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Natural fertility: When less can be more
As reproductive specialists, part of our obligation is to improve a woman’s or couple’s ability to conceive in the most cost-effective manner, ideally through natural attempts at conception. While assisted reproductive technologies (ART) have provided impressive pregnancy rates across many diagnoses, including unexplained infertility, this advanced procedure comes with a significant financial cost to those without insurance and an emotional burden from the lack of a guaranteed outcome. Infertility procedures have minimal associated but potentially significant risks, most importantly multiple gestations. Contrary to popular belief, ovulation induction with intrauterine insemination (IUI) treatment has a greater risk of high-order multiple gestation when compared with IVF, given the inability of the former to control the number of embryos that may enter and implant in the endometrial cavity and the increased use of single embryo transfers with the latter. The specialist should evaluate the woman or couple for the basic issues of ovulation, tubal, and sperm function, as well as for lifestyle and environmental factors that can impede reproduction. As a result, “one size fits all” should not apply to patients, specifically those with infertility. This month’s column will present the detrimental effect of environmental and lifestyle factors on the goal of enhancing fertility through natural cycles of urine luteinizing-hormone timed intercourse.
Nutrition
Often overlooked in the infertility evaluation, an optimal diet improves fertility for both partners. Processed meat has been associated with reduced sperm quality. In ART, red meat has been associated with decreased embryo blastocyst formation. Lower trans fatty acids and higher omega-3s may improve fecundity. Considered one of the best overall diets, the Mediterranean diet consists of plant-based foods, such as whole grains, vegetables, legumes, fruits, nuts, seeds, herbs, and spices. Olive oil is the main source of added fat whereas fish, seafood, dairy, and poultry should be eaten in moderation. Fatty fish, such as mackerel, herring, sardines, albacore tuna, and salmon, are rich in omega-3 fatty acids, which have been shown to improve fecundity and IVF success, and have a positive association with blastocyst embryo development.1-3
Stress
The emotional effect of an infertility diagnosis has been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities.4 Whether stress causes or is a result of infertility has been a longstanding debate.5 Nevertheless, stress is the number-one reason patients discontinue fertility treatment.6 As fertility specialists, we must be cognizant of the devastation endured by infertility patients and maintain an open dialogue, as well as provide resources for coping strategies and counseling.
One popular method of improving mental health and fertility has been acupuncture. Initial enthusiasm originated from one of the first studies to explore the use of acupuncture during IVF. This was a prospective randomized study that showed treated patients had an approximately 100% improvement in clinical pregnancy rate. Unfortunately, there was no appropriate control group, just untreated controls.7 A subsequent study by the same investigator added a placebo acupuncture control group and did not show a statistically significant increase in pregnancy rates.8 Finally, a meta-analysis and reanalysis did not demonstrate any improvement in pregnancy outcome, whereas three of the studies analyzed suggested a possible reduction in pregnancies; placebo acupuncture was shown to have a higher success rate.9-11 While acupuncture is relatively safe, there appears to be only a placebo effect that may be helpful.
The effect of stress on reproduction has been addressed in one of my previous columns.
Alcohol and caffeine
The damaging effects of alcohol on the fetus during pregnancy are legion – abnormal facial features, microcephaly, low birth weight, hyperactive behavior, vision or hearing deficits, speech and language delays, and intellectual disability. Less known is the amount of alcohol that may have an effect during preconception. One of the first reports on the effect of alcohol on IVF concluded: a 13% decrease in the number of eggs aspirated; a 2.86 times increase in risk of not achieving pregnancy; and a 2.21 times increase in risk of miscarriage. For men, one additional drink per day increased the risk of not achieving a live birth from 2.28 to 8.32 times.12 Subsequent studies demonstrate a 16% reduction in IVF pregnancies in women who have at least four drinks per week; when the couple drank at least four drinks per week, the pregnancy rate decreased by 21%.13
However, a study from Denmark did not demonstrate a negative effect of low to moderate pretreatment amounts of alcohol and caffeine on IVF outcomes.14 Nevertheless, there is evidence that reducing or abstaining from alcohol intake may improve IVF outcomes.15 While there have been reports of higher miscarriage rates from caffeine,16,17 not all reports support a negative association.18
Smoking
The use of tobacco has been estimated to contribute to 13% of female infertility in a dose-response manner, including secondhand smoke. During ART, smoking reduces ovarian response to gonadotropins and decreases IVF success by up to 50%. Discontinuing smoking for 6 months beforehand appears to restore normal outcomes.19-20
The American Society for Reproductive Medicine Practice Committee on smoking provides the following invaluable information to share with patients on the harmful reproductive effects of smoking:21
- Early menopause by accelerating the loss of eggs.
- Higher rates of miscarriage and ectopic pregnancy.
- A decrease in sperm function.
- Possible genetic damage to eggs and sperm.
- Reduced sperm in son from maternal smoking.
Weight and exercise
Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction;22 a lower chance for conception;23 and infertility.24 Obese women have higher rates of miscarriage and recurrent miscarriage, reduced success with ART, an increased number of canceled cycles, and poorer quality oocytes retrieved. During pregnancy, obese women have three to four times higher rates of gestational diabetes and preeclampsia,25 as well as likelihood of having a fetus with macrosomia and birth defects, and a 1.3-2.1 times higher risk of stillbirth.26
Regarding physical activity, the rate of pregnancies (39.0% vs. 16.0%, P = .002) and live births (24.4% vs. 7.4% (P = .004) were higher with regular exercise vs. being sedentary. Obese women who exercised regularly had a live birth rate over threefold higher compared with those who were not active.27 Moderation should be employed given that women who exercise to exhaustion have 2.3 times the odds of fertility problems.28 In men, obesity has been shown to increase estrogens and reduce spermatogenesis. Exercise has improved semen parameters and testosterone. Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment.29 As in women, men experience negative effects from high-intensity exercise, including bicycling, which can result in decreased semen parameters, follicle-stimulating hormone, LH, and testosterone levels.30
In couples desiring a more natural approach to infertility, fertility specialists can address environmental and lifestyle factors that may improve reproduction. When natural attempts at conception are not applicable or successful, IUI and ART are appropriate treatment options after considering estimated success rates as well as the physical, emotional, and financial investment of patients.
Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
References
1. Wise LA et al. Am J Epidemiol. 2018;187:60-74.
2. Chui Y-H. Hum Reprod. 2018;33:156-65.
3. Ferreira Braga DPA et al. Reprod Biomed Online. 2015;31:30-8.
4. Domar AD et al. J Psychosom Obstet Gynaecol. 1993;14[suppl]:45-52.
5. Trolice MP. J Assist Reprod Genet. 2021 Apr;38[4]:873-5.
6. Gameiro S et al. Hum Reprod Update. 2012;18[6]:652-69.
7. Paulus WE et al. Fertil Steril. 2002;77:721-4.
8. Paulus WE et al. Hum Reprod. 2003;18:S18(abstr).
9. Wing SSE et al. Hum Reprod. 2009;24:341-8.
10. Hong Zheng C et al. Fertil Steril. 2012;97:599-611.
11. Meldrum DR et al. Fertil Steril. 2013;99:1821-4.
12. Klonoff-Cohen H et al. Fertil Steril. 2003;79:330-9.
13. Rossi BV et al. Obstet Gynecol. 2011;117:136-42.
14. Abadia L et al. Hum Reprod. 2017;32:1846-54.
15. Gormack AA et al. Hum Reprod. 2015;30:1617.
16. James JE. BMJ Evid Based Med. 2021;26:114-15.
17. Gaskins AJ et al. Eur J Nutr. 2018 Feb;57:107-17.
18. Machtinger R et al. Fertil Steril. 2017;108:1026-33.
19. Hughes EG et al. Fertil Steril. 1994;62:807.
20. de Ziegler D et al. Fertil Steril. 2013;100:927-8.
21. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2018;110:611-8.
22. Brewer CJ, Balen AH. Reproduction. 2010;140:347-64.
23. Wise LA et al. Hum Reprod. 2010;25:253-64.
24. Silvestris S et al. Reprod Biol Endocrinol. 2018;16[1]:22.
25. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.
26. Aune D et al. JAMA. 2014;311:1536-46.
27. Palomba S et al. Reprod Biomed Online. 2014;29:72-9.
28. Gudmundsdottir SL et al. Hum Reprod. 2009;24[12]:3196-204.
29. Gaskins AJ et al. Hum Reprod. 2014;29:2575-82.
30. Wise LA et al. Fertil Steril. 2011;95:1025-30.
As reproductive specialists, part of our obligation is to improve a woman’s or couple’s ability to conceive in the most cost-effective manner, ideally through natural attempts at conception. While assisted reproductive technologies (ART) have provided impressive pregnancy rates across many diagnoses, including unexplained infertility, this advanced procedure comes with a significant financial cost to those without insurance and an emotional burden from the lack of a guaranteed outcome. Infertility procedures have minimal associated but potentially significant risks, most importantly multiple gestations. Contrary to popular belief, ovulation induction with intrauterine insemination (IUI) treatment has a greater risk of high-order multiple gestation when compared with IVF, given the inability of the former to control the number of embryos that may enter and implant in the endometrial cavity and the increased use of single embryo transfers with the latter. The specialist should evaluate the woman or couple for the basic issues of ovulation, tubal, and sperm function, as well as for lifestyle and environmental factors that can impede reproduction. As a result, “one size fits all” should not apply to patients, specifically those with infertility. This month’s column will present the detrimental effect of environmental and lifestyle factors on the goal of enhancing fertility through natural cycles of urine luteinizing-hormone timed intercourse.
Nutrition
Often overlooked in the infertility evaluation, an optimal diet improves fertility for both partners. Processed meat has been associated with reduced sperm quality. In ART, red meat has been associated with decreased embryo blastocyst formation. Lower trans fatty acids and higher omega-3s may improve fecundity. Considered one of the best overall diets, the Mediterranean diet consists of plant-based foods, such as whole grains, vegetables, legumes, fruits, nuts, seeds, herbs, and spices. Olive oil is the main source of added fat whereas fish, seafood, dairy, and poultry should be eaten in moderation. Fatty fish, such as mackerel, herring, sardines, albacore tuna, and salmon, are rich in omega-3 fatty acids, which have been shown to improve fecundity and IVF success, and have a positive association with blastocyst embryo development.1-3
Stress
The emotional effect of an infertility diagnosis has been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities.4 Whether stress causes or is a result of infertility has been a longstanding debate.5 Nevertheless, stress is the number-one reason patients discontinue fertility treatment.6 As fertility specialists, we must be cognizant of the devastation endured by infertility patients and maintain an open dialogue, as well as provide resources for coping strategies and counseling.
One popular method of improving mental health and fertility has been acupuncture. Initial enthusiasm originated from one of the first studies to explore the use of acupuncture during IVF. This was a prospective randomized study that showed treated patients had an approximately 100% improvement in clinical pregnancy rate. Unfortunately, there was no appropriate control group, just untreated controls.7 A subsequent study by the same investigator added a placebo acupuncture control group and did not show a statistically significant increase in pregnancy rates.8 Finally, a meta-analysis and reanalysis did not demonstrate any improvement in pregnancy outcome, whereas three of the studies analyzed suggested a possible reduction in pregnancies; placebo acupuncture was shown to have a higher success rate.9-11 While acupuncture is relatively safe, there appears to be only a placebo effect that may be helpful.
The effect of stress on reproduction has been addressed in one of my previous columns.
Alcohol and caffeine
The damaging effects of alcohol on the fetus during pregnancy are legion – abnormal facial features, microcephaly, low birth weight, hyperactive behavior, vision or hearing deficits, speech and language delays, and intellectual disability. Less known is the amount of alcohol that may have an effect during preconception. One of the first reports on the effect of alcohol on IVF concluded: a 13% decrease in the number of eggs aspirated; a 2.86 times increase in risk of not achieving pregnancy; and a 2.21 times increase in risk of miscarriage. For men, one additional drink per day increased the risk of not achieving a live birth from 2.28 to 8.32 times.12 Subsequent studies demonstrate a 16% reduction in IVF pregnancies in women who have at least four drinks per week; when the couple drank at least four drinks per week, the pregnancy rate decreased by 21%.13
However, a study from Denmark did not demonstrate a negative effect of low to moderate pretreatment amounts of alcohol and caffeine on IVF outcomes.14 Nevertheless, there is evidence that reducing or abstaining from alcohol intake may improve IVF outcomes.15 While there have been reports of higher miscarriage rates from caffeine,16,17 not all reports support a negative association.18
Smoking
The use of tobacco has been estimated to contribute to 13% of female infertility in a dose-response manner, including secondhand smoke. During ART, smoking reduces ovarian response to gonadotropins and decreases IVF success by up to 50%. Discontinuing smoking for 6 months beforehand appears to restore normal outcomes.19-20
The American Society for Reproductive Medicine Practice Committee on smoking provides the following invaluable information to share with patients on the harmful reproductive effects of smoking:21
- Early menopause by accelerating the loss of eggs.
- Higher rates of miscarriage and ectopic pregnancy.
- A decrease in sperm function.
- Possible genetic damage to eggs and sperm.
- Reduced sperm in son from maternal smoking.
Weight and exercise
Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction;22 a lower chance for conception;23 and infertility.24 Obese women have higher rates of miscarriage and recurrent miscarriage, reduced success with ART, an increased number of canceled cycles, and poorer quality oocytes retrieved. During pregnancy, obese women have three to four times higher rates of gestational diabetes and preeclampsia,25 as well as likelihood of having a fetus with macrosomia and birth defects, and a 1.3-2.1 times higher risk of stillbirth.26
Regarding physical activity, the rate of pregnancies (39.0% vs. 16.0%, P = .002) and live births (24.4% vs. 7.4% (P = .004) were higher with regular exercise vs. being sedentary. Obese women who exercised regularly had a live birth rate over threefold higher compared with those who were not active.27 Moderation should be employed given that women who exercise to exhaustion have 2.3 times the odds of fertility problems.28 In men, obesity has been shown to increase estrogens and reduce spermatogenesis. Exercise has improved semen parameters and testosterone. Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment.29 As in women, men experience negative effects from high-intensity exercise, including bicycling, which can result in decreased semen parameters, follicle-stimulating hormone, LH, and testosterone levels.30
In couples desiring a more natural approach to infertility, fertility specialists can address environmental and lifestyle factors that may improve reproduction. When natural attempts at conception are not applicable or successful, IUI and ART are appropriate treatment options after considering estimated success rates as well as the physical, emotional, and financial investment of patients.
Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
References
1. Wise LA et al. Am J Epidemiol. 2018;187:60-74.
2. Chui Y-H. Hum Reprod. 2018;33:156-65.
3. Ferreira Braga DPA et al. Reprod Biomed Online. 2015;31:30-8.
4. Domar AD et al. J Psychosom Obstet Gynaecol. 1993;14[suppl]:45-52.
5. Trolice MP. J Assist Reprod Genet. 2021 Apr;38[4]:873-5.
6. Gameiro S et al. Hum Reprod Update. 2012;18[6]:652-69.
7. Paulus WE et al. Fertil Steril. 2002;77:721-4.
8. Paulus WE et al. Hum Reprod. 2003;18:S18(abstr).
9. Wing SSE et al. Hum Reprod. 2009;24:341-8.
10. Hong Zheng C et al. Fertil Steril. 2012;97:599-611.
11. Meldrum DR et al. Fertil Steril. 2013;99:1821-4.
12. Klonoff-Cohen H et al. Fertil Steril. 2003;79:330-9.
13. Rossi BV et al. Obstet Gynecol. 2011;117:136-42.
14. Abadia L et al. Hum Reprod. 2017;32:1846-54.
15. Gormack AA et al. Hum Reprod. 2015;30:1617.
16. James JE. BMJ Evid Based Med. 2021;26:114-15.
17. Gaskins AJ et al. Eur J Nutr. 2018 Feb;57:107-17.
18. Machtinger R et al. Fertil Steril. 2017;108:1026-33.
19. Hughes EG et al. Fertil Steril. 1994;62:807.
20. de Ziegler D et al. Fertil Steril. 2013;100:927-8.
21. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2018;110:611-8.
22. Brewer CJ, Balen AH. Reproduction. 2010;140:347-64.
23. Wise LA et al. Hum Reprod. 2010;25:253-64.
24. Silvestris S et al. Reprod Biol Endocrinol. 2018;16[1]:22.
25. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.
26. Aune D et al. JAMA. 2014;311:1536-46.
27. Palomba S et al. Reprod Biomed Online. 2014;29:72-9.
28. Gudmundsdottir SL et al. Hum Reprod. 2009;24[12]:3196-204.
29. Gaskins AJ et al. Hum Reprod. 2014;29:2575-82.
30. Wise LA et al. Fertil Steril. 2011;95:1025-30.
As reproductive specialists, part of our obligation is to improve a woman’s or couple’s ability to conceive in the most cost-effective manner, ideally through natural attempts at conception. While assisted reproductive technologies (ART) have provided impressive pregnancy rates across many diagnoses, including unexplained infertility, this advanced procedure comes with a significant financial cost to those without insurance and an emotional burden from the lack of a guaranteed outcome. Infertility procedures have minimal associated but potentially significant risks, most importantly multiple gestations. Contrary to popular belief, ovulation induction with intrauterine insemination (IUI) treatment has a greater risk of high-order multiple gestation when compared with IVF, given the inability of the former to control the number of embryos that may enter and implant in the endometrial cavity and the increased use of single embryo transfers with the latter. The specialist should evaluate the woman or couple for the basic issues of ovulation, tubal, and sperm function, as well as for lifestyle and environmental factors that can impede reproduction. As a result, “one size fits all” should not apply to patients, specifically those with infertility. This month’s column will present the detrimental effect of environmental and lifestyle factors on the goal of enhancing fertility through natural cycles of urine luteinizing-hormone timed intercourse.
Nutrition
Often overlooked in the infertility evaluation, an optimal diet improves fertility for both partners. Processed meat has been associated with reduced sperm quality. In ART, red meat has been associated with decreased embryo blastocyst formation. Lower trans fatty acids and higher omega-3s may improve fecundity. Considered one of the best overall diets, the Mediterranean diet consists of plant-based foods, such as whole grains, vegetables, legumes, fruits, nuts, seeds, herbs, and spices. Olive oil is the main source of added fat whereas fish, seafood, dairy, and poultry should be eaten in moderation. Fatty fish, such as mackerel, herring, sardines, albacore tuna, and salmon, are rich in omega-3 fatty acids, which have been shown to improve fecundity and IVF success, and have a positive association with blastocyst embryo development.1-3
Stress
The emotional effect of an infertility diagnosis has been demonstrated to be equivalent to a diagnosis of cancer and other major medical morbidities.4 Whether stress causes or is a result of infertility has been a longstanding debate.5 Nevertheless, stress is the number-one reason patients discontinue fertility treatment.6 As fertility specialists, we must be cognizant of the devastation endured by infertility patients and maintain an open dialogue, as well as provide resources for coping strategies and counseling.
One popular method of improving mental health and fertility has been acupuncture. Initial enthusiasm originated from one of the first studies to explore the use of acupuncture during IVF. This was a prospective randomized study that showed treated patients had an approximately 100% improvement in clinical pregnancy rate. Unfortunately, there was no appropriate control group, just untreated controls.7 A subsequent study by the same investigator added a placebo acupuncture control group and did not show a statistically significant increase in pregnancy rates.8 Finally, a meta-analysis and reanalysis did not demonstrate any improvement in pregnancy outcome, whereas three of the studies analyzed suggested a possible reduction in pregnancies; placebo acupuncture was shown to have a higher success rate.9-11 While acupuncture is relatively safe, there appears to be only a placebo effect that may be helpful.
The effect of stress on reproduction has been addressed in one of my previous columns.
Alcohol and caffeine
The damaging effects of alcohol on the fetus during pregnancy are legion – abnormal facial features, microcephaly, low birth weight, hyperactive behavior, vision or hearing deficits, speech and language delays, and intellectual disability. Less known is the amount of alcohol that may have an effect during preconception. One of the first reports on the effect of alcohol on IVF concluded: a 13% decrease in the number of eggs aspirated; a 2.86 times increase in risk of not achieving pregnancy; and a 2.21 times increase in risk of miscarriage. For men, one additional drink per day increased the risk of not achieving a live birth from 2.28 to 8.32 times.12 Subsequent studies demonstrate a 16% reduction in IVF pregnancies in women who have at least four drinks per week; when the couple drank at least four drinks per week, the pregnancy rate decreased by 21%.13
However, a study from Denmark did not demonstrate a negative effect of low to moderate pretreatment amounts of alcohol and caffeine on IVF outcomes.14 Nevertheless, there is evidence that reducing or abstaining from alcohol intake may improve IVF outcomes.15 While there have been reports of higher miscarriage rates from caffeine,16,17 not all reports support a negative association.18
Smoking
The use of tobacco has been estimated to contribute to 13% of female infertility in a dose-response manner, including secondhand smoke. During ART, smoking reduces ovarian response to gonadotropins and decreases IVF success by up to 50%. Discontinuing smoking for 6 months beforehand appears to restore normal outcomes.19-20
The American Society for Reproductive Medicine Practice Committee on smoking provides the following invaluable information to share with patients on the harmful reproductive effects of smoking:21
- Early menopause by accelerating the loss of eggs.
- Higher rates of miscarriage and ectopic pregnancy.
- A decrease in sperm function.
- Possible genetic damage to eggs and sperm.
- Reduced sperm in son from maternal smoking.
Weight and exercise
Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction;22 a lower chance for conception;23 and infertility.24 Obese women have higher rates of miscarriage and recurrent miscarriage, reduced success with ART, an increased number of canceled cycles, and poorer quality oocytes retrieved. During pregnancy, obese women have three to four times higher rates of gestational diabetes and preeclampsia,25 as well as likelihood of having a fetus with macrosomia and birth defects, and a 1.3-2.1 times higher risk of stillbirth.26
Regarding physical activity, the rate of pregnancies (39.0% vs. 16.0%, P = .002) and live births (24.4% vs. 7.4% (P = .004) were higher with regular exercise vs. being sedentary. Obese women who exercised regularly had a live birth rate over threefold higher compared with those who were not active.27 Moderation should be employed given that women who exercise to exhaustion have 2.3 times the odds of fertility problems.28 In men, obesity has been shown to increase estrogens and reduce spermatogenesis. Exercise has improved semen parameters and testosterone. Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment.29 As in women, men experience negative effects from high-intensity exercise, including bicycling, which can result in decreased semen parameters, follicle-stimulating hormone, LH, and testosterone levels.30
In couples desiring a more natural approach to infertility, fertility specialists can address environmental and lifestyle factors that may improve reproduction. When natural attempts at conception are not applicable or successful, IUI and ART are appropriate treatment options after considering estimated success rates as well as the physical, emotional, and financial investment of patients.
Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
References
1. Wise LA et al. Am J Epidemiol. 2018;187:60-74.
2. Chui Y-H. Hum Reprod. 2018;33:156-65.
3. Ferreira Braga DPA et al. Reprod Biomed Online. 2015;31:30-8.
4. Domar AD et al. J Psychosom Obstet Gynaecol. 1993;14[suppl]:45-52.
5. Trolice MP. J Assist Reprod Genet. 2021 Apr;38[4]:873-5.
6. Gameiro S et al. Hum Reprod Update. 2012;18[6]:652-69.
7. Paulus WE et al. Fertil Steril. 2002;77:721-4.
8. Paulus WE et al. Hum Reprod. 2003;18:S18(abstr).
9. Wing SSE et al. Hum Reprod. 2009;24:341-8.
10. Hong Zheng C et al. Fertil Steril. 2012;97:599-611.
11. Meldrum DR et al. Fertil Steril. 2013;99:1821-4.
12. Klonoff-Cohen H et al. Fertil Steril. 2003;79:330-9.
13. Rossi BV et al. Obstet Gynecol. 2011;117:136-42.
14. Abadia L et al. Hum Reprod. 2017;32:1846-54.
15. Gormack AA et al. Hum Reprod. 2015;30:1617.
16. James JE. BMJ Evid Based Med. 2021;26:114-15.
17. Gaskins AJ et al. Eur J Nutr. 2018 Feb;57:107-17.
18. Machtinger R et al. Fertil Steril. 2017;108:1026-33.
19. Hughes EG et al. Fertil Steril. 1994;62:807.
20. de Ziegler D et al. Fertil Steril. 2013;100:927-8.
21. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2018;110:611-8.
22. Brewer CJ, Balen AH. Reproduction. 2010;140:347-64.
23. Wise LA et al. Hum Reprod. 2010;25:253-64.
24. Silvestris S et al. Reprod Biol Endocrinol. 2018;16[1]:22.
25. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.
26. Aune D et al. JAMA. 2014;311:1536-46.
27. Palomba S et al. Reprod Biomed Online. 2014;29:72-9.
28. Gudmundsdottir SL et al. Hum Reprod. 2009;24[12]:3196-204.
29. Gaskins AJ et al. Hum Reprod. 2014;29:2575-82.
30. Wise LA et al. Fertil Steril. 2011;95:1025-30.
