have been revealed by follicular in vitro culture techniques. Recent developments in multi-step culture techniques have made it possible to activate, develop, and in vitro mature (IVM) ovarian cortex tissue primordia to produce metaphase II oocytes [ 34 ]. The advantages of IVM include reduced risk of OHSS and polycystic ovaries, lower medication costs, reduced stress, and lower monitoring burden. In contrast, it has been observed that chances of live birth with IVM are slightly lower than with IVF. Ovarian tissue cryopreservation and IVF have improved the chances of preserving fertility in prepubescent girls and adolescent women who are more likely to experience primary ovarian insufficiency (POI) from gonadotoxic chemotherapy for cancer or other serious illnesses. As long as some dormant follicles are still present in the ovarian cortex, fascinating developments in this technology may make it possible to isolate oocytes from females who have undergone POI or who have gone through natural menopause. An artificial ovary could be developed in a mouse model using scaffolds made through 3D printing for tissue engineering [ 35 , 36 ]. Microfluidic culture techniques can be used to mimic the menstrual cycle by promoting follicle development [ 37 ].

Co-treatment with gonadotropins and letrozole in IVF

Gonadotropin stimulation and the oral medication letrozole used during IVF cycles may be beneficial, especially for breast cancer women receiving fertility preservation treatment, according to recent research [ 38 - 41 ]. Letrozole and ovarian stimulation are employed in the treatment of breast cancer patients to reduce blood oestrogen levels. According to these studies, breast cancer patients who received letrozole and gonadotropins for the duration of the stimulation had lower estradiol concentrations than they would have anticipated but also had more mature oocytes available for cryopreservation than breast cancer-free controls who received conventional COH [ 41 ]. It has been associated with positive effects, including decreased gonadotropin doses that minimise the cost of IVF therapy and enhanced oocyte and mature oocyte counts while retaining the same pregnancy rate as conventional stimulation. On the other hand, gonadotropin stimulation may lead to OHSS, profound hypoestrogenemia, as well as more time-consuming and complex stimulation protocols. In 2005, the impact of letrozole on intraovarian testosterone levels and the success of IVF cycles was investigated. According to Garcia-Velasco et al., the use of letrozole 2.5 mg during the initial five days of gonadotropin stimulation significantly raised the levels of androstenedione and testosterone in follicular fluid and improved the success of IVF cycles. Letrozole considerably outperformed the control group in terms of both the number of recovered oocytes and the implantation rate.

Pre-treatment with dehydroepiandrosterone/testosterone

Numerous strategies have been investigated in an effort to raise intrafollicular androgen concentrations in people who do not respond well to medication because intraovarian androgens may significantly impact early follicular development. To increase the ovarian sensitivity to FSH and follicular response to gonadotrophin therapy in low-responder IVF patients, transdermal testosterone was utilised as a pre-treatment [ 42 ]. As the quantity of cumulus oocyte complexes grew, so did the frequency of clinical pregnancies and live deliveries. According to Gleicher et al., individuals with low ovarian reserve received dehydroepiandrosterone (DHEA) for 30 to 120 days as a supplement (25 mg three times per day). They found that individuals who had received treatment had higher anti-mullerian hormone (AMH) levels and greater conception rates when compared to patients who had not received treatment. DHEA may lessen aneuploidy and miscarriage, according to the same study team's hypothesis [ 43 , 44 ]. Wiser et al. carried out a prospective randomised controlled experiment to ascertain the effect of DHEA supplementation on the effectiveness of IVF in patients who had poor responses. They discovered that the DHEA group had much higher rates of live birth and higher-quality embryos compared to the controls. In both groups, the number of zygotes and eggs was the same. It is unknown whether DHEA helps older women or persons who respond slowly because not many randomised controlled studies have been conducted on these populations.

New approaches to assess endometrial receptivity

The endometrial receptivity array (ERA), a microarray study of implantation-associated gene expression, and ultrasound assessment of sub-endometrial wave frequency are novel techniques for evaluating endometrial receptivity in IVF facilities.

Reproductive genetics

IVF and reproductive genetics are long considered the industry's frontiers,. Preimplantation genetic testing (PGT) of embryos to find chromosomal abnormalities has become more popular as a result of the introduction of next-generation sequencing. The use of PGT for monogenic disorders has expanded along with the popularity of infertile couple carrier screening. It has many advantages such as improved embryo selection, preventing transfer of embryos that will not implant, less time-consuming procedures, reduced costs, and lastly, it has a positive impact on psychological well-being. However, being an invasive procedure is one of its major disadvantages. Other demerits include a cycle with no transfer and embryo mosaicism. Future treatments for severe monogenic disorders may employ germline genome modification (GGM), thanks to advancements in micromanipulation methods and CRISPR-Cas9 gene-editing tools [ 45 ]. The UK is currently conducting clinical trials for mitochondrial replacement therapy (MRT), a more advanced treatment than GGM for heritable mtDNA problems [ 46 ].

Conclusions

In the future, more and more people will use IVF, thereby changing the way a large portion of the human population reproduces. In the near future, IVF will likely be used in several regions worldwide to conceive up to 10% of all children. Given the rapid advancement of reproductive genetics and IVG science and technology, it is essential that regulatory organisations and the general public work together to develop a framework for evaluating the moral implications of emerging technologies. Emerging technologies should be incorporated into clinical practice with the help of a carefully planned clinical trial. The IVM technique reduces the risk of OHSS while enhancing patient safety. IVM may also be advantageous for patients who need to preserve their fertility or who do not respond well to other mentioned treatment modalities. It is now evident that technological advancement, the evolution of necessary tools, as well as the accumulation of experience and training among those performing the procedure have all contributed to success rates rising to as much as 56%. For women over the age of 35 years, this technique is feasible.

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

The authors have declared that no competing interests exist.