Infertility in Women
In the U.S., about 10% of women ages 15 - 44, or about 6.1 million women, have difficulty getting pregnant or carrying a baby to term.
Risk Factors
Risk factors for female infertility include:
Causes
Infertility may be caused by an underlying medical condition that damages the fallopian tubes, interferes with ovulation, or causes hormonal complications. These medical conditions include:
Diagnosis
If you have been unable to conceive after 1 year of unprotected sex, talk with your doctor about having your fertility evaluated. Fertility testing should especially be performed if a woman is over 35 years old or if either partner has known risk factors for infertility. An analysis of the man's semen should be performed before the female partner undergoes any invasive testing.
Treatment
Treatment for infertility should first address any underlying medical condition that may be contributing to fertility problems. If this step does not restore fertility, there are several treatment approaches:
Infertility is the failure of a couple to become pregnant after one year of regular, unprotected intercourse. In both men and women the fertility process is complex.
Infertility affects about 10% of all couples. About a third of infertility problems are due to female infertility, and another third are due to male infertility. In the remaining cases, infertility affects both partners or the cause is unclear. Although this report specifically addresses infertility in women, it is important for the male partner to be tested at the same time. [For more information, see In-Depth Report #67: Infertility in men.]
The primary organs and structures in the reproductive system are:
The menstrual cycle is regulated by the complex surge and fluctuations of many different reproductive hormones, which work together to prepare a women’s body for pregnancy.
The hypothalamus (an area in the brain) and the pituitary gland control six important hormones:
During a woman’s monthly menstrual cycle, her body prepares for conception and pregnancy. The average menstrual cycle is about 28 days but anywhere from 21 days to 35 days is considered normal. The menstrual cycle is divided into three phases: Follicular, Ovulatory, and Luteal.
Follicular Phase. The follicular phase begins with the first day of menstrual bleeding:
Ovulatory Phase. The ovulatory phase occurs halfway through the menstrual cycle (about 14 days after the start of the follicular phase.) Ovulation, the critical process for conception, occurs during the ovulatory phase. A woman’s fertile period starts about 3 - 5 days before ovulation and ends 24 - 48 hours after it. During the ovulatory phase:
Luteal Phase. The luteal phase begins immediately after ovulation and ends when the next menstrual period starts. The luteal phase lasts about 12 - 16 days. During the luteal phase:
Conception occurs when an egg is fertilized by a sperm. The so-called "fertile window" is about 6 days long. It starts about 5 days before ovulation and ends the day of ovulation. Fertilization occurs as follows:
Typical Menstrual Cycle | ||
Menstrual Phases | Typical No. of Days | Hormonal Actions |
Follicular (Proliferative) Phase | Cycle Days 1 - 6: Beginning of menstruation to end of blood flow. | Estrogen and progesterone start out at their lowest levels. FSH levels rise to stimulate maturity of follicles. Ovaries start producing estrogen and levels rise, while progesterone levels remains low. |
Cycle Days 7 - 13: The endometrium (the inner lining of the uterus) thickens to prepare for egg implantation. | ||
Ovulation | Cycle Day 14: | Surge in LH. Largest follicle bursts and releases egg into fallopian tube. |
Luteal (Secretory) Phase, also known as the Premenstrual Phase | Cycle Days 15 - 28: | Ruptured follicle develops into corpus luteum, which produces progesterone. Progesterone and estrogen stimulate blanket of blood vessels to prepare for egg implantation. |
If fertilization occurs: | Fertilized egg attaches to blanket of blood vessels that supplies nutrients for the developing placenta. Corpus luteum continues to produce estrogen and progesterone. | |
If fertilization does not occur: | Corpus luteum deteriorates. Estrogen and progesterone levels drop. The blood vessel lining sloughs off and menstruation begins. |
Most cases of female infertility are due to medical conditions that cause:
Ovulation is the release of the egg that occurs during the monthly menstrual cycle. Problems that affect ovulation, and the hormones involved with ovulation, are the most common cause of female infertility. They include:
A blocked fallopian tube can prevent sperm from reaching and fertilizing the egg. Blockage in the fallopian tubes can also prevent a fertilized egg from traveling to the uterus for implantation. Conditions that can block or damage fallopian tubes include:
Other possible causes of female infertility include:
In the U.S., about 10% of women ages 15 - 44, or about 6.1 million women, have problems getting pregnant or carrying a baby to term.
Fertility declines as a woman ages. Fertility begins to decline when a woman reaches her mid-30s, and rapidly declines after her late 30s. As a woman ages, her ovaries produce fewer eggs. In addition, the quality of the eggs is poorer than those of younger women. Older women have a higher risk for eggs with chromosomal abnormalities, which increase the risk for miscarriage and birth defects. Older women are also more likely to have health problems that may interfere with fertility.
Although most of a woman's estrogen is manufactured in her ovaries, 30% is produced by fat cells, which transform male hormones produced by the adrenal glands into estrogen. Because a normal hormonal balance is essential for the process of conception, extreme weight levels (either high or low) can contribute to infertility.
Being Overweight. Being overweight or obese (fat levels that are 10 - 15% above normal) can contribute to infertility in various ways. Obesity is also associated with polycystic ovarian syndrome (PCOS), an endocrinologic disorder that can cause infertility.
Being Underweight. Body fat levels 10 - 15% below normal can completely shut down the reproductive process. Women at risk include:
Cigarette smoking can harm a woman’s ovaries and contribute to a decrease in eggs. Studies show that women who smoke are more likely to reach menopause earlier than women who do not smoke.
Alcohol and caffeine use may contribute to infertility.
Exposure to environmental hazards (such as herbicides, pesticides, and industrial solvents) may affect fertility. Estrogen-like chemicals that interfere with normal hormones are of particular concern for infertility in men and for effects on offspring of women. Phthalates, chemicals used to soften plastics, are under particular scrutiny because they may disrupt hormones.
Neurotransmitters (chemical messengers in the brain) act in the hypothalamus gland, which controls both reproductive and stress hormones. It is not clear if stress has any significant effect on fertility or fertility treatments. Several large studies indicate it does not.
In any fertility work-up, both male and female partners are tested if pregnancy fails to occur after a year of regular unprotected sexual intercourse. Fertility testing is particularly important if a woman is over 35 years old or if either partner has known risk factors for infertility. An analysis of the man's semen should be performed before the female partner undergoes any invasive testing.
The first step in any infertility work up is a complete medical history and physical examination. The doctor will ask about the patient's history of sexual activity, especially frequency and timing of intercourse. Menstrual history, lifestyle issues (smoking, drug and alcohol use, and caffeine consumption), any medications being taken, and a profile of the patient's general medical and emotional health can help the doctor decide on appropriate tests.
Before beginning an expensive fertility work-up, you can try the following steps. They are are free or low-cost and can be helpful:
Several laboratory tests may be used to detect the cause of infertility and monitor treatments:
Hormonal Levels. Blood and urine tests are taken to evaluate hormone levels. Hormonal tests for ovarian reserve (the number of follicles and quality of the eggs) are especially important for older women.
Examples of possible results include:
Clomiphene Challenge Test. Clomiphene citrate (Clomid, Serophene, generic), a standard fertility drug, may be used to test for ovarian reserve. With this test, the doctor measures FSH on day 3 of the cycle. The woman takes clomiphene orally on days 5 and 9 of the cycle. The doctor measures FSH on the tenth day. High levels of FSH either on day 3 or day 10 indicate a poor chance for a successful outcome.
Tissue Samples. To rule out luteal phase defect, premature ovarian failure, or absence of ovulation, the doctor may take tissue samples of the uterus 1 - 2 days before a period to determine if the corpus luteum is adequately producing progesterone. Samples taken from the cervix may be cultured to rule out infection.
Tests for Autoimmune Disease. Tests for autoimmune disease, such as hypothyroidism and type 1 diabetes, should be considered in women with recent ovarian failure that is not caused by genetic abnormalities.
If an initial fertility work-up does not reveal abnormalities, more extensive tests may help reveal abnormal tubal or uterine findings. The four major approaches for examining the uterus and fallopian tubes are:
Combinations of these imaging procedures may be used to confirm diagnoses.
Ultrasound and Sonohysterography. Ultrasound is the standard imaging technique for evaluating the uterus and ovaries. It is also used for detecting fibroids, ovarian cysts and tumors, and obstructions in the urinary tract. It uses sound waves to produce an image of the organs and causes very little discomfort.
Transvaginal sonohysterography uses ultrasound along with saline infused into the uterus, which enhances the visualization of the uterus. This technique is proving to be more accurate than standard ultrasound in identifying potential problems. It is currently the gold standard for diagnosing polycystic ovaries.
Hysteroscopy. Hysteroscopy is a procedure that may be used to detect the presence of endometriosis, fibroids, polyps, pelvic scar tissue, and blockage at the ends of the fallopian tubes. Some of these conditions can be corrected during the procedure by cutting away any scar tissue that may be binding organs together or by destroying endometrial implants.
Hysteroscopy may be done in a doctor’s office or in an operating room, depending on the type of anesthesia used. The procedure uses a long flexible or rigid tube called a hysteroscope, which is inserted into the vagina and advanced through the cervix to reach the uterus. A fiber-optic light source and a tiny camera in the tube allow the doctor to view the cavity. The uterus is filled with saline or carbon dioxide to inflate the cavity and provide better viewing. This can cause cramping.
There are small risks of bleeding, infection, and reactions to anesthesia. Many patients experience temporary discomfort in the shoulders after the operation due to residual carbon dioxide that puts pressure on the diaphragm.
Hysterosalpingography. Hysterosalpingography is performed to discover possible blockage in the fallopian tubes and abnormalities in the uterus:
There is a small risk of pelvic infection, and antibiotics may be prescribed prior to the procedure.
Laparoscopy. Laparoscopy is a minimally invasive surgical procedure. It requires general anesthesia and is performed in an operating room. The surgeon makes a very small incision below the belly button and inserts an instrument called a laparoscope, which is similar to a hysteroscope. (The difference is that a laparoscope is inserted through the abdomen, while a hysteroscope is inserted through the vagina and cervix.) Through the laparoscope, the surgeon can view the uterus, fallopian tube, and ovaries. Laparoscopy is most helpful for identifying endometriosis or other adhesions that may affect fertility.
Treatment for infertility should first address any underlying medical condition that may be contributing to fertility problems. Drugs, surgery, or both may be used to treat these conditions. Surgery may also be used to repair blockage in fallopian tubes.
Several approaches are used to treat infertility:
Some doctors recommend that if a couple fails to conceive after 1 - 2 years of frequent unprotected sex, they should consult a fertility expert. Women who are 35 or older, however, may want to begin exploring their options if they do not become pregnant within 6 months to a year.
Choosing a good fertility clinic is important. Those offering assisted reproductive techniques are not always regulated by the government, and abuses have been reported, including lack of informed consent, unauthorized use of embryos, and failure to routinely screen donors for disease.
The clinic should always provide the following information:
Advanced fertility procedures and medications are extremely expensive and often not covered by insurance. Couples should be cautious about offers of rebates in the event of failure; the clinics offering them are often significantly more expensive than those that don't offer such gimmicks.
Women who are undergoing cancer treatments and who want to become pregnant should see a reproductive specialist to discuss their options. According to the American Society of Clinical Oncology's guidelines, the fertility preservation method with the best chance of success is embryo cryopreservation. This procedure involves harvesting a woman's eggs (oocytes), followed by in vitro fertilization and freezing of embryos for later use. Other treatments under investigation include egg preservation, collecting and freezing unfertilized eggs, removing and freezing a part of the ovary for later reimplantation, and using hormone therapy to protect the ovaries during chemotherapy. Women may be able to access these investigational approaches through enrolling in clinical trials.
Fertility drugs are often used alone as initial treatment to induce ovulation. If they fail as sole therapy, they may be used with assisted reproductive procedures, such as in vitro fertilization, to produce multiple eggs, a process called superovulation.
According to the American Society for Reproductive Medicine, fertility drugs can be divided into three main categories:
Clomiphene citrate (Clomid, Serophene, generic) is usually the first fertility drug prescribed for women with infrequent periods and long menstrual cycles. Unlike more potent drugs used in superovulation, clomiphene is gentler and works by blocking estrogen, which tricks the pituitary into producing follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This boosts follicle growth and the release of the egg. Clomiphene can be taken by mouth, is relatively inexpensive, and the risk for multiple births (about 5%, mostly twins) is lower than with other drugs.
Women with the best chances for success with this drug are those who have the following conditions:
Women with poorer chances of success with this drug have the following conditions:
One or two tablets are taken each day for 5 days, usually starting 2 - 5 days after the period starts. If successful, ovulation occurs about a week after the last pill has been taken. If ovulation does not occur, then a higher dose may be given for the next cycle. If this regimen is not successful, treatment may be prolonged or additional drugs may be added. Doctors usually do not recommend more than 6 cycles.
Clomiphene often reduces the amount and quality of cervical mucus and may cause thinning of the uterine lining. In such cases, other hormonal drugs may be given to restore thickness. Other side effects of clomiphene include ovarian cysts, hot flashes, nausea, headaches, weight gain, and fatigue. There is a 5% chance of having twins with this drug, and a slightly increased risk for miscarriage.
If clomiphene does not work or is not an appropriate choice, gonadotropin drugs are a second option. Gonadotropins include several different types of drugs that contain either a combination of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), or only FSH. Whereas clomiphene works indirectly by stimulating the pituitary gland to secrete FSH, (which prompts follicle production), gonadtropin hormones directly stimulate the ovaries to produce multiple follicles.
Gonadotropins are given by injection. (Your doctor may show you how to self-administer the injection.) Gonadotropins include:
Gonadotropin drugs are either natural compounds extracted from urine or synthetic compounds that are genetically engineered in a laboratory using recombinant DNA.
Human Menopausal Gonadotropin (hMG). HMG drugs, also called menotropins, contain a mixture of both FSH and LH. These drugs (Menopur, Repronex, Humegon) are all derived from the urine of postmenopausal women. HMG is administered as a series of injections 2 - 3 days after the period starts. Injections are usually given for 7 - 12 days, but the time may be extended if ovulation does not occur. In such cases, a shot of human chorionic gonadotropin (hCG) may trigger ovulation.
Human Chorionic Gonadotropin (hCG). Human chorionic gonadotropin (hCG) is similar to LH. It mimics the LH surge, which stimulates the follicle to release the egg. Natural hCG drugs, derived from the urine of pregnant women, include Pregnyl, Profasi, Novarel, and APL. Ovidrel is the only available genetically modified hCG drug. Ovidrel has fewer side effects at the injection site, and its quality can be better controlled than the natural drugs. It is generally used after hMG or FSH to stimulate the final maturation stages of the follicles. Ovulation, if it occurs, does so about 36 - 72 hours after administration.
Follicle Stimulating Hormone (FSH). Urofollitropin (Bravelle, Fertinex) is a purified form of FSH, derived from the urine of postmenopausal women. Follitropin drugs (Gonal-F, Follistim) are synthetic versions of FSH. These FSH drugs are sometimes given in combination with an hCG drug.
GnRH Analogs (Agonists or Antagonists). Gonadotropin-releasing hormone (GnRH) is a hormone produced in the hypothalamus part of the brain. GnRH stimulates the pituitary gland to produce LH and FSH. GnRH analogs are synthetic drugs that are classified as either agonists or antagonists. They are similar to natural GnRH but have very different actions. While natural GnRH stimulates LH and FSH, these drugs actually prevent the LH and FSH surge that occurs right before ovulation. This action helps prevent the premature release of the eggs before they can be harvested for assisted reproductive technologies.
Multiple Births. Overproduction of follicles can lead to ovarian enlargement. This event increases the risk for multiple births. There is a 25% chance of multiple births (about 17% for twins and 8% for triplets and or more).
Ovarian Hyperstimulation Syndrome. The most serious complication with superovulation is ovarian hyperstimulation syndrome (OHS), which is associated with the enlarged ovary (although the precise cause is unknown). This can result in dangerous fluid and electrolyte imbalances and endanger the liver and kidney. OHS is also associated with a higher risk for blood clots. In rare cases, it can be fatal. Symptoms include abdominal bloating, nausea, vomiting, and shortness of breath.
Bleeding and Rupture of Ovarian Cysts. Overproduction of follicles, if unchecked, may result in bleeding and rupture of ovarian cysts.
Cancer Concerns. There has been concern that clomiphene and gonadotropins may increase the risks for ovarian and breast cancer. Most evidence to date does not indicate that ovulation-stimulating drugs increase the risks for these types of cancers. Some studies suggest that clomiphene, which is chemically related to the breast cancer drug tamoxifen, may actually decrease the risk for breast cancer.
Letrozole and Aromatase Inhibitors. Aromatase inhibitors block aromatase, an enzyme that is largely responsible for producing estrogen in body tissues outside of the ovaries. These drugs include anastrozole (Arimidex) and letrozole (Femara). These drugs are used for treating breast cancer and are being investigated for stimulating ovulation in infertile women. Although letrozole is not approved for treatment of infertility, it has become widely used for this purpose in recent years.
Progesterone. Progesterone is a hormone that is produced by the body during the menstrual cycle. Progesterone drugs are sometimes given to women who have experienced frequent miscarriages (a possible sign of progesterone deficiency). A progesterone drug may also be given after egg retrieval during an in vitro fertilization (IVF) cycle to help thicken the uterine lining (endometrium) so it can better hold the egg following implantation.
Tamoxifen. Tamoxifen (Nolvadex, generic) is a drug known as a selective estrogen-receptor modulator (SERM). It is used to treat or prevent breast cancer in certain women. It is also being studied in fertility treatments to induce ovulation. Tamoxifen works in a similar to clomiphene but may pose more health hazards, including a risk for blood clots and uterine cancer.
Glucocorticoids. Glucocorticoids are steroid hormones that are sometimes used in combination with IVF and intracytoplasmic sperm injection (ICSI) to help make the lining of the uterus more responsive to egg implantation. However, recent reviews caution that glucocorticoids do not help improve pregnancy success rates and should not be used routinely with assisted reproductive technologies.
Assisted reproductive technologies (ART) are medical techniques that help couples conceive. These procedures involve either:
Fertilization may occur either in the laboratory or in the uterus. In the U.S., the number of live birth deliveries from ART has dramatically increased in the last decade. About 45,000 live births (deliveries of one or more infants) occur in the U.S. each year using assisted reproductive technologies.
Technically, the term ART refers only to fertility treatments, such as in vitro fertilization (IVF) and its variants, which handle both egg and sperm.
Artificial insemination (AI) involves placing the sperm directly in the cervix (called intracervical insemination) or into the uterus (called intrauterine insemination, or IUI).
IUI is the standard AI procedure. It involves placing washed sperm into the woman’s uterine cavity through a long, thin catheter. The procedure is performed when a woman is ovulating and is used for patients whose tubes are not blocked from endometriosis or scarring.
IUI is the least complex and least expensive of fertility procedures and is often tried first in uncomplicated cases of infertility. However, recent studies indicate that IUI combined with fertility injections poses a greater risk for multiple births and has a lower rate of pregnancy success than IVF.
For these reasons, some doctors now suggest that women skip the gonadotropin-stimulating injection step, and that couples who fail to conceive after three cycles of IUI combined with clomiphene pills proceed directly to IVF.
Most assisted reproductive technologies procedures use in vitro fertilization (IVF). An in vitro procedure is one that is performed in the laboratory. Advances in these procedures have dramatically increased the rate of live births. IVF can be performed with a woman’s own eggs and sperm, or with donor eggs and sperm.
In the past, IVF was used mainly to treat women with damaged fallopian tubes. It is now used as a fertility treatment for cases when the woman has endometriosis, the man has fertility problems, or the cause of a couple’s infertility is unexplained.
A standard IVF cycle is divided into the following steps:
Embryo Transfer Guidelines. The American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technologies (SART) have joint guidelines on the number of embryos that should be transferred during IVF procedures:
These embryo numbers are recommended for women with favorable prognoses. For patients who have failed to become pregnant after at least two IVF cycles, or who have a less favorable prognosis, the doctor may consider adding one additional embryo. The guidelines apply to both fresh and frozen embryos.
Other IVF Procedures. About 1 - 2% of IVF procedures use adaptations called gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT), which transfers the gametes (egg and sperm) into a women’s fallopian tube rather than her uterus. In GIFT, the egg is harvested as with IVF and mixed with sperm, and is then injected into the woman’s fallopian tube where fertilization occurs. In ZIFT, the egg is fertilized with sperm in the laboratory before being transferred to the fallopian tube. For GIFT and ZIFT a woman must have at least one functioning fallopian tube.
Success Rates. Not all IVF cycles result in pregnancy, and not all IVF-achieved pregnancies result in live births. When a woman’s own eggs are used, results are better with fresh embryos than frozen embryos. According to the most recent statistics from the U.S. Centers for Disease Control (CDC), about 31% of ART cycles (mostly IVF) with fresh embryos resulted in a live birth of one or more babies. Success rates provided by fertility clinics are not always a reliable indicator as they depend on many variables, especially the age of the woman.
Data indicate that the chances of IVF resulting in live birth are about:
Some women try acupuncture during an IVF cycle to increase their chances for pregnancy success. While acupuncture is not harmful, there is no conclusive evidence that it boosts success rates.
Complications. Data have been conflicting on whether IVF increases the risk for genetic abnormalities and birth defects. In general, the overall risks for birth defects appear to be small. Studies indicate that most children conceived through IVF are healthy and have normal cognitive development and school performance.
The main risk of IVF is the consequences of multiple pregnancies. Multiple pregnancies increase the risks for a mother and her babies. In particular, there is increased risk for premature delivery and low birth weight. These factors can cause heart and lung problems and developmental disabilities in children.
Intracytoplasmic sperm injection (ICSI) is an assisted reproductive technology used for couples when male infertility is the main problem. It involves injecting a single sperm into an egg obtained from in vitro fertilization (IVF). The procedure is very simple:
The greatest concern with this procedure has been whether it increases the risk for birth defects. Many, but not all, studies have reported no higher risks of birth defects in children born using ICSI procedures. However, if the father’s infertility was due to genetic issues, this genetic defect may be passed on to male children conceived through ICSI.
Another concern has been whether the ICSI procedure is being overused. ICSI use has increased 5-fold over the past decade and is now used in 65% of ART procedures, even though the proportion of men receiving treatment for male infertility has remained the same. Some doctors recommend ICSI for women who have failed prior IVF attempts or who have few or poor-quality eggs, even if their male partners have normal semen measurements. According to the Society for Assisted Reproductive Technology, there is little evidence that ICSI helps improve pregnancy success for couples who do not have a problem with male factor infertility.
Although there are no dietary or nutritional cures for infertility, a healthy lifestyle is important. Some ovulatory problems may be reversible by changing behavioral patterns. Some tips include:
Both male and female hormone levels fluctuate according to the time of day, and they vary from day to day, month to month, and seasonally. Some timing tips might be helpful.
Monitoring Basal Body Temperature. To determine the most likely time of ovulation and therefore the time of fertility, a woman should take her body temperature, called her basal body temperature. This is the body's temperature as it rises and falls in accord with hormonal fluctuations.
By studying the temperature patterns after a few months, couples can begin to anticipate ovulation and plan their sexual activity accordingly. Couples should try to avoid becoming fixated on the chart, however, in scheduling their sexual activity.
Frequency of Intercourse. It is not clear how often a couple should have intercourse in order to conceive. Some doctors think that having sex more than 2 days a week adds no benefits. In addition, frequent sexual activity lowers sperm count per ejaculation. Some studies have indicated, however, that having intercourse every day, or even several times a day, before and during ovulation, improves pregnancy rates. Although sperm count per ejaculation is low, a constantly replenished semen supply is more likely to result in a fertilized egg.
The fertility treatment process presents a roller coaster of emotions. There are almost no sure ways to predict which couples will eventually conceive. Some couples with multiple problems will overcome great odds, while other, seemingly fertile, couples fail to conceive. Many of the new treatments are remarkable, but a live birth is never guaranteed. The emotional burden on the couple is considerable, and some planning is helpful.
On a reassuring note, a large study of infertile women indicated that stress levels do not affect the outcome of fertility treatments. The study found no difference in stress levels between women who became pregnant and those who did not. Women who are feeling stressed by problems with fertility or the challenges of the fertility treatment process should not feel additionally concerned that their emotional state may affect their chances of becoming pregnant.
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Review Date:
12/19/2012 Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc. |