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Research and Reviews

Epidemiology of Infertility and Recurrent Loss in Society with Fewer Children

JMAJ 52(1): 23–28, 2009

Harumi KUBO*1

Abstract Since there has been no improvement in the current downward trend in Japan’s birth rate, the growing population of potential patients with infertility is a significant social problem. Underlying the factors of infertility are psycho- logical factors related to the current stress of modern-day society, sexually transmitted diseases, increased smoking rates among young females, weight abnormalities such as and resulting from diet, an age-related decrease in reproductive function resulting from late and late childbearing (social infertility), and increasing numbers of patients with polycystic ovary syndrome, , or uterine myoma. Eighty to 90% of these factors contributing to infertility are derived from personal lifestyle and are considered to be preventable. On the other hand, 50–70% of recurrent pregnancy loss is of unknown cause, and currently there are no established standard tests or treatment policies. However, it is important to carry out close systematic investigation of the couple to determine the cause of infertility, including chromosomal or endocrine factors, blood coagulation function, uterine deformity, autoimmune diseases, and infectious diseases. Treatment specific to the cause should be provided to the patient, and the cause should be prevented if possible. It is proposed that, to prevent infertility and recurrent pregnancy loss, males and females of reproductive age undergo regular check- ups of reproductive function once a year. It is expected that this kind of effort may lead to improvement of the downward trend in the birthrate.

Key words Infertility and recurrent pregnancy loss, Declining birth rate, Assisted reproductive technology, Infertility prevention activities

probability of establishing pregnancy per repro- Infertility/Recurrent Pregnancy Loss ductive cycle among sexually mature couples and Declining Birth Rate who wish to have a child is considered to be 20–25%. Of couples who want to have a child, Infertility is decreased or complete lack of fecun- 80% and 90% achieve pregnancy within a year dity due to impaired reproductive function, which and within 2 years, respectively. In Japan, infer- is essential for the continuation of life. tility refers to the absence of pregnancy after is the ability to establish a clinical pregnancy at least 2 years of normal sexual activity by a in the cycles of a couples’ reproductive activities. couple that wants to achieve pregnancy. How- In contrast, in cases of recurrent pregnancy loss, ever, in western countries, infertility is defined fecundity is maintained, but fails to produce as a couple’s inability to conceive after one year newborns. Recurrent pregnancy loss includes of regular . Considering the recurrent (2 or more ) and recent trends of late marriage, late childbearing, habitual abortion (3 or more miscarriages). and falling birthrates in Japan, the definition of Although various fecundity curves in relation the inability to conceive after one year of sexual to the age of females have been reported, the life seems to be more appropriate.

*1 Chief Director, NPO Japan Association, Tokyo, Japan ([email protected]). This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol.137, No.1, 2008, pages 17–22).

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Infertility is regarded as a medical problem bility of having a healthy newborn is related to if medical intervention is required to achieve the maternal age, a phenomenon reportedly asso- conception when an infertile couple wants to ciated with maternal age-related chromosomal have a child. abnormality (aneuploid) of the fertilized egg. The population of individuals with potential On the other hand, recurrent pregnancy loss, infertility is said to be 10–15% of the overall sometimes included in broadly defined infertility, population of reproductive age, yielding an esti- generally refers to the failure of having a child mated 2,400,000 infertile individuals in Japan. because of recurrent abortion or stillbirth after According to the American Society for Repro- the establishment of pregnancy. This term is con- ductive Medicine (ASRM), there are 6,100,000 sidered to be synonymous with habitual abortion. infertile individuals in the US. A World Health Therefore, balanced chromosomal translocation, Organization (WHO) survey of 7,273 couples autoimmune disease, and with infertility revealed that infertility was attrib- of the parent, rather than accidental chromo- utable to female factors alone in 41% cases, both somal abnormality of the fertilized egg, are known male and female factors in 24%, male factors to be causes. However, the cause of recurrent alone in 24%, and unknown causes in 11%. pregnancy loss is unknown in most cases, and Despite the fact that infertility is common thus has no strict medical definition. Recurrent in both men and women, it differs from life- pregnancy loss is currently a syndrome covering threatening diseases including cancer or AIDS, a wide spectrum of clinical conditions including so no one worries about the possibility that he repeated intrauterine fetal death in or after the or she may be infertile or makes an effort to pre- second trimester. vent infertility. The reason for this may be that, even if the individual is infertile, various organs Actual Status of Medical Care for of the cardiovascular system, alimentary system, Infertility and Recurrent Pregnancy Loss etc., which are important for the health and life sustaining of the individual are normal and cause Assisted reproductive technology (ART) has no problems in daily living activities. Therefore, become much more common in Japan as well as individual patients generally do not recognize in other countries since the world’s first baby abnormalities of the reproductive system until conceived through in vitro fertilization was born they marry and attempt to conceive a child. in the UK in 1978. ART is now commonly avail- However, in Japan late marriage and late able in university hospitals and infertility clinics, childbearing have become increasingly common, serving as a useful treatment for infertility in this and thus more women tend to have the first child society with its decreasing numbers of children in their early to late 30s, resulting in a situation in and providing good steady results. which most women recognize their infertility and by ART as a whole—including in vitro fertiliza- recurrent pregnancy loss in their late 30s. Along tion and transfer (IVF-ET)—has been with aging, decreases and abnor- increasing year by year, and the number of ART- malities of the genital organs increase, making related births is over 19,000 per year, and over infertility more intractable. Therefore, consider- 150,000 cumulatively (as of 2005).2 In addition, in ing the current social situation of Japan, women regard to factors such as severe younger than 35 years who have failed to con- and , medical ceive after one year of trying and those aged 35 procedures for intractable male infertility have years or older who have failed to conceive after been common since the development of the tech- 6 months of trying are likely to be infertile and nique of intracytoplasmic sperm injection (ICSI). should undergo examination for infertility early, On the other hand, high frequencies of bal- regardless of the current definition of infertility. anced chromosomal translocation among patients In general, a healthy child can be expected with recurrent pregnancy loss have long been at delivery if a pregnancy has been established, reported. In translocation, chromosomes break but unfortunately the rate of is 34% at two sites and switch positions when rearranged. for women in their 40s and 18% for those in their Since total gene dosage remains unchanged, with 30s. In contrast, the corresponding rate is about all the necessary gene dosage being present, the 10% for women in their 20s.1 Thus, the proba- carrier of a balanced translocation is normal and

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has no difference in health from those without Table 1 Preventable infertility factors translocation. However, when gametes (egg and • Lifestyle sperm) are formed, it is possible that the egg or Irregular lifestyle habits sperm may have an imbalance in the distribution Life environment, stress of genetic material, and the egg or sperm with the Smoking, drinking translocational imbalance may abort spontane- Obesity, underweight, diet Pregnancy in adolescence, induced abortion ously even if fertilized. Favorite foods, regularly used drugs In this connection, preimplantation genetic Occupational diseases, environmental endocrine disrupters diagnosis (PGD) of patients with recurrent preg- • Lifestyle-related diseases nancy loss is attracting attention these days. Metabolic syndrome Through this technique, one or two blastomeres ED (erectile dysfunction), FSD (female ) • Endocrine and debilitating diseases from each four- to eight-cell stage embryo obtained Polycystic ovary syndrome (insulin-resistant) through ART are submitted to karyotypic analy- Endometriosis sis of chromosomes, and only the embryo with Menstruation-related syndrome normal or a balanced translocation is used for Hypothalamic-pituitary-ovarian dysfunction transfer to prevent abortion. In Japan, the use Autoimmune disease Anemia of PGD was discussed carefully because of the • Infectious diseases concern that PGD of genetic disorders may be STD ( trachomatis, Neisseria gonorrhoea, etc.) related to the concept of eugenics, and the Japan Pelvic infectious disease Society of and Gynecology has drawn up a societal rule that PGD only be permitted on Viral disease, febrile disease • Iatrogenic infertility a case-by-case basis under an approval system Pelvic surgery limited to serious genetic disorders. However, Radiotherapy and for malignant tumor since 2006, PGD of fertilized eggs using ART has Asherman’s syndrome begun to be reviewed and permitted for indi- Tubal interruption and vasoligation vidual cases to prevent recurrent pregnancy loss. Conization • Social infertility However, PGD of fertilized eggs still has many Aging, late marriage, late childbearing problems including the presupposition that ART No marriage, no childbearing be applied to females who are capable of achiev- Sexless couples ing a natural pregnancy, and the lack of difference Homosexuals between birth rates in cases of followed natural pregnancy and those in cases of PGD.3 There are also issues of financial and psy- chological burden on couples with infertility or issue. Such factors include psychological factors recurrent pregnancy loss, because ART is not caused by the stresses of modern society, sexually covered by health insurance. In actuality, there transmitted diseases, increased smoking rates are considerable differences in expenses borne among young women, weight abnormalities such by patients among different institutions. Con- as obesity and underweight, decreased repro- sidering the context of these circumstances ductive function resulting from late marriage around and the future and late childbearing (social infertility), and means of practicing infertility treatment in a gynecologic disorders such as polycystic ovary society characterized by a declining birth rate, syndrome, endometriosis, and uterine myoma. it would appear meaningful to provide insurance Of these infertility factors, 80–90% are related coverage of care for infertility and recurrent to the individual’s lifestyle and thus considered pregnancy loss. to be preventable (Table 1). On the other hand, the cause remains unclear Epidemiology and Prevention of in 50–70% of cases of recurrent pregnancy loss, Infertility and Recurrent Pregnancy Loss and there is no established standard examination or any treatment policies. However, it is important In Japan, where there has been no reversal in the to carry out systematic testing of chromosomes, declining birth rate, the tendency toward increas- endocrine factors, blood coagulation function, ing potential infertility factors is a major social uterine deformity, autoimmune diseases, and infec-

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tions in parents to elucidate the cause. Patients contribute to the occurrence of endometriosis. should receive treatment specific to the cause, and There are various measures to prevent stress, the cause, if preventable, should be eliminated. depending on the social environment of the indi- The etiology and epidemiology of infertility and vidual. However, in general, it is useful to abstain preventive measures are described in the follow- from stimulants such as caffeine, and to be open ing paragraphs. and emotionally available. Other methods include exercise, yoga, and other hobbies to reduce stress, Psychologic stress consulting a psychologist or counselor to keep Psychologic stress is defined as the perception peace of mind, and practicing religious devotion. of a threat or obstacle. In the early phase of stress, bodily systems increase their activities. Habitual smoking This increase in activities is further enhanced by Although not widely known, habitual smoking the excessive secretion of adrenaline from the carries the risk of jeopardizing reproductive and sympathetic nervous system. function as well as inducing respiratory or circu- Therefore, acute stress is manifested as increased latory disorders and cancers. Although smoking heart rate, elevated blood pressure, increased has generally been decreasing in both men and respiratory rate, perspiration, and cold sensa- women in Japan in recent years, there is concern tion. However, conversely, chronic stress induces that the percentage of smokers has been increas- depression and suppressed immune function. ing among young women who have not yet Couples undergoing treatment for infertility reached sexual maturity, with the smoking rate or recurrent pregnancy loss are under enormous currently about 25% (1 out of 4 persons). chronic stress. However, there are almost no It is apparent from the results of studies that reports documenting the responsibility of stress smoking is injurious to ovarian function, and itself for inducing infertility or recurrent preg- the degree of damage is thought to depend on nancy loss. However, it has been reported that the amount and duration of smoking. , high stress may cause impaired hormone pro- tar, and other chemical substances contained in duction, suppressed , spasmus of the tobacco suppress the production of and uterine tube, or defect in spermatogenesis result- other ovarian hormones related to ovulation, and ing from pelvic circulatory disturbance. induce gene defects of the egg. This may acceler- It is also said that endometriosis, which is ate follicle atresia and result in early menopause. related to infertility, has been increasing recently. The risk of early menopause occurring at the age According to 1997 data from the then Ministry of 44 years or younger is about 2-fold higher in of Health and Welfare, about 120,000 women women who smoke than in those who do not. It visited healthcare facilities because of endome- has also been reported that not only smoking triosis, and the number of patients as a whole was but also secondhand smoking accelerates meno- estimated to be about 1,000,000. In particular, pause by about 2 years. When age is matched, the endometriosis is more common in women in prevalence of menopause is 10–20% higher in their early 30s, with a reported prevalence rate of females with smoking or secondhand smoking. one per 150, although the actual prevalence is Damage from smoking may not be partly revers- thought to be slightly higher. The cited causes of ible, but it is possible to halt further increases in endometriosis include a complex social life and damage as a result of smoking cessation. Young other stress factors. Disrupted hormone balance women who smoke may think that smoking is due to these factors causes the suppression of trendy, looks nice, or will make them more slen- ovarian function. For instance, it is generally der, and they may ruin their health as a result of considered that endometriosis is aggravated by smoking. Although the responsibility for such stress related to daily or social rhythms including damage rests with the smokers themselves, warn- irregular eating and sleeping, busyness, or bore- ings should be given. dom and interpersonal relationships. In addition, Among males, when benzopyrene (an ingre- the content of dioxin, an endocrine-disrupting dient found in tobacco)-bound sperm DNA is chemical, in breast milk in Japan is reportedly detected by staining, the score calculated from 10- to 200-fold higher than the European stan- the detection rate and concentration is signifi- dard. It is speculated that various chemicals also cantly higher in smokers. The score has been

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correlated with the concentration of cotinine (a tility) as well as causing secondary infections in metabolite of nicotine in the body) in . In sexual partners. smokers, the majority of sperm are benzopyrene- Chlamydia infection, the main cause of salpin- bound, and these factors are considered to cause gitis and pelvic peritonitis, can induce infertility. fragmentation of sperm DNA, creating a factor Chlamydia DNA is detected from the cervical for infertility. mucus in an average 29% (25–50%) of patients with the above diseases.4 In recent years, STD Weight factors infections have also been increasing in Japan; It has been pointed out that obesity or under- STD surveillance has found chlamydia infection weight is involved in about 12% of female cases in 2–3% of subjects, and in 0.5–1.5%. of infertility. Infertility risk is 2.7-fold higher in However, this chlamydia infection rate is based obese women ( [BMI]Ͼ30). A only on hospital visitors. In a survey covering similar trend is also observed in thin women. It 3,190 randomly selected high school students (by has been reported that obese women have lower the Japanese Society for Sexually Transmitted rates of egg collection and conception after any Diseases in 2004), the overall chlamydia infection infertility treatment including ART, and exhibit rate was 11.4% (7.3% for males and 13.9% for higher rates of initial miscarriage. females), with the highest rates by age being The correlation between body weight and fer- 8.6% and 23.5% for males and females, respec- tility is mainly based on the fact that the exces- tively, at the age of 16 years.5 sive estrogen produced in fat cells suppresses To prevent infertility, including cases from the production of ovarian steroids. In obese STDs, it is useful to carry out annual screenings women, excessive estrogen causes a decrease for reproductive function in males and females in the possibility of conception, almost as if it who have reached reproductive age. To achieve were a contraceptive. Conversely, in thin women, the most accurate chlamydia examination, urine, estrogen production in fat cells is insufficient, cervical mucus, or urethral mucus samples should causing irregular menstrual cycles and possibly be used to detect antigens of Chlamydia tracho- inducing early menopause. In any case, inade- matis by the PCR or LCR technique. However, quate weight can lead to impaired ovulation and in view of the necessary time and cost, it is useful irregular sexual menstrual cycles. to measure the serum antibody titer for a screen- In men, obesity causes an increase in aromatase ing test. activity in fat cells, inducing hyperestrogenism and suppression of the hypothalamic-pituitary- Aging (social infertility) testicular system. This also causes hypoandro- Social infertility cases related to late marriage genism, resulting in suppressed spermatogenesis and late childbearing recently have been increas- and sexual function. ing in Japan. About 20% of couples do not intend to have their first child until at least age 35. How- Sexually transmitted diseases (STDs) ever, it is biologically evident that reproductive Everyone recognizes the possibility of conception capacity decreases with age, and that decreased when unprotected intercourse occurs. However, chance of pregnancy is a physiologic change that it is not well known that the risk of contracting occurs with aging. However, hardly any women an STD is increased if are not used. are aware of the fact that the age-related decrease Contracting an STD is likely to damage future in reproductive capacity begins in the late 20s. . STDs can be transmitted by unprotected Females have more than a million oocytes at sexual contact, and epidemiologists consider that the time of birth. These oocytes gradually become one in three sexually active young people may atretic follicles, and the number of oocytes contract an STD by the age of 24 years. Common decreases to about 300,000 in . During STDs include chlamydia infection, gonorrhea, the subsequent life of the woman, no eggs will syphilis, genital herpes, scabies, crab lice, and HIV. be regenerated. Therefore, the number of eggs Since these STD infections have few characteristic in a woman decreases steadily with aging. In symptoms, it is possible that patients are unaware addition, aged eggs are associated with higher of their STD infection, and thus the disease may frequencies of chromosomal abnormality (aneu- become intractable and cause sequelae (e.g., infer- ploid), and as a result, the infertility rate and

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miscarriage rate increase with aging. Although is considered to be decreased, encouraging early the infertility rate remains less than 10% in women childbearing and suggesting a poor prognosis for under 30 years of age, problems in fertility occur infertility treatment. Social infertility due to aging in 15% of them in their early 30s and in about is a by-product of the modern gender-equal society. 22% of them in their late 30s. It is thought that It is important to consider the couple’s situation after 40 years of age, about 30% of women have in light of their work-life balance. no chance of natural pregnancy.6 On the other hand, in men, the testes begin to However, the rate of aging in reproductive shrink and soften in the 40s, resulting in slightly function varies among different individuals. It is deteriorated spermatogenesis, decreased motility therefore difficult to set criteria for evaluating of sperm, and increased numbers of sperm with the annual changes in fertility of each woman. morphological or chromosomal abnormalities. It recently has become possible to estimate age- However, weakening of the reproductive and related ovarian reserve by determining the levels sexual functions in men is not as rapid a change of FSH, basal E2, anti-Mullerian duct hormone as is menopause in women. If physically healthy, (AMH), and inhibin B on day 3 of the menstrual men may have testes that maintain spermato- cycle. If the ovarian reserve shows accelerated genesis even into their 90s. aging as compared with the physical age, fertility

References

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