Rooney, Kristin L.; Domar, Alice D.
The prevalence of infertility is estimated to be one in eight couples of childbearing age and the cost of infertility treatment is frequently not covered by medical insurance. There is some evidence that certain lifestyle habits may have an adverse impact on fertility, including the efficacy of the advanced reproductive technologies (ARTs). It is important to understand which behaviors have the greatest negative impact, so that appropriate recommendations can be made to patients.
PURPOSE OF REVIEW
The purpose of this review is to summarize the current data on lifestyle behaviors and their effect on infertility treatment outcome. The focus was primarily on six lifestyle habits: BMI – high and low, exercise, diet including supplements, caffeine, alcohol, smoking, and antidepressant medications.
A comprehensive literature search was performed using the PubMed database as well as the recent abstracts from the 2013 annual meeting of the American Society of Reproductive Medicine. Key words included infertility, BMI, exercise, nicotine, alcohol, caffeine, antidepressant medication, and dietary supplements.
The results of our literature search found many observational studies on BMI and diet; however, limited research was conducted over the last 12 months evaluating the effects of exercise, smoking, caffeine, and antidepressant use on ART.
The prevalence of obesity has grown exponentially in the last few decades. According to the Centers for Disease Control, a woman with a BMI greater than 30 is considered obese . Data from 2008 shows that obesity affects 14% of women in the world, and an estimated 297 million women over the age of 20 are obese .
Obesity is associated with many health conditions: diabetes, hypertension, and heart disease, and although not often discussed, it is linked to infertility as well. Epidemiological data suggest that obesity accounts for 6% of primary infertility . Unfortunately, data also show that patients with a BMI greater than 30 have up to 68% less chance to have a live birth following their first ART cycle compared with women with a BMI less than 30 .
Given the low in-vitro fertilization (IVF) success rates, many researchers have sought to answer why obese patients are less likely to conceive with IVF. Overweight and obesity are associated with lower implantation and live-birth rates, and are at increased risk for cycle cancellation [5,6▪]. There is a correlation between obesity and risk of spontaneous abortion as well; obesity was associated with 22% increased risk compared with women of normal weight [7▪].
A retrospective review of IVF live-birth outcome data from 2008 to 2010 found maternal obesity was linked to an increased risk of preterm birth (very early preterm birth at 28 weeks to preterm birth at 37 weeks). The study suggests that preconception maternal obesity and short stature are correlated with an increased risk of delivering at 28–32 weeks .
Kayatas et al.'s [9▪] research found that body composition, specifically fat mass, is adversely associated with the success of IVF. Fat mass seems to have a greater impact on fertility than other measures of obesity.
Bergh et al.[10▪] found that the rate of aneuploidy is not affected by BMI, consequently leading to the belief that pregnancy loss is because of other factors. According to Huang et al., obesity does not harm implantation potential; their recent research looks at endometrial receptivity and lipid metabolic genes correlation to implantation. BMI does not impact the relationship of follicle-stimulating hormone or antral follicle count with anti-Mullerian hormone .
A review of 692 fresh and 355 frozen autologous cycles found lower implantation (P = 0.0021) and live birth (P = 0.0071) rates in fresh cycles ; however, no difference was observed in frozen cycles. Thus, the research shows that success of IVF is dependent on BMI .
Donor egg is a viable option for obese women; however, counseling patients to decrease their BMI may still improve success. Several recent studies found no differences in embryo implantation, miscarriage, or live-birth rate when comparing obese women to nonobese women using donor egg [14,15]. Hence, data suggest that oocyte quality rather than endometrial receptivity may be influencing IVF outcomes in obese women using their own eggs . Although several studies found BMI to have no difference on donor oocyte cycles, a recent study of 170 cycles found women with BMI greater than 30 had a significantly lower clinical pregnancy rate and implantation rate compared with women with a BMI less than 30 (pregnancy rate: 53.3% vs. 72.9% and implantation rate: 39% vs. 58.5%) .
Although research supports the theory that low BMI is also associated with lower pregnancy rates in infertile women, there is a clear bias in the literature toward the risk of obesity. Numerous studies which examined the impact of low or high BMI found that both had a negative impact, but the abstracts only mentioned obesity as a risk factor. A PubMed search using BMI and IVF as search words was performed, and the first abstract which mentioned low BMI was #71.
Women with a low BMI (under 20, 19, or 18.5, depending on the study) have lower clinical pregnancy rates than normal weight women . Underweight women also have an increased risk of miscarriage: a retrospective analysis of 594 patients showed pregnancy loss was 11% for underweight women compared to 0.5% for those with normal BMI [6▪].
Most research on the impact of weight loss does not show a positive relationship between weight loss and pregnancy in ART patients . However, encouraging patients to maintain a normal BMI may be beneficial to cycle outcome. There is some research which does indicate that weight loss is associated with a higher spontaneous pregnancy rate . A recent study on bariatric surgery indicated that patients who undergo bariatric surgery have more and better quality oocytes retrieved than obese women who do not undergo surgery .
Although previous research supported a connection between exercise and decreased fecundity, more recent research indicates that moderate exercise is associated with the highest pregnancy rates, regardless of BMI .
Aerobic exercise has a positive effect on improving ovarian morphology, both ovarian volume and number of follicles, in women with polycystic ovary syndrome (PCOS) .
An observation study of women in Australia found women with PCOS report better dietary intake than women without PCOS but increased sedentary behavior . Therefore, lifestyle interventions may be beneficial for women with PCOS.
Exercise has a positive impact on endometriosis treatment. Recent research, performed on rats, shows physical exercise reduces cell invasion and production, and increases the apoptosis on endometriosis lesion .
A study of 23 infertile couples in Australia reviewed the Fertility ASsessment and advice Targeting lifestyle choices and behaviors (FAST) program. The study demonstrated improved behaviors of the patients who participated in an individual lifestyle assessment and received continued support from the clinic. Exercise was increased, caffeine and alcohol consumption declined, and smoking was reduced or discontinued . Given the small sample size, however, the program needs to be assessed with more patients prior to making widespread recommendations.
Diet: including supplements
Although little research was conducted in 2013 regarding diet and fertility, two studies noted the benefits of certain foods. Endometriosis may be impacted by dairy. A retrospective study found that women who consume greater amounts of dairy (high and low fat) in adolescence may halt the progression of endometriosis and also reduce pain symptoms in adulthood . For women with PCOS, adding cinnamon supplements to their diet may increase menstrual cycle regularity .
Several studies reviewed the benefits of vitamin supplements and infertility, specifically looking at vitamins D, C, E, iron, and fatty acids. When looking at the impact of vitamin D on women trying to conceive, the findings were conflicting. Whereas some studies found vitamin D supplements beneficial to improving reproductive health, other research cited no differences.
For women who are vitamin D deficient, supplementation may normalize the serum anti-Mullerian hormone levels . Vitamin D has also been linked to the testosterone level in healthy women; it may function as modulator of androgen activity, consequently having a positive influence on reproduction .
Conversely, a recent randomized, double-blind trial looking at 52 patients found no significant difference between IVF cycle outcomes for patients taking vitamin D supplements compared to the control group [30▪▪].
Over 400 women were surveyed about their vitamin D intake in an attempt to assess whether women who did not consume enough vitamin D took longer to conceive. The study found that nearly half the women did not meet the minimum estimated requirement of 400 IU per day. Even though the minimum vitamin D requirement was not met, no statistically significant differences were noted in the length of time it took to conceive .
Research on antioxidant intake in women found that the time to pregnancy was shorter for women with BMI less than 25 when they increased their vitamin C intake; women with BMI greater than 25 benefited when increasing beta-carotene. Women less than 35 years of age decreased time to pregnancy by increasing both beta-carotene and vitamin C; women aged 35 and older benefited by increasing vitamin E .
Research on rats demonstrates that iron deficiency has a significant effect on infertility .
A study by Jungheim et al. found an increase of polyunsaturated fatty acids may be correlated with higher implantation and pregnancy rates.
There is inconsistent evidence on the relationship between caffeine and fertility, and there is no recent research.
Caffeine in general does not show a significant negative impact on time to pregnancy in normal women ; however, some research indicates that caffeine intake of more than 50 mg/day is linked to lower pregnancy rates in IVF patients .
A study of over 600 women reviewed the effect of coffee and tea on IVF. Increased caffeine serum levels adversely affected the number of eggs; coffee consumption was correlated with the number of miscarriages and high tea consumption resulted in a decline in the number of good embryos .
It is universally suggested that alcohol should be avoided when undergoing IVF.
Female alcohol consumption is associated with fewer oocytes obtained, lower pregnancy rates, and a 2.21 times increased risk of miscarriage [38,39].
A study of 37 women deemed at-risk drinkers were randomized to a brief intervention vs. assessment only. The women in the brief intervention group had a notable decrease in the number of drinks or drinking days compared with the assessment only group; however, there were no differences in the likelihood of implantation failure, chemical pregnancy, spontaneous abortion, preterm birth, or live birth [40▪]. Brief intervention and assessment only led to a decrease in alcohol use but did not reveal changes in IVF outcomes.
Cigarette smoking is associated with infertility, pregnancy loss, and IVF failure. Up to 13% of female infertility is caused by cigarette smoking . Women who smoke experience decreased fertility and higher risk of miscarriage. There is strong evidence that nicotine has a significant negative impact on fertility . Smokers add 10 years to their reproductive ages – a 25-year-old smoker has the same reproductive potential as a 35-year-old nonsmoker.
Cigarette smoke contains many harmful components that can adversely affect fertility, including maturation of follicles, embryo transport, endometrial receptivity, endometrial angiogenesis, uterine blood flow, and uterine myometrium .
Results from a study on rats found that intrauterine exposure to cigarette smoke reduced the ovarian reserve of female offspring , thus causing concern that maternal smoking may have an impact on ovarian function.
The use of antidepressant during pregnancy is associated with increased risks of miscarriage, birth defects, preterm birth, newborn behavioral syndrome, persistent pulmonary hypertension of the newborn, and possible longer term neurobehavioral effects [45▪▪].
On the basis of the literature review, there is no evidence of improved pregnancy outcomes with antidepressant use. There is some indication that psychotherapy, including cognitive–behavioral therapy as well as physical exercise, is associated with significant decreases in depressive symptoms in the general population [45▪▪]. Be aware that infertility patients may underreport their use of antidepressant medication: in a recent study, 11.1% of the patients self-reported on the patient portal that they were currently taking antidepressant medication. However, only 3% reported antidepressant use to the anesthesiologist prior to their oocyte retrieval [45▪▪].
Actual lifestyle behaviors
Despite the written recommendations to limit exercise, smoking, alcohol, and caffeine, as well as to eliminate herbs entirely, in a recent analysis of actual lifestyle behaviors in cycling patients at Boston IVF , in the month prior to an IVF cycle: 92% exercised, 3% smoked, 73% drank alcohol, 76% drank caffeine, and 14% took herbs. During the actual IVF cycle, 100% exercised, 2% smoked, 49% drank alcohol, 77% drank caffeine, and 12% took herbs .
In a similar study in Germany, 7.3% were underweight, 25% were overweight, 33% of women exercised vigorously (>4.4 h/week), 11% smoked more than 5 cigarettes a day, 4.6% drank alcohol regularly, and 8.4% took medication ‘detrimental to fertility’ .
Lifestyle habits may have a significant impact on pregnancy rates in infertile women. Unfortunately, there is a paucity of research in this area, other than observational studies on the relationship between high BMI and ART outcome. There is some research to support certain lifestyle modifications in infertile women. Despite patient education efforts, cycling infertility patients do not follow lifestyle modification recommendations. Physicians and nurses need to take a more active role in educating patients on the impact of lifestyle factors on fertility and fertility treatment outcome.
Conflicts of interest
A.D.D. and K.L.R. do not have any conflicts of interest to disclose.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
4. Moragianni VA, Jones SM, Ryley DA. The effect of body mass index on the outcomes of first assisted reproductive technology cycles. Fertil Steril
5. Luke B, Brown MB, Stern JE, et al. Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates. Hum Reprod
6▪. Davies DM, Caswell WA, Reed J, et al. Are the adverse effects of weight on reproductive potential an embryo or endometrial factor? Fertil Steril
2013; 100 (Suppl.):S85–S86.
This is one of the few studies which have looked at the negative influence of low BMI on reproductive potential.
7▪. Hahn KA, Wise LA, Mikkelsen EM, et al. A prospective study of body mass index and risk of spontaneous abortion. Fertil Steril
2013; 100 (Suppl.):S336.
A good prospective study linking obesity to pregnancy loss.
8. Dickey RP, Xiong X, Xie Y, et al. Effect of maternal height and weight on risk for preterm singleton and twin births resulting from IVF in the United States, 2008–2010. Am J Obstet Gynecol
9▪. Kayatas S, Boza AT, Api M, et al. Does body composition can be used as a predictive factor of cycle fecundity in unexplained infertile women? Fertil Steril
2013; 100 (Suppl.):S335.
One of the first explanations of the causative relationship between obesity and treatment failure.
10▪. Bergh CM, Reda CV, Glujovsky D, Bergh PA. Effect of body mass index on aneuploidy. Fertil Steril
2013; 100 (Suppl.):S151.
Another important study on the actual causative factor of obesity on implantation rather than egg quality.
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2013; 100 (Suppl.):S298.
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29. Chang E, Kim YS, Won HJ, et al. Association between sex steroid, ovarian reserve and vitamin D levels in healthy fertile women. Fertil Steril
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30▪▪. Polak de Fried E, Bossi NM, Notrica JA, Vazquez Levin MH. Vitamin-D treatment does not improve pregnancy rates in patients undergoing ART: a prospective, randomized, double-blind placebo controlled trial. Fertil Steril
2013; 100 (Suppl.):S493–S494.
Much attention has been paid recently on the lower pregnancy rates of women who have low vitamin D levels, leading to the theory that vitamin D supplementation may increase pregnancy rates. This is a small but well designed RCT which did not show improvements in pregnancy rates with vitamin D supplementation.
31. Pacis MM, Goldman MB, Fung JL, Reindollar RH. Is there an association between vitamin D intake and time to conception? Data from the FAST trial. Fertil Steril
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This is one of the few RCTs which addressed lifestyle behavior in infertility patients. Although the intervention had a positive impact on alcohol consumption, it did not impact reproductive outcome.
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45▪▪. Domar AD, Moragianni VA, Ryley DA, Urato AC. The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond. Hum Reprod
SSRI use in infertility patients is common; this is the first review on the potential negative impact of SSRI use on fertility, IVF outcome, pregnancy outcome, and neonatal health. Alternatives to SSRI use for infertility patients are also reviewed.
46. Domar AD, Conboy L, Denardo-Roney J, Rooney KL. Lifestyle behaviors in women undergoing in vitro fertilization: a prospective study. Fertil Steril
47. Schilling K, Toth B, Rösner S, et al. Prevalence of behaviour-related fertility disorders in a clinical sample: results of a pilot study. Arch Gynecol Obstet