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Indian Journal for the Practising Doctor

Clinical Update: Infertility

Author(s): Karim, FA

Vol. 4, No. 6 (2008-01 - 2008-02)

Karim, FA

ISSN: 0973-516X


Fatima Abdul Karim, MD, FACOG, FICOG, is Associate Professor, Depatment of Gynaecology & Obstetrics, Islamic International University, Malayasia.


Around the world, infertility represents a major health, social and economic problem. In the West, where infertility is not infrequent, couples have to spend between $10,000 and $150,000 for infertility evaluations and treatment. Infertility keeps the woman childless, depriving her of the greatest joy of being a woman, ie motherhood. To worsen the situation, in developing countries, the inability to have children can prove to be a great curse for the woman. It can result in stigmatization and abandonment by the husband and family. Unfortunately, the highest rates of infertility occur in the developing world, where facilities for diagnosis and treatment are limited for such couples. When available, prohibitive cost precludes access of the poor couple to such amenities which are usually available in private sector at a very high cost. Governments in countries still fighting overpopulation can not be expected to wake up to the plight of a childless couple. Accordingly, infertility will continue to remain on the backburner for some more time in developing countries.


Infertility is the failure of a couple to conceive after trying to do so for at least one full year. In primary infertility, pregnancy has never occurred. In secondary infertility, one or both members of the couple have previously conceived, but are unable to conceive again after a full year of trying.

Description

Currently, in the United States, about 20% of couples struggle with infertility at any given time1. Infertility has increased as a problem over the last 30 years. Some studies pin the blame for this increase on social phenomena, including the tendency for marriage to occur at a later age, which means that couples are trying to start families at a later age. It is well known that fertility in women decreases with increasing age, as illustrated by the following statistics:

Table 1: Relation of Increasing Age with Infertility2

Age of the Married Prevalence of Infertility
Women (yr) (%)
16-20 4.5%
35-40 31.8
> 40 70%

Nowadays, individuals often have multiple sexual partners before they marry and try to have children. This increase in numbers of sexual partners has led to an increase in sexually transmitted diseases. Scarring from these infections, particularly from pelvic inflammatory disease, seems to be in part responsible for the increase noted in infertility. Currently the highest rates of infertility on a global scale are found in sub-Saharan Africa, which can partly be attributed to high rates of sexually transmitted infections (STIs) and complications of delivery or unsafe abortions. Furthermore, use of first generation intrauterine contraceptive devices (IUD; IUCD) contributed to an increased rate of pelvic inflammatory disease, with subsequent scarring.

Causes and symptoms2

Unlike most medical problems, infertility is an issue requiring the careful evaluation of two separate individuals, as well as an evaluation of their interactions with each other. In about 3-4% of couples, no cause for their infertility can be discovered. On an average, 35-40% of the time, the problem is either in the male or in the female partner; about 20% of the time, both of them have some problem.

The main factors involved in causing infertility3, listing from the most to the least common, include:

  • Male problems: 35%
  • Ovulation problems: 20%
  • Tubal problems: 20%
  • Endometriosis: 10%
  • Cervical factors: 5%.

Male factors

Male infertility can be caused by a number of different characteristics of the sperm. To check for these characteristics, a sample of semen is obtained and examined under the microscope (semen analysis).

The common causes of male-factor infertility are:

  • Infections
  • Hormonal Imbalances
  • Sexual Dysfunction
  • Sperm Quantity and Quality
  • Blockages and Other Anatomical Problems
  • Varicocele
  • Immune System Disorders
  • Hypospadias

Male infertility is related to testicular disease, hormone deficiencies and structural problems with the male reproductive organs, as well as exposure to certain chemicals, chemotherapy agents or radiation treatment for cancer. Men can be born with testicles that have not descended properly from the abdominal cavity into the scrotal sac, or may be born with only one instead of the normal two testicles. Testicle size can be smaller than normal. Substances such as alcohol, marijuana and other illegal drugs, anabolic steroids and some herbal remedies – especially those that affect hormone levels – have been linked to low sperm count and/or abnormal sperm movement or shape.. Nicotine has been shown to have some negative effect on testosterone production, which adversely affects sperm production and development. Also, certain illnesses that include high fever can temporarily affect sperm count and motility.

Infections

Infections in the male reproductive organs can be caused by sexually transmitted diseases, mumps contracted as an adult, and different pathogenic bacteria. Unless noticeable symptoms occur, these infections can go untreated. Severe infection can cause scarring, blockages and/or other damage to the male reproductive organs.

Hormonal Imbalances

Hypothalamus and pituitary gland dysfunction can affect sperm production and sexual function. Thyroid problems also can lead to low levels of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) required for sperm production.

Sexual Dysfunction

Male sexual dysfunction can be related to medical conditions and psychological issues including stress. In some cases, age plays a part. Although age-related changes in male fertility are not as pronounced as those in the female, sex drive, sexual function and the ability to conceive can be diminished by changes in the testes, the quality of sperm and hormone-related problems. Still, men continue to produce sperm and can conceive at ages well beyond those at which women experience menopause and the end of fertility.

Many males produce plentiful, high quality sperm but they experience problems ejaculating. With premature and delayed ejaculation, timing prevents orgasm and the release of sperm into the vagina during intercourse.

Retrograde ejaculation is when semen is released backwards, into the bladder, as a result of trauma, nerve damage or other problems from prostate or lower back surgery, birth defects and diseases including diabetes and multiple sclerosis. Retrograde ejaculation also is linked to certain prescription drugs, including those for depression and high blood pressure.

Sperm Quantity and Quality4

Although only one sperm is needed for conception, millions are released during intercourse to increase the chance of pregnancy. A fertile male ejaculates at least 2 milliliters of semen with the right consistency to transport at least 40 million sperm toward the waiting ovum. Of these, at least 50% should be moving vigorously through the liquid, 2% must be moving forward and at least 4% should have a normal shape – an elliptical head and tail to provide the thrust they need.

Poor sperm count and quality are indicators of male-related infertility. If a semen sample also includes too many white blood cells, bacteria, sexually transmitted diseases or infection also may be contributing to the problem. Males exposed to DES (diethylstilbestrol), a synthetic hormome taken by pregnant women in the 1960s and 1970s, also may have anatomical abnormalities and problems with sperm count, movement and shape.

Blockages and Other Anatomical Problems

Structural defects in reproductive organs can stop the passage of sperm from the testis, where they develop, to the ejaculatory duct. Blockages result from birth defects or scar tissue formed after infection or surgery. Vasectomy, an elective sterilization procedure, prevents the flow of sperm by cutting and tying off the ends of the vas deferens, which carries sperms from the epididymis to the ejaculatory duct.

Some experts believe that varicoceles (blocked and enlarged veins around the testes), cause infertility by raising the temperature in the scrotum and decreasing sperm production. However, others discount the effect of varicocele because they also are found in fertile men.

Immune System Disorders

In some cases where sperm are first or once again produced, the male’s immune system identifies them as foreign substances and creates antisperm antibodies. The antibodies are designed to destroy the invading cells by attaching themselves to the sperm, preventing their passage or fertilization.

Hypospadias

In this condition, the opening of the urethra is not located at the end of the penis, thus semen can’t be ejaculated into the vagina during intercourse.

Female Causes

Ovulatory problems

The first step in diagnosing ovulatory problems is to make sure that an ovum is being produced each month. A woman’s morning body temperature is slightly higher around the time of ovulation. A woman can measure and record her temperatures daily and a chart can be drawn to show whether or not ovulation has occurred. Luteinizing hormone is released just before ovulation. A simple urine test can be done to check if it has been released around the time that ovulation is expected.

Pelvic adhesions and endometriosis;

Pelvic adhesions and endometriosis can cause infertility by preventing the sperm from reaching the egg or interfering with fertilization. Pelvic adhesions are fibrous scars. These scars can be the result of past infections, such as pelvic inflammatory disease, or infections following abortions or prior births. Previous surgeries can also leave behind scarring.

Endometriosis may lead to pelvic adhesions. Endometriosis is the abnormal location of uterine tissue outside of the uterus. When uterine tissue is planted elsewhere in the pelvis, it still bleeds on a monthly basis with the start of the normal menstrual period. This leads to irritation within the pelvis around the site of this abnormal tissue and bleeding, and may cause scarring.

Pelvic adhesions cause infertility by blocking the fallopian tubes. The ovum may be prevented from traveling down the fallopian tube from the ovary or the sperm may be prevented from traveling up the fallopian tube from the uterus.

A hysterosalpingogram can show if the fallopian tubes are blocked. Scarring also can be diagnosed by examining the pelvic area by laparascopy (in which a scope is inserted into the abdomen through a tiny incision made near the umbilicus).

Cervical factors

Mucus produced by the cervix helps to transport the sperm into the uterus. Injury to the cervix or scarring of the cervix after surgery or infection can result in a smaller than normal cervical opening, making it difficult for the sperm to enter. Injury or infection can also decrease the number of glands in the cervix, leading to a smaller amount of cervical mucus. In other situations, the mucus produced is the wrong consistency (perhaps too thick) to allow sperm to travel through. In addition, some women produce antibodies that are specifically directed to identify sperm as foreign invaders and to kill them.

Pelvic Inflammatory Disease and Infertility: Pelvic inflammatory disease (PID), an infection of the internal female reproductive organs, usually affects the uterus, one or both fallopian tubes, the ovaries, and surrounding pelvic tissues, which become inflamed, irritated, and swollen. PID is caused by untreated STIs, tuberculosis, and other types of bacteria and microorganisms. PID can lead to infertility, because of the scar tissue that forms around the pelvic organs. This scar tissue can cause blockage and distortion of the fallopian tubes so that the egg cannot get access to the uterus. Studies5,6 show that, after one episode of PID, a woman has an estimated 15% chance of infertility. After two episodes, the risk rises to 35%. After three episodes, the risk for infertility is nearly 75%.

Cervical mucus can be examined under a microscope to diagnose whether cervical factors are contributing to infertility. The interaction of a live sperm sample from the male partner and a sample of cervical mucus from the female partner can also be examined. This procedure is called a post-coital test.

Role of Infection in Infertility

Many recent reports, including those from the USA and Germany, show that the most common cause of infertility is a uterine infection7-15. Of women being evaluated for infertility, 40% were infected with chlamydia, mycoplasma or ureaplasma, as were 36% of those with a previous history of uterine infection and 50% of those with tubal blockage. More than 60% had evidence of a past infection16. Studies confirmed that the more partners a woman had, the more likely she was to be infected17, although she could infected by a single contact18.

Infection can prevent pregnancy by blocking the fallopian tubes19-21. It can damage sperm22, so they can’t swim effectively toward the egg23, and it can cause abortions, premature birth and low birth weight24-28.

STIs and Infertility

Sexually transmitted infection is strongly associated with production of infertility. Throughout the world, 38% of infertility can be traced to a previous sexually transmitted infection (STI). When left untreated, many STIs can place the victim at risk for becoming infertile. Untreated gonorrhea and chlamydia in women can spread into the pelvic area and infect the uterus, fallopian tubes, and ovaries - leading to pelvic inflammatory disease (PID). In men, chlamydia can affect the testicles – also leading to problems with fertility. As indicated above, the highest prevalence of infertility is currently found in sub-Saharan Africa, and it is chiefly attributed to a high incidence of STIs there.

Presence of infection can manifest as burning on urination, discomfort when the bladder is full or an urgency to void. Women may have only spotting between periods25.

Infection with chlamydia is the most common cause of blocked fallopian tubes that cause infertility. First, chlamydia paralyzes the cilia so the ovum can’t reach the uterus, then it blocks the tubes so that nothing can pass into the uterus. Even asymptomatic infections were found to lead or contribute to infertility. Studies10 suggested that unsuspected C. trachomatis infection induced an inflammatory reaction in the uterus that impaired embryo implantation and/or facilitated immune rejection after uterine transfer of in vitro fertilized embryos.

In one study, 60% of infertile women had C. trachomatis antibodies, which coincided with 71% in those with bilateral tubal occlusion16. Antibody studies conducted in the Netherlands gave conflicting results: The first study showed that having antibodies against chlamydia was a potent predictor of blocked tubes26. The second study, however, revealed that many women infected with chlamydia didn’t have high antibody titres to chlamydia27.

Significantly enough, partners can be infected with mycoplasma or ureaplasma28,29, without any symptoms, yet all available tests can’t find them30. A dipstick urine test may diagnose the infection31,32. Semen from 91% of infertile men yielded anaerobic bacteria33.

Management

When should a couple be offered help?

Although it can take some couples longer than 12 months to achieve pregnancy, many people seek infertility treatment if they haven’t achieved pregnancy after 12 months of unprotected and well-timed intercourse. In the USA they advise couples to seek help if the woman has been trying to conceive for more than 12 months and:

  • is over 35 years of age
  • has irregular menstrual cycles
  • has a history of pelvic infection
  • has had two or more pregnancy losses
  • the partner had an undescended testicle at birth or a hernia repair,
  • The partner has a history of urinary infections

Evaluation of Infertility: Evaluation of infertility should include

Female:

  • FSH (menopause),
  • TSH (thyroid disease),
  • Prolactin (brain tumor),
  • Progesterone (7 days after expected ovulation, around 21 days after start of menstruation),
  • HSG (to check if uterine tubes are open).
  • If masculinization: testosterone, DHEAS,
  • 17-oh progesterone, sonogram of ovaries.

Male: semen analysis.

Evaluation of sperm quantity and quality:

i) Sperm count refers to the number of sperm present in a semen sample. The normal number of sperm present in just one ml of semen is over 20 million. An individual with only 5-20 million sperm per ml of semen is considered sub-fertile, an individual with less than 5 million sperm per ml of semen is considered infertile.

ii) Sperm are also examined for sperm motility (to see how well they swim).

iii) To see that most have normal structure. Not all sperm within a specimen of semen will be perfectly normal. Some may be immature, and some may have abnormalities of the head or tail. A normal semen sample will contain no more than 25% abnormal forms of sperm.

iv) Volume of the semen sample is important. An abnormal amount of semen could affect the ability of the sperm to successfully fertilize an ovum. Another test can be performed to evaluate the ability of the sperm to penetrate the outer coat of the ovum. This is done by observing whether sperm in a semen sample can penetrate the outer coat of a guinea pig ovum; fertilization cannot occur, of course, but this test is useful in predicting the ability of the individual’s sperm to penetrate a human ovum.

Treatment of the underlying cause

Males: Treatment of male infertility includes addressing known reversible factors first; for example, discontinuing any medication known to have an effect on spermatogenesis or ejaculation, as well as decreasing alcohol intake, and treating thyroid or other endocrine disease. Testosterone in low doses can improve sperm motility.

Other treatments of male infertility include collecting semen samples from multiple ejaculations, after which the semen is put through a process that allows the most motile sperm to be sorted out. These motile sperm are pooled together to create a concentrate that can be deposited into the female partner’s uterus at a time that coincides with ovulation. In cases where the male partner’s sperm is proven to be absolutely unable to cause pregnancy in the female partner, and with the consent of both partners, donor sperm may be used for this process. Depositing the male partner’s sperm or donor sperm by mechanical means into the female partner are both forms of artificial insemination. Islamic clergy takes strong objection to using a man’s sperm who is not the husband.

a) Infection

Medications – antibiotics can be effective in treating infections of the male reproductive disorders; however, it is important to treat them early to avoid permanent damage. Surgery – may be required in cases where infection has resulted in scarring or blockages that affect sperm production and/or ejaculation.

b) Hormone Imbalances

Medication – may be prescribed to correct certain hormonal imbalances. Human chorionic gonadotropin (hCG) supports the production of testosterone in the male reproductive organs. Clomiphene citrate helps the hypothalamus and pituitary glands produce the chemical that stimulates LH and FSH production. These in turn regulate testosterone production and improve sperm production.

c) Sexual Dysfunction

Medication – may be available to address sexual dysfunction depending on the nature of the problem and the cause. Fertility medications can be prescribed to restore hormonal balance, increase the sex drive, restore sexual function or improve performance. Oral medications may be effective in improving retrograde ejaculation by helping the bladder neck close during ejaculation. Surgery – recommended in cases where sexual dysfunction results from scarring, blockages or growths that can be removed surgically. Insemination – in cases involving retrograde ejaculation, sperm may be found in the urine. If healthy sperm can be extracted, insemination is an option. In cases where timing is the problem, collection of sperm through masturbation and insemination may be recommended.

Therapy – “performance anxiety” that contributes to several forms of sexual dysfunction can be addressed with therapy directed at the cause and/or focused on techniques to reduce stress and restore sexual confidence and function.

d) Poor Sperm Count or Quality

Medication – antibiotics may be prescribed to treat infection affecting sperm quality. Surgery – microsurgical epididymal sperm aspiration (MESA and TESA) are surgical techniques recommended when there are few or no sperm in the ejaculate as a result of vasectomy, congenital absence of the vas deferens or epididymis, prior failed surgery or epididymal scarring from infection. Tissue is collected from the testes and processed in the laboratory to remove healthy sperm for use with intra-cytoplasmic sperm injection (ICSI). Used with in vitro fertilization (IVF), ICSI involves injection of a single sperm into the core of an egg.

e) Blockages and Other Anatomical Problems

Surgery – vasectomy reversal (vasovasostomy) is a microsurgical technique that involves removal of scarred sections and reconnection of the vas deferns so sperm can travel out of the epididymis and into the ejaculate. Epididymal repair (vasoepididymostomy) may be an option if vasovasostomy won’t work because there are no sperm present in the vas deferns. This surgery is used to remove obstructions in the epididymis caused by pressure from testicular fluids, leakage of sperm into surrounding tissues after a vasectomy, infections, trauma or congenital defects. Vasoepididymostomy restores the flow of semen by stitching the inner and outer layers of the vas directly to the epididymis and its inner tubule, at a point above an obstruction. Some recommend surgery for varicocele repair – a microsurgical technique used to tie off the vein to eliminate the swelling.

f) Immune System Disorders

Medication – steroids may be prescribed to destroy the antibodies.

Sperm washing – collected through masturbation, sperm is washed in the laboratory to remove antibodies. The options are to inject them directly into the female during Intrauterine Insemination (IUI) or into a laboratory dish containing eggs retrieved from the female during in vitro fertilization (IVF).

g) Treatment Options for Hypospadias

Insemination – semen is collected through masturbation, washed of impurities and injected directly into the uterus during intrauterine insemination.

Surgery – permanent correction of the problem with surgery may be an option.

Females

Treatment of ovulatory problems depends on the underlying cause. If a thyroid or pituitary problem is responsible, simply treating that problem can restore fertility. Medication, as clomiphene, can also be used to stimulate fertility; these drugs increase the risk of multiple births (twins, triplets, etc.).

Hysterosalpingography tests whether the dye can travel through the patient’s fallopian tubes. A few women become pregnant following this exam. It is thought that the dye material in some way helps flush out the tubes, decreasing any existing obstruction.

Pelvic adhesions can be treated during laparoscopy. The adhesions are cut using special instruments. Endometriosis can be treated with certain medications, but may also require surgery to repair any obstruction caused by adhesions. Treatment of cervical factors includes antibiotics in the case of an infection, steroids to decrease production of anti-sperm antibodies, and artificial insemination techniques to completely bypass the cervical mucus.

ART: Assisted reproductive techniques include in vitro fertilization (IVF), gamete intra-fallopian transfer (GIFT), and zygote intra-fallopian tube transfer (ZIFT). These are usually used after other techniques to treat infertility have failed.

In vitro fertilization involves the use of a drug to induce the simultaneous release of many eggs from the female’s ovaries, which are retrieved surgically. Meanwhile, several semen samples are obtained from the male partner, and a sperm concentrate is prepared. The ova and sperm are then combined in a laboratory, where several of the ova may be fertilized. Cell division is allowed to take place up to the embryo stage. While this takes place, the female may be given drugs to ensure that her uterus is ready to receive an embryo. Three or four of the embryos are transferred to the female’s uterus, and the wait begins to see if any or all of them implant and result in an actual pregnancy.

Success rates of IVF are still rather low. Most centres report pregnancy rates between 10-20%. Since most IVF procedures put more than one embryo into the uterus, the chance for a multiple birth is greatly increased in couples undergoing IVF.

GIFT involves retrieval of both multiple ova and semen, and the mechanical placement of both within the female partner’s fallopian tubes, where one hopes that fertilization will occur. ZIFT involves the same retrieval of ova and semen, and fertilization and growth in the laboratory up to the zygote stage, at which point the zygotes are placed in the fallopian tubes. Both GIFT and ZIFT seem to have higher success rates than IVF.

Treatment of infection: In view of the recent findings that infection, whether manifest or occult, is the most common cause of infertility, many experts feel that all patients should be given a fair trial of antibiotics before they undergo elaborate and costly evaluation and treatment modalities for infertility. Recent consensus is for Azithromycin (250 mg once a day for 8 days) or Biaxin (500 mg BID for 10 days), for chlamydia and mycoplasma infections34,35. Recent reports from the University of Maryland9 and Germany1 suggest that before patient consults an infertility doctor to help her, she should take antibiotics to treat a possible hidden infection. In a carefully controlled study, 38% of the women in the PID-positive group and 68% in the PID-negative group conceived within a period of one year after having completed a treatment with antibiotics20. Some authors recommend that all couples with elevated titers of C trachomatis antibody be treated with doxycycline prior to the first IVF attempt to optimize pregnancy rates and minimize infectious complications15.

Prognosis

It is very hard to obtain statistics regarding the prognosis of infertility because many different problems may exist within an individual or couple trying to conceive. In general, it is believed that of all couples who undergo a complete evaluation of infertility followed by treatment, about half will ultimately have a successful pregnancy. Of those couples who do not choose to undergo evaluation or treatment, about 5% will go on to conceive after a year or more of infertility.

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