Infertility

Infertility
Classification and external resources
ICD-10	N46, N97.0
ICD-9	606, 628
DiseasesDB	21627
MedlinePlus	001191
eMedicine	med/3535 med/1167
MeSH	D007246

Infertility is fundamentally the inability to conceive offspring. Infertility also refers to the state of a woman who is unable to carry a pregnancy to full term. There are many biological causes of infertility, including some that medical intervention can treat.^[2] Infertility has increased by 4 percent since the 1980s, mostly from problems with fecundity due to an increase in age.^[3] About 40 percent of the issues involved with infertility are due to the man, another 40 percent due to the woman, and 20 percent result from complications with both partners.^[4]

Women who are fertile experience a natural period of fertility before and during ovulation, and they are naturally infertile during the rest of the menstrual cycle. Fertility awareness methods are used to discern when these changes occur by tracking changes in cervical mucus or basal body temperature.

Definition

Definitions of infertility differ. Demographers tend to define infertility as childlessness in a population of women of reproductive age, whereas the epidemiological definition refers to "trying for" or "time to" a pregnancy, generally in a population of women exposed to a probability of conception.^[5] The time needed to pass (during which the couple tries to conceive) for that couple to be diagnosed with infertility differs between different jurisdictions. Existing definitions of infertility lack uniformity, rendering comparisons in prevalence between countries or over time problematic. Therefore, data estimating the prevalence of infertility cited by various sources differs significantly.^[5] A couple that tries unsuccessfully to have a child after a certain period of time (often a short period, but definitions vary) is sometimes said to be subfertile, meaning less fertile than a typical couple. Both infertility and subfertility are defined as the inability to conceive after a certain period of time (the length of which vary), so often the two terms overlap.

World Health Organization

The World Health Organization defines infertility as follows:^[6]

“	Infertility is the inability to conceive a child. A couple may be considered infertile if, after two years of regular sexual intercourse, without contraception, the woman has not become pregnant (and there is no other reason, such as breastfeeding or postpartum amenorrhoea). Primary infertility is infertility in a couple who have never had a child. Secondary infertility is failure to conceive following a previous pregnancy. Infertility may be caused by infection in the man or woman, but often there is no obvious underlying cause.	”

United States

One definition of infertility that is frequently used in the United States by reproductive endocrinologists, doctors who specialize in infertility, to consider a couple eligible for treatment is:

• a woman under 35 has not conceived after 12 months of contraceptive-free intercourse. Twelve months is the lower reference limit for Time to Pregnancy (TTP) by the World Health Organization.^[7]
• a woman over 35 has not conceived after 6 months of contraceptive-free sexual intercourse.

These time intervals would seem to be reversed; this is an area where public policy trumps science. The idea is that for women beyond age 35, every month counts and if made to wait another 6 months to prove the necessity of medical intervention, the problem could become worse. The corollary to this is that, by definition, failure to conceive in women under 35 isn't regarded with the same urgency as it is in those over 35.

United Kingdom

In the UK, the NICE guidelines define infertility as failure to conceive after regular unprotected sexual intercourse for 2 years in the absence of known reproductive pathology.^[8]

Other definitions

Researchers commonly base demographic studies on infertility prevalence on a five-year period.^[9] Practical measurement problems, however, exist for any definition, because it is difficult to measure continuous exposure to the risk of pregnancy over a period of years.

Primary vs. secondary infertility

Couples with primary infertility have never been able to conceive,^[10] while, on the other hand, secondary infertility is difficulty conceiving after already having conceived (and either carried the pregnancy to term or had a miscarriage). Secondary infertility is not present if there has been a change of partners (this follows tautologically from the convention of speaking of couples, rather than individuals, as being infertile; if there is a change of partners, then a new couple is created, with its own chances to be infertile.)

Prevalence

Prevalence of infertility varies depending on the definition, i.e. on the time span involved in the failure to conceive.

• Some estimates suggest that worldwide "between three and seven per cent of all couples or women have an unresolved problem of infertility. Many more couples, however, experience involuntary childlessness for at least one year: estimates range from 12% to 28%." ^[11]

• Fertility problems affect one in seven couples in the UK. Most couples (about 84 out of every 100) who have regular sexual intercourse (that is, every two to three days) and who do not use contraception get pregnant within a year. About 92 out of 100 couples who are trying to get pregnant do so within two years.^[12]
• Women become less fertile as they get older. For women aged 35, about 94 out of every 100 who have regular unprotected sexual intercourse get pregnant after three years of trying. For women aged 38, however, only 77 out of every 100 do so. The effect of age upon men's fertility is less clear.^[12]
• In people going forward for IVF in the UK, roughly half of fertility problems with a diagnosed cause are due to problems with the man, and about half due to problems with the woman. However, about one in five cases of infertility has no clear diagnosed cause.^[13]
• In Britain, male factor infertility accounts for 25% of infertile couples, while 25% remain unexplained. 50% are female causes with 25% being due to anovulation and 25% tubal problems/other.^[14]
• In Sweden, approximately 10% of couples wanting children are infertile.^[15] In approximately one third of these cases the man is the factor, in one third the woman is the factor, and in the remaining third the infertility is a product of factors on both parts.

Causes

This section deals with unintentional causes of sterility. For more information about surgical techniques for preventing procreation, see Sterilization (surgical procedure).

Causes in either sex

Factors that can cause male as well as female infertility are:

• DNA damage
  • DNA damage reduces fertility in female ovocytes, as caused by smoking,^[16] other xenobiotic DNA damaging agents (such as radiation or chemotherapy)^[17] or accumulation of the oxidative DNA damage 8-hydroxy-deoxyguanosine^[18]
  • DNA damage reduces fertility in male sperm, as caused by oxidative DNA damage,^[19] smoking,^[16] other xenobiotic DNA damaging agents (such as drugs or chemotherapy)^[20] or other DNA damaging agents including reactive oxygen species, fever or high testicular temperature^[21]
• Genetic factors
  • A Robertsonian translocation in either partner may cause recurrent spontaneous abortions or complete infertility.
• General factors
  • Diabetes mellitus, thyroid disorders, adrenal disease
• Hypothalamic-pituitary factors
  • Hyperprolactinemia
  • Hypopituitarism
  • The presence of anti-thyroid antibodies is associated with an increased risk of unexplained subfertility with an odds ratio of 1.5 and 95% confidence interval of 1.1–2.0.^[22]
• Environmental factors
  • Toxins such as glues, volatile organic solvents or silicones, physical agents, chemical dusts, and pesticides.^[23][24] Tobacco smokers are 60% more likely to be infertile than non-smokers.^[1]

German scientists have reported that a virus called Adeno-associated virus might have a role in male infertility,^[25] though it is otherwise not harmful.^[26] Mutation that alters human DNA adversely can cause infertility, the human body thus preventing the tainted DNA from being passed on^{[citation needed]}.

Specific female causes

The following causes of infertility may only be found in females. For a woman to conceive, certain things have to happen: intercourse must take place around the time when an egg is released from her ovary; the systems that produce eggs and sperm have to be working at optimum levels; and her hormones must be balanced.^[27]

For women, problems with fertilisation arise mainly from either structural problems in the Fallopian tube or uterus or problems releasing eggs. Infertility may be caused by blockage of the Fallopian tube due to malformations, infections such as chlamydia and/or scar tissue. For example, endometriosis can cause infertility with the growth of endometrial tissue in the Fallopian tubes and/or around the ovaries. Endometriosis is usually more common in women in their mid-twenties and older, especially when postponed childbirth has taken place.^[28]

Another major cause of infertility in women may be the inability to ovulate. Malformation of the eggs themselves may complicate conception. For example, polycystic ovarian syndrome is when the eggs only partially developed within the ovary and there is an excess of male hormones. Some women are infertile because their ovaries do not mature and release eggs. In this case synthetic FSH by injection or Clomid (Clomiphene citrate) via a pill can be given to stimulate follicles to mature in the ovaries.

Other factors that can affect a woman's chances of conceiving include being overweight or underweight, or her age as female fertility declines after the age of 35^{[citation needed]}.

Sometimes it can be a combination of factors, and sometimes a clear cause is never established.

Common causes of infertility of females include:

• ovulation problems (e.g. polycystic ovarian syndrome, PCOS, the leading reason why women present to fertility clinics due to anovulatory infertility.^[29])
• tubal blockage
• pelvic inflammatory disease
• age-related factors
• uterine problems
• previous tubal ligation
• endometriosis
• advanced maternal age

Specific male causes

The main cause of male infertility is low semen quality. In men who have the necessary reproductive organs to procreate, infertility can be caused by low sperm count due to endocrine problems, drugs, radiation, or infection. There may be testicular malformations, hormone imbalance, or blockage of the man's duct system. Although many of these can be treated through surgery or hormonal substitutions, some may be more indefinite.^[30] Infertility associated with viable, but immotile sperm may be caused by primary ciliary dyskinesia.

Combined infertility

In some cases, both the man and woman may be infertile or sub-fertile, and the couple's infertility arises from the combination of these conditions. In other cases, the cause is suspected to be immunological or genetic; it may be that each partner is independently fertile but the couple cannot conceive together without assistance.

Unexplained infertility

In the US, up to 20% of infertile couples have unexplained infertility.^[31] In these cases abnormalities are likely to be present but not detected by current methods. Possible problems could be that the egg is not released at the optimum time for fertilization, that it may not enter the fallopian tube, sperm may not be able to reach the egg, fertilization may fail to occur, transport of the zygote may be disturbed, or implantation fails. It is increasingly recognized that egg quality is of critical importance and women of advanced maternal age have eggs of reduced capacity for normal and successful fertilization. Also, polymorphisms in folate pathway genes could be one reason for fertility complications in some women with unexplained infertility.^[32]

Assessment

If both partners are young and healthy and have been trying to conceive for one year without success, a visit to a physician or women's health nurse practitioner (WHNP) could help to highlight potential medical problems earlier rather than later. The doctor or WHNP may also be able to suggest lifestyle changes to increase the chances of conceiving.^[33]

Women over the age of 35 should see their physician or WHNP after six months as fertility tests can take some time to complete, and age may affect the treatment options that are open in that case.

A physiiann or WHNP takes a medical history and gives a physical examination. They can also carry out some basic tests on both partners to see if there is an identifiable reason for not having achieved a pregnancy. If necessary, they refer patients to a fertility clinic or local hospital for more specialized tests. The results of these tests help determine the best fertility treatment.

Treatment

Treatment depends on the cause of infertility, but may include counselling, fertility treatments, which include in vitro fertilization. According to ESHRE recommendations, couples with an estimated live birth rate of 40% or higher per year are encouraged to continue aiming for a spontaneous pregnancy.^[34] Treatment methods for infertility may be grouped as medical or complementary and alternative treatments. Some methods may be used in concert with other methods. Drugs used for women include Clomiphene citrate, Human menopausal gonadotropin, Follicle-stimulating hormone, Human chorionic gonadotropin, Gonadotropin-releasing hormone analogs, Aromatase inhibitor, Metformin.

At-home conception kit

In 2007 the FDA cleared the first at home tier one medical conception device to aid in conception. The key to the kit are cervical caps for conception. This at home [cervical cap] insemination method allows all the semen to be placed up against the cervical os for six hours allowing all available sperm to be placed directly on the cervical os. For low sperm count, low sperm motility, or a tilted cervix using a cervical cap aids conception. This is a prescriptive medical device, but not commonly prescribed by physicians.^[35]

Assisted Natural Conception

For some causes of infertility, assisted natural conception can provide couples with a pregnancy rate at least as high as the one provided by fertility treatment.^{[citation needed]} This is typically for couples with unexplained infertility, sperm count above 5M/ml, one tube blocked, or other mild infertility causes.^{[citation needed]}

Medical treatments

Medical treatment of infertility generally involves the use of fertility medication, medical device, surgery, or a combination of the following. If the sperm are of good quality and the mechanics of the woman's reproductive structures are good (patent fallopian tubes, no adhesions or scarring), physicians may start by prescribing a course of ovarian stimulating medication. The physician or WHNP may also suggest using a conception cap cervical cap, which the patient uses at home by placing the sperm inside the cap and putting the conception device on the cervix, or intrauterine insemination (IUI), in which the doctor or WHNP introduces sperm into the uterus during ovulation, via a catheter. In these methods, fertilization occurs inside the body.

If conservative medical treatments fail to achieve a full term pregnancy, the physician or WHNP may suggest the patient undergo in vitro fertilization (IVF). IVF and related techniques (ICSI, ZIFT, GIFT) are called assisted reproductive technology (ART) techniques.

ART techniques generally start with stimulating the ovaries to increase egg production. After stimulation, the physician surgically extracts one or more eggs from the ovary, and unites them with sperm in a laboratory setting, with the intent of producing one or more embryos. Fertilization takes place outside the body, and the fertilized egg is reinserted into the woman's reproductive tract, in a procedure called embryo transfer.

Other medical techniques are e.g. tuboplasty, assisted hatching, and Preimplantation genetic diagnosis.

Tourism

Fertility tourism is the practice of traveling to another country for fertility treatments.^[36] It may be regarded as a form of medical tourism. The main reasons for fertility tourism are legal regulation of the sought procedure in the home country, or lower price. In-vitro fertilization and donor insemination are major procedures involved.

Ethics

There are several ethical issues associated with infertility and its treatment.

• High-cost treatments are out of financial reach for some couples.
• Debate over whether health insurance companies (e.g. in the US) should be required to cover infertility treatment.
• Allocation of medical resources that could be used elsewhere
• The legal status of embryos fertilized in vitro and not transferred in vivo. (See also Beginning of pregnancy controversy).
• Pro-life opposition to the destruction of embryos not transferred in vivo.
• IVF and other fertility treatments have resulted in an increase in multiple births, provoking ethical analysis because of the link between multiple pregnancies, premature birth, and a host of health problems.
• Religious leaders' opinions on fertility treatments.
• Infertility caused by DNA defects on the Y chromosome is passed on from father to son. If natural selection is the primary error correction mechanism that prevents random mutations on the Y chromosome, then fertility treatments for men with abnormal sperm (in particular ICSI) only defer the underlying problem to the next male generation.

Many countries have special frameworks for dealing with the ethical and social issues around fertility treatment.

• One of the best known is the HFEA – The UK's regulator for fertility treatment and embryo research. This was set up on 1 August 1991 following a detailed commission of enquiry led by Mary Warnock in the 1980s

• A similar model to the HFEA has been adopted by the rest of the countries in the European Union. Each country has its own body or bodies responsible for the inspection and licencing of fertility treatment under the EU Tissues and Cells directive ^[37]

• Regulatory bodies are also found in Canada ^[38] and in the state of Victoria in Australia ^[39]

Psychological impact

The consequences of infertility are manifold and can include societal repercussions and personal suffering. Advances in assisted reproductive technologies, such as IVF, can offer hope to many couples where treatment is available, although barriers exist in terms of medical coverage and affordability. The medicalization of infertility has unwittingly led to a disregard for the emotional responses that couples experience, which include distress, loss of control, stigmatization, and a disruption in the developmental trajectory of adulthood.^[40]

Infertility may have profound psychological effects. Partners may become more anxious to conceive, increasing sexual dysfunction.^[41] Marital discord often develops in infertile couples, especially when they are under pressure to make medical decisions. Women trying to conceive often have clinical depression rates similar to women who have heart disease or cancer.^[42] Even couples undertaking IVF face considerable stress.^[43]

The emotional losses created by infertility include the denial of motherhood as a rite of passage; the loss of one’s anticipated and imagined life; feeling a loss of control over one’s life; doubting one’s womanhood; changed and sometimes lost friendships; and, for many, the loss of one’s religious environment as a support system.^[44]

Emotional stress and marital difficulties are greater in couples where the infertility lies with the man.^[45]

Social impact

In many cultures, inability to conceive bears a stigma. In closed social groups, a degree of rejection (or a sense of being rejected by the couple) may cause considerable anxiety and disappointment. Some respond by actively avoiding the issue altogether; middle-class men are the most likely to respond in this way.^[46]

In an effort to end the shame and secrecy of infertility, Redbook in October 2011 launched a video campaign, The Truth About Trying, to start an open conversation about infertility, which strikes one in eight women in the United States. In a survey of couples having difficulty conceiving, conducted by the pharmaceutical company Merck, 61 percent of respondents hid their infertility from family and friends.^[47] Nearly half didn't even tell their mothers. The message of those speaking out: It's not always easy to get pregnant, and there's no shame in that.

There are legal ramifications as well. Infertility has begun to gain more exposure to legal domains. An estimated 4 million workers in the U.S. used the Family and Medical Leave Act (FMLA) in 2004 to care for a child, parent or spouse, or because of their own personal illness. Many treatments for infertility, including diagnostic tests, surgery and therapy for depression, can qualify one for FMLA leave. It has been suggested that infertility be classified as a form of disability.^[48]

Infertility in developing countries

Infertility is often not seen (by the West) as being an issue outside industrialized countries.^[49] This is because of assumptions about overpopulation problems and hyper fertility in developing countries, and a perceived need for them to decrease their populations and birth rates.^[50] Fertility treatments, even simple ones such as treatment for STIs that cause infertility, are therefore not usually made available to individuals in these countries.^[51]

Despite this, infertility has profound effects on individuals in developing countries, as the production of children is often highly socially valued and is vital for social security and health networks as well as for family income generation.^[52] Infertility in these societies often leads to social stigmatization and abandonment by spouses.^[53] Infertility is, in fact, common in sub-Saharan Africa. Unlike in the West, secondary infertility is more common than primary infertility, being most often the result of untreated STIs or complications from pregnancy/birth.^[54]

High costs may also be a factor and research by the Genk Institute for Fertility Technology, in Belgium, claimed a much lower cost methodology (about 90% reduction) with similar efficacy, which may be suitable for some fertility treatment.^[55]

Fictional representation

Perhaps except for infertility in science fiction, films and other fiction depicting emotional struggles of assisted reproductive technology have had an upswing first in the latter part of the 2000s decade, although the techniques have been available for decades.^[56] Yet, the amount of people that can relate to it by personal experience in one way or another is ever growing, and the variety of trials and struggles is huge.^[56]

Pixar's Up contains a depiction of infertility in an extended life montage that lasts the first few minutes of the film.^[57]

Other individual examples are referred to individual subarticles of assisted reproductive technology

See also

• Advanced maternal age
• Childlessness
• Conception device
• Inherited sterility in insects
• Medical ethics
• Oncofertility, fertility in cancer patients
• Surrogate marriage

References

Inhorn, Marcia C. 2003. "Global infertility and the globalization of new reproductive technologies: illustrations from Egypt." Social Science & Medicine 56(9):1837-1851. Lock, Margaret and Vinh-Kim Nguyen. 2011. An anthropology of biomedicine: Wiley-Blackwell.

Further reading

• Fertility: Assessment and Treatment for People with Fertility Problems. London: RCOG Press. 2004. ISBN 1-900364-97-2. 
• Pamela Mahoney Tsigdinos (2009). Silent Sorority: A Barren Woman Gets Busy, Angry, Lost and Found. BookSurge Publishing. p. 218. ISBN 1-4392-3156-7. 

External links

• RCOG clinical guidelines for infertility (concise guidelines)
• Fertility: Assessment and Treatment for People with Fertility Problems, 2004 (extensive guidelines)
• Fertility treatment and clinics in the UK
• GeneReviews/NCBI/NIH/UW entry on CATSPER-Related Male Infertility
• CBC Digital Archives – Fighting Female Infertility
• InterNational Council on Infertility Information Dissemination
• Infertility not just a Female Problem
• Assisted Reproduction in Judaism
• Facing Life Without Children When It Isn’t by Choice
• Patient Voices – Infertility
• World Congress on Controversies in Obstetrics, Gynecology & Infertility (COGI)
• Penn Researcher Looks at Infertility’s Impact on Women
• Infertility and IVF threatment

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v t e Assisted reproductive technology Infertility Female Male Fertility testing Fertility clinic Fertility tourism Fertility medication GnRH agonists Estrogen antagonists Clomifene Aromatase inhibitor Gonadotropins Menotropins hCG FSH In vitro fertilisation (IVF) and expansions Ovarian hyperstimulation Transvaginal ovum retrieval Embryo transfer Assisted zona hatching Intracytoplasmic sperm injection Autologous endometrial coculture zygote intrafallopian transfer Cytoplasmic transfer Egg donation gestational carrier Preimplantation genetic diagnosis In vitro maturation Oocyte selection Other methods Gamete intrafallopian transfer Sex selection Artificial insemination Sperm donation Surrogacy Reproductive surgery reverse vasectomy Semen collection Cryopreservation oocyte semen ovarian tissue embryos Donation Sperm Egg Embryo Sperm bank Donor registration Donor Sibling Registry Ethics Religious response to ART Accidental incest Three-parent babies In fiction See subsections in e.g. surrogacy and sperm donation reproduction and pregnancy in speculative fiction M: ♀ FRS anat/phys/devp noco/cong/npls, sysi/epon proc/asst, drug (G1/G2B/G3CD) M: OBS phys/devp/memb mthr/fetu/infc, epon proc, drug (2A/G2C)

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