Ectopic Pregnancy: Causes, Diagnosis and Treatment

An ectopic pregnancy is any gestation that implants outside of a woman’s uterus. The most common site is in the fallopian tube, but it can also occur in the ovary, the cervix, outer surface of the uterus or elsewhere with the abdomen. Estimates put the incidence of ectopic pregnancy at about 1 out of every 200 pregnancies; however, it has been reported to occur in about 1 out of every 30 IVF pregnancies. Ectopic pregnancy is one of the most dangerous complications of pregnancy. If undetected, the ectopic pregnancy will continue to grow and will typically rupture; resulting in calamitous intra-abdominal bleeding. If not treated quickly, such an event could be fatal.

Monitoring pregnancies both hormonally and with ultrasound technology now makes it possible to completely prevent catastrophic events associated with ectopic pregnancies. Within the last two decades, treatment of ectopic pregnancies has evolved from emergency surgery with tubal removal and blood transfusion, to out-patient surgery with tubal repair or even treatment with medication. The key with ectopic pregnancy is to diagnose early and manage the outcome instead of waiting for events to unfold.

The fertilization of the human egg normally takes place within the fallopian tube. The embryo then takes about 5 to 6 days to complete its journey to the uterus, where it implants into the endometrium. Anything that delays the passage of the embryo down the fallopian tube can result in the embryo hatching and sending its “root system” into the wall of the fallopian tube and initiating growth within the tube. One of the most common predisposing factors is pelvic inflammatory disease (PID) in which microorganisms, such as Chlamydia and Gonococcus, damage the inner lining (endosalpinx) and eventually also the muscular walls of the tube(s) by creating scar tissue.

The endosalpinx has a very complex and delicate internal architecture, with small hairs and secretions that help to propel the embryo toward the uterine cavity. Once damaged, this lining does not regenerate. This is one of the reasons why women who manage to conceive following surgery to unblock fallopian tubes damaged by PID, have about a 1 in 4 chance of a subsequent pregnancy developing within the fallopian tube. Another cause of ectopic pregnancies are congenital malformations of the fallopian tube associated with shortening of, or small pockets and side channels within, the tube. These can interrupt the smooth passage of the embryo down the fallopian tube. There has even been some suggestion that premature appearance of hormones like progesterone, which relax muscle contractions within the fallopian tube, may also create an increased risk of ectopic pregnancy.

A woman who has had one ectopic pregnancy has an almost four-fold higher risk of another ectopic implantation in a future pregnancy. With every subsequent ectopic, this risk increases dramatically. Since the lining of the fallopian tube does not represent an optimal site for healthy implantation, a large percentage of pregnancies that gain early attachment to its inner lining will be absorbed before the woman even knows that she is pregnant. This is often referred to as a tubal abortion.

When an ectopic pregnancy occurs after ART, it is most likely the result of a uterine contraction causing a carefully placed embryo to be ejected into the fallopian tube. Various strategies to reduce the risk of this occurring are typically employed. The use of ultrasound guidance to place embryos and the use of minimal fluid to transfer them helps. There is some evidence that transferring blastocysts that are ready to implant instead of earlier embryos may also reduce the incidence. Sometimes however, despite the best laid plans, ectopic pregnancies do occur.

Diagnosis of an Ectopic Pregnancy
The easiest and most common method of diagnosing an ectopic pregnancy is by tracking the rate of rise in the blood levels of the “hormone of pregnancy,” human chorionic gonadotropin (hCG). With a normal intrauterine pregnancy, blood levels of hCG will usually double every two days throughout the first nine to ten weeks. However, an increase of at least 60% is still reassuring. A slower rate of increase in hCG more commonly suggests an impending miscarriage of one or more of the embryos that have implanted. However, it might be a sign of an ectopic pregnancy. Thus, the hCG levels should be followed serially until a clear pattern emerges.

The diagnosis of an ectopic is most often determined by a vaginal ultrasound examination. Performed by someone with sufficient expertise using a modern ultrasound machine, this test should reveal an ectopic pregnancy before it ruptures and becomes a surgical emergency. If the tube has already ruptured or internal bleeding has occurred, ultrasound examination will detect the presence of free fluid in the abdominal cavity, which is a more ominous sign.

If there has been a significant amount of intra-abdominal bleeding, irritation of the peritoneal membrane will cause the abdominal wall to become tense and, depending on the amount of blood in the abdomen, to distend. In such cases, any pressure on the abdominal wall will evoke significant pain and when a vaginal examination is done, movement of the cervix can be excruciatingly painful – especially on the side of the affected fallopian tube.

The most common conditions that must be ruled out when an ectopic pregnancy is suspected are:

• A hemorrhagic cyst of the ovary
• Appendicitis
• Acute pelvic inflammatory disease (PID)
• An inevitable miscarriage

Solutions: Surgical and Medical Management

Surgical: In some situations, laparoscopy is performed for diagnostic purposes. This may be necessary if a woman has a heterotopic pregnancy; one embryo implanted in the uterus and one in the fallopian tube. If an ectopic pregnancy is in fact detected, a small longitudinal incision over the tubal pregnancy will allow for its removal, without necessitating removal of the tube. In such situations, it may be possible to save the normally implanted embryo. Bleeding points on the fallopian tube can usually be accessed directly and bleeding can often be stopped through the laparoscope. Sometimes the damage to the fallopian tube has been so extensive that the entire tube will require removal. On occasions where very severe intra-abdominal bleeding heralds a potential catastrophe, a laparotomy is performed to stop the bleeding more rapidly. In such cases, a blood transfusion is usually required and may be life saving.

Medical: The introduction of Methotrexate (MTX) therapy for the treatment of ectopic pregnancy has profoundly reduced the need for surgery in most patients. MTX is a chemotherapeutic that kills rapidly dividing cells, such as those present in the “root system” of a developing fetus. Low doses of MTX are used to treat ectopic pregnancy since the fetal tissue is very sensitive. Accordingly, the side effects for the treatment are minimal. It is important to confirm that the ectopic pregnancy has not yet ruptured prior to administering MTX and is not too far along to be treated safely in this fashion.

The administration of MTX is by intramuscular injection. Prior to its administration, blood is drawn to get a baseline blood hCG level. After the injection of MTX the patient is allowed to return home with strict instructions that she should always have someone with her and never be alone in the ensuing week. The concern is that if she was to be on her own and internal bleeding occurred, she might not be able to get to the hospital quickly enough. In reality, this situation rarely occurs, but it is wise to be cautious. Instructions are also given to look for early signs that might point towards a worsening situation such as the sudden onset of severe pain, light-headedness or fainting. The patient returns to the doctor’s office four days later to check the blood HCG level, noting that it may have risen a bit. Three days later (7 days after MTX), the level is checked again. By this time, the HCG level should have dropped at least 15% from the value on day 4. If not, a second MTX injection is given and the blood levels are tested twice weekly until HCG level is undetectable. Once this occurs, vaginal bleeding will usually begin within a week or two.

Recent advances in the field of ultrasound diagnosis along with the introduction of MTX therapy have revolutionized the treatment of ectopic pregnancy and have significantly reduced both the high morbidity and mortality rates previously associated with this condition. When an ectopic pregnancy occurs following infertility treatment, there is the added advantage that the physician will be on the lookout for the earliest possible signs of trouble. The performance of a vaginal ultrasound within two weeks of a positive blood pregnancy (hCG) test following IVF allows for early detection of the unruptured pregnancy and timely intervention with MTX and/or laparoscopy.

Pelvic Inflammatory Disease and Fertility

Pelvic Inflammatory Disease (PID) refers to a moderate to severe infection of the female pelvis including the uterus, fallopian tubes, ovaries, bowel, and the smooth membrane that lines the surface of the pelvic cavity (the peritoneum).

It has been estimated that about 1 million women develop PID annually in the United States. Less than one-third of these women present with an acute pelvic infl ammatory disease. The remaining cases usually go undetected until the woman presents with symptoms of infertility. In fact, more that 60% of patients who undergo surgery or in vitro fertilization and embryo transfer (IVF/ET) for the treatment of infertility secondary to pelvic inflammatory disease, do not have a history of previously diagnosed acute PID.

Acute PID may present as an acute illness with fever with severe lower abdominal pain. In this, the most dramatic presentation of PID, there is frequently a nonirritating yellow or blood stained vaginal discharge. Pain is typically severe enough to prompt urgent medical attention.

Subacute PID is more common and less severe. Its presentation is so gradual that it often goes unnoticed until superimposed acute PID occurs, or chronic incapacitating symptoms prompt the woman to seek medical attention because it has gone on long enough to become chronic.

Chronic PID is the result of untreated or unsuccessfully managed acute or subacute PID. The most common form of PID, it isn’t detected until symptoms of pelvic pain, heavy and painful menstrual periods, pain with intercourse (dyspareunia) and infertility trigger an evaluation that discovers extensive pelvic scar tissue.

Sexually Transmitted PID caused by Gonorrhea or Chlamydia are by far the most common causes of PID. The infections can rapidly invade via the cervix and uterus into the fallopian tube(s). These pencil length passages are highly specialized to promote the active passage of sperm traveling up from the uterus to meet up with an egg released by the ovary. After fertilization, which typically occurs near the site of egg release, the resulting embryo will slowly travel back to uterus—a journey that normally takes about 5 days.

The fallopian tubes are lined with cells whose function is to protect and nurture eggs, sperm and embryos during their journey. At their ends, the fallopian tubes have small delicate finger-like projections (fimbriae) that draw close to, envelop, and “pick-up” the eggs from the ovaries at the time of ovulation. Inflammation due to Chlamydia Trachomatis or Neisseria Gonorrhea damages and often permanently destroys the specialized lining of the fallopian tubes. In severe cases, it can result in fusion of the fimbriae, thereby blocking the ends of the tubes and compromising their mobility and their potential to facilitate timely passage of eggs, sperm and embryos.

Pus that has accumulated inside the tubes often passes into the pelvic cavity, producing peritonitis and resulting in the formation of scar tissue (adhesions) which further disrupts normal pelvic anatomy as well as the relationship between the tubes and the ovaries. This
may prevent the fallopian tubes from collecting the eggs during ovulation. In cases where the ends of the fallopian tubes are blocked, pus may collect and distend the tubes. The pus is usually absorbed over time and replaced by clear, straw-colored fluid. The resulting occluded, fluid-filled, distended, and often functionless fallopian tube is referred to as a hydrosalpinx.

Sexually transmitted PID almost invariably affects both fallopian tubes. Even in cases where a dye x-ray test (hysterosalpingogram) or laparoscopy (a procedure where a telescope-like instrument is passed through the belly button to visualize the pelvic structures) indicates that only one fallopian tube has been infected, the other tube is almost invariably involved. A new procedure called tuboscopy (where a thin fiber-optic telescope is passed into the fallopian tube(s) to evaluate the inner structure has confirmed that the tubes of PID victims, who seemingly have normal pelvic anatomy, often have internal scarring and/or adhesion. This could account for the low success rate seen with tubal reparative surgeries and the high ectopic pregnancy rate (8-15%) in PID patients who subsequently conceive.

Most fertility specialists would agree that IVF is the treatment of choice for almost all forms of tubal infertility. One exception that is commonly cited involves surgical reversal of tubal ligation. It is correctly argued that the chance of having a baby being born within a year of such surgery is about 50%. Those who favor surgical tubal reversal over IVF in such cases often site the national IVF birth rate of 25% as an argument in favor of this position. However, in selective IFV centers of excellence, where the anticipated birth rate following a singe attempt at IVF in women under 40 years is almost double the national average, and the birth rate following three IVF attempts is in the order of 80%, this recommendation is outdated.

Surgery to unblock fallopian tubes or clear adhesions resulting from an inflammatory process due to infections with gonorrhea or Chlamydia is truly an exercise in futility. The chance of pregnancy occurring following such an undertaking is less than 2% per month, and less than 25% in three years. We concur with a recent opinion by the Chairman of Gynecology and Obstetrics at UCLA, that in the modern context, infertility surgery for fallopian tubes damaged by inflammation should be considered an “anachronism”.

Given the high incidence of ectopic pregnancy following tubal surgery (20-25%), the fact that surgery requires hospitalization for a number of days, general anesthesia, associated pain, and a signifi cant risk of post-operative complications make tubal surgery less appealing. Furthermore, greater than 70% of the women that choose tubal surgery ultimately need IVF anyway. To make matters worse, some women have undergone more than one attempt at surgical tubal restoration. Since second and third attempts at surgery are even less likely to result in a pregnancy than the first attempt, such practice is worse than unwise.

Ureaplasma Infection: Its Effect on Fertility and IVF Outcome

Ureaplasma urealyticum is a bacteria that belongs to the mycoplasma family. It can be detected in the reproductive tract of as many as 40% of individuals (male and female). Ureaplasma probably does not prevent normal conception in the majority of cases, because the uterine cavity remains sterile even in women whose cervical mucous cultures positive for the organism. However, when present in the woman's cervical secretions, the organism can be unintentionally dragged into the uterine cavity through introduction of a catheter into the uterus at the time of embryo transfer (ET) or intrauterine insemination (IUI). Molecular biologists have shown that contamination of rapidly growing cell cultures, by this organism and its close “relative", mycoplasma hominis rapidly destroys such cells. The implanting embryo is indeed an example of an organism that comprises rapidly growing cells in a biological culture medium (the uterine lining), and as such, the cells of the trophoblast that form the "root system” of the embryo are vulnerable to intrauterine infection with Ureaplasma. However, even if the uterine cavity were to become infected, the infection willl be purged with the shedding of the infected lining at the time of the next menstruation.

While infection with Ureaplasma rarely produces symptoms in the woman, it sometimes causes symptomatic prostatitis or epydidimitis in men. Although ureaplasma can be transmitted from one partner to the other by sexual intercourse, it may also be acquired by other means, since a large percentage of couples in monogamous relationships will culture positive for the organism. It is very difficult for the organism to grow in the laboratory. Accordingly, the reproductive secretions of both partners should be evaluated (sperm and cervical mucus) individually. Successful culturing of ureaplasma requires a specialized media in which the specimens can be transported safely from the physician’s office to the microbiology laboratory.

If both partners culture negative, we can assume that there is no infection present. However, if one partner cultures positive and the other negative, we would err on the side of caution, by assuming that the negative result was caused by the difficulty in culturing the organism. When ureaplasma is detected in the reproductive secretions of either partner, both should be treated concurrently with the appropriate antibiotic (doxycycline, zithromax, erythromycin, ciprofloxin, or metranidazole).

Unfortunately, in approximately 30-40% of couples infected ureaplasma urealyticum, the bacteria will have built resistance to mainstay traditional antibiotics such as tetracyclines (e.g. doxycycline) and erythromycin (e.g. Zythromax) derivatives. In such cases, ciprofloxin or metronidazole (Flagyl) therapy might be needed. This is the reason that we prefer to document cure by reculturing each partner prior to beginning ovarian stimulation for an IVF cycle.

Several authors have shown a difference in pregnancy rates among patients with ureaplasma infection who were treated with antibiotics and those who were not. Other reports have not been able to identify an effect on outcome from ureaplasma infection. Thus, until the final verdict is in regarding the roll of ureaplasma with regard to its effect on IVF implantation, we prefer to err on the side of caution and ensure that this organism is absent in cervical secretions and semen before transferring embryos. To this end, my patients all receive prophylactic antibiotic therapy around the time of embryo transfer. This is administered as oral ciprofloxin. A day or two prior to embryo transfer, vaginal cleomycin suppositories are added.

Pelvic Tuberculosis: On the Rise in the U.S.A.

While pelvic tuberculosis is a common cause of infertility in developing countries and in Asia (India in particular), its rarity as a cause of infertility in the United States has led to the diagnosis often being missed. However, the condition is definitely on the rise in the United States as a result of the influx of immigrants from Asia and other third world countries where tuberculosis is common.

Pelvic tuberculosis is often a silent disease. It may be present for 10 to 20 years without producing any symptoms – the woman remaining in apparent excellent health. Infertility is often one, and sometimes the only, reason that women investigate for the presence of the condition.

Pelvic tuberculosis usually presents with one or more of the following signs and symptoms:

• Pelvic pain, dysmenorrhea (pain with menstruation), dyspareunia (pain with intercourse), chronic lower abdominal pain or discomfort, and chronic back pain
• Abdominal distention, usually due to ascites (collection of free fluid in the abdominal-pelvic cavity
• Tuberculosis-related infertility is most commonly due to tuberculous salpingitis (tubal inflammation) which occurs in 75% of cases, ovulation dysfunction that often presents with absent, excessive or non-cyclical menstruation, largely attributable to ovarian involvement (40% of cases) and uterine (endometrial) tuberculosis (30%)
• Local tuberculous lesions may appear on the external genitalia, cervix, and/or vagina.
  
  The diagnosis is made is based on:
  
• Clinical suspicion: Evidence of concomitant, pulmonary tuberculosis, the detection of calcifications on pelvic X-rays, a typical tubal pattern on hysterosalpingogram (dye X-ray test)
• Findings at laparoscopy or laparotomy and the subsequent pathologic examination of biopsy material obtained during these procedures
• Blood tests such as a differential blood count and erythrocyte sedimentation rate
• Microscopic and bacteriologic examination is the primary method for diagnosing pelvic tuberculosis:

1. Most commonly a dilatation and curettage (D&C) of the uterus is performed a few days prior to menstruation. The surgeon takes care to avoid using an antiseptic to clean the vagina and cervix while preparing for the D&C, lest the antiseptic kill any tuberculous bacilli present in the specimen thereby rendering a falsely negative culture result. Instead a physiologic salt solution is used to cleanse the operative field. Upon collection, the specimen of uterine curettings is immediately divided into two parts. The first is placed in a physiologic salt solution and expeditiously delivered to the bacteriologic lab for culturing. A specialized culture medium (e.g., Loewenstein Jensen medium) is used for this purpose. Some of the curettings are also used for Guinea pig inoculation. While menstrual products can also be cultured, this approach is less effective. The second portion of the specimen is fixed and then stained for the detection of the acid-fast Bacillus, mycobacterium tuberculosis. The Ziel Nielsen stain is one of the methods used.
2. Biopsy specimens of lesions on the external genitalia, vagina, cervix and pelvic cavity can also be subjected to histopathologic examination, culture and guinea pig inoculation.

Even in the presence of established tuberculosis, histopathologic examination will only be positive about 50% of the time. Cultures, although more reliable, can also yield false-negative results. Accordingly, it is often necessary to repeat such tests several times if the diagnosis is strongly suspected.

Treatment is primarily directed towards the eradication of the infection by means of specific chemotherapeutics such as Para-amino-salicylic acid (PAS), isoniazid (INH), rifampicin (Rifampin) and streptomycin derivatives. Pelvic surgery (other than to remove distended or infected lesions and damaged fallopian tubes) has little therapeutic benefit. Provided that the tuberculous process has not destroyed the uterine lining, in vitro fertilization (IVF) following successful anti-bacterial treatment is the only rational method of treating infertility associated with pelvic tuberculosis.

Anti-Sperm Antibodies: How Do They Affect Fertility and What Role Do They Play in IVF Outcome?

The presence of sperm antibodies reduces male fertility significantly, but does not usually prevent conception altogether. Rather, the effects are graduated; i.e., the larger the immunologic response (concentration of antibodies), the less likely it is that a pregnancy will occur. When the blood level rises above 40%, natural conception is highly unlikely to occur.

Like any other kind of antibody manufactured by the body, sperm antibodies are formed in response to antigens. These antigens are proteins, which appear on the outer sperm membranes as the young sperm cells develop within the male testes. In the man’s own body, his sperm are regarded as foreign invading proteins and as such would normally be targeted for attack. However, under normal conditions, direct contact between the man’s blood and sperm is prevented by a cellular structure in the testes called the blood/testis barrier. This barrier is formed by so-called, Sertoli cells, which abut very closely against each other, forming tight junctions that separate the developing sperm cells from the blood and prevent immunologic stimulation. However, the blood/ testis barrier can be broken by physical or chemical injury or by infection. When this barrier is breached, sperm antigens escape from their immunologically protected environment and come in direct contact with blood elements that launch an immunologic attack.

Once sperm and blood come in contact, whether in the male or female, specific antibodies are produced against them by specialized blood cells call T- and B-lymphocytes. The three main types of sperm antibodies produced are Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM). These antibodies bind to the proteins (antigens) on the sperm’s head, midpiece or tail. The antibodies formed may be of the circulatory type (in the blood serum) or secretory type (in the tissue). This is important because high levels of antibodies in the blood serum do not invariably mean that the antibodies will find their way to the semen where they can affect the sperm. For example, the concentration of IgG is much lower in secretions of the reproductive tract than it is in the blood. Conversely, the local level of IgA is higher in the reproductive secretions than in the blood. This is an important point, which we will return to later.

Once sperm antibodies have formed, they can affect sperm in several different ways. Some antibodies will cause sperm to stick together or agglutinate. Agglutinated sperm clump together in dense masses and thus are unable to migrate through the cervix into the uterus. Other antibodies mark the sperm for attack by Natural killer (NK) cells of the body's immune system (ie; opsonizing antibodies).

Some antibodies cause reactions between the sperm membrane and the cervical mucus preventing the sperm from swimming through the cervix (i.e., immobilizing antibodies). Antibodies can also block the sperm's ability to bind to the zona pellucida of the egg, a prerequisite for fertilization (i.e., blocking antibodies).

Finally, there is recent evidence that the fertilized egg shares some of the same antigens that are found on the sperm. It is possible that sperm antibodies present in the mother can react with the early embryo, resulting in its destruction by phagocytic cells (ie; phagocytic antibodies).

There are a number of diagnostic tests available to detect the presence of sperm antibodies. These are performed by flow cytometry and the ELISA (enzyme-linked immunoabsorbent assay), the Franklin-Dukes sperm agglutination assay or the Immunobead Binding Test (IBT), to name a few. At SIRM, the indirect Immunobead Binding Test (IBT) is used to detect antibodies present in the blood serum, in cervical mucus or on the sperm surface.

In the male, IgA and IgG are found in the semen although there is controversy as to whether they originate locally (secreted by testicular cells) or cross over from the circulation. Antibodies of the IgM class are not found in semen.

Like the source of some antibodies, the question of the critical levels of sperm antibodies is also hotly debated among clinicians. There seems to be general agreement that blood levels above 30% by the IBT are associated with significant fertility problems.

Studies have shown that pregnancy is highly unlikely following natural intercourse or intrauterine insemination when either the woman or the man harbors significant antisperm antibodies.

While there have been isolated reports that administration of corticosteroids (eg; prednisone) will temporarily suppress antibody production, pregnancy rates are poor. Besides, corticosteroid therapy carries with it the risk of significant side effects, some of which (although infrequent) can be serious. As an example, in the man, spontaneous fractures (especially of the neck of the femur) have been reported in 2% of cases. I do not recommend this treatment.

In Vitro Fertilization (IVF) with Intracytoplasmic Sperm Injection (ICSI) is the best option for conception in the presence of significant antisperm antibodies. Here, each egg is injected with a single sperm, so whether or not there are antibodies attached to the outer surface of the sperm becomes irrelevant.. In fact, pregnancy and birth rates are the same as in cases where IVF is performed for reasons other than male factor infertility. IVF/ICSI success rates are also unaffected by the concentration of antisperm antibodies.

*Intrauterine insemination (IUI - sometimes referred to as artificial insemination) of processed sperm is contraindicated in cases of moderate or severe male immunologic infertility because it does NOT improve pregnancy rates over NO TREATMENT AT ALL.

Spotting (Light Vaginal Bleeding) in Early Pregnancy: What Does It Mean and What to Do About It

Spotting or light bleeding during early pregnancy can cause a great deal of alarm to the unsuspecting woman. However, as long as the bleeding does not progressively increase in amount and is not associated with abdominal cramping it is usually innocent and does not lead to miscarriage. Such innocuous bleeding is often due to local trauma to that part of the cervix that protrudes into the upper vagina. It often results from the hormonal changes in early pregnancy, that causes the fragile, delicate glandular lining of the inner cervical canal to roll outward (evert), exposing the delicate surface of the inner lining of the cervical canal to abrasive vaginal secretions. In some cases, trauma at the time of sexual vaginal penetration or mechanical irritation caused by vaginal suppositories will traumatize the “everted” inner cervical lining, causing local bleeding

This having been said, any bleeding in pregnancy warrants prompt investigation to make certain that the conceptus is viable, exclude an inevitable miscarriage and sometiumes an ectopic pregnancy. A speculum examination must be done to examine the cervix for signs of an eversion and local bleeding. In pregnancies beyond 5 weeks, this should always be followed by a vaginal ultrasound examination, to confirm the existence of a viable intrauterine gestation that is appropriately developed for the stage of pregnancy, exclude intrauterine bleeding and in the event that no intrauterine pregnancy is observed, and to try and exclude a tubal (ectopic) pregnancy.

Women who present with such vaginal “spotting” should be advised to avoid sexual vaginal penetration until the bleeding has stopped for at least 1 week. Orgasm should not be discouraged as it poses no threat to the pregnancy.

Lupron Therapy and IVF

All gonadotropin releasing hormone (GnRH) agonists act by rapidly expunging reservoirs of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. GnRH agonists can be administered by intramuscular injection (e.g. Lupron, Buserelin) or through intranasal administration (Nafarelin, Synarel). The intramuscular route which insures more even absorption is preferred.

At SIRM we prescribe leuprolide acetate (Lupron) to launch most IVF controlled ovarian hyperstimulation (COH) cycles. Lupron is very similar in structure to GnRH. As such, its initial effect (for about 2-4 days or so) is to stimulate the pituitary gland to produce both LH and FSH. As soon as the pituitary starts to recognize the difference in chemical structure between the Leuprolide and normal GnRH, it profoundly reduces its output of biologically active LH and FSH production. This is referred to as “pituitary down-regulation” and the effect continues for as long as Lupron therapy is maintained uninterrupted. The initial increase in FSH and LH production during the first 4-6 days of leuprolide therapy is accompanied by a transient, but very significant increase in estrogen release by the ovary. The initial rise in LH and FSH production results in a rise in estradiol, and the subsequent pituitary “down-regulation” is followed by a precipitous fall in blood estrogen levels, until gonadotropin or estrogen administration commences.

The reason that agonists are administered to women receiving Gonadotropin therapy for IVF is because of its ability to suppress LH and so prevent a premature rise in LH which is most likely to occur in older women or those with have diminished ovarian reserve. When this happens the cells lining the follicles undergo premature change (premature luteinization), compromising further follicle development and egg/embryo quality. Such premature luteinization (previously referred to as “premature LH surge”) severely compromises further follicle development as well as egg/embryo quality. Women with reduced ovarian reserve (who are resistant to ovarian stimulation) are most susceptible to this happening.

There is often talk of agonists “over-suppressing” ovarian response to gonadotropins. The reason for this concern is that agonists probably compete with FSH for receptor binding sites on the granulosa cells that line the ovarian follicles and produce estrogen…and so can blunt ovarian follicle response to FSH. However, since antagonists apparently do not exert the same effect, by supplanting Lupron with an antagonist prior to starting gonadotropin therapy, avoids this problem (see the agonist/antagonist conversion protocol -A/ACP below). While both antagonists and agonists block LH activity, antagonists do so much more rapidly (within hours) than agonists (within a few days).

Use of Lupron to Launch COH for IVF
At SIRM we launch COH for IVF by putting the woman on a birth control pill (BCP) for 10-25 days, to suppress ovarian response to FSH/LH. Thereupon, Lupron is overlapped with the BCP for 2-4 days. Then the BCP is discontinued and daily Lupron therapy is continued until menstruation ensues. By varying the length of time on Lupron it is possible to control the timing of the onset of menstruation and reduce the incidence of cycle cancellation due to ovarian cyst formation. Menstruation will usually occur 4-7 days after stopping the BCP. Thereupon, one of two variations in approach is taken. Either the long Lupron approach or the agonist/antagonist conversion protocol (A/ACP) is used. With the A/ACP, Lupron is supplanted by low dosage antagonist therapy. In both cases, daily Gonadotropin (FSH and LH) injections are concomitantly initiated and continued with the agonist or antagonist until the day of the hCG trigger.

In some cases of markedly diminished ovarian reserve, we preempt the initiation of gonadotropin therapy with “estrogen priming”. It involves twice weekly injections of estradiol valerate for 8-10 days and then we initiate Gonadotropin therapy which is continued until more than 50% of the developing follicles reach at least 12mm in diameter. The addition of estrogen in this way is believed to improve ovarian response to gonadotropins as well as endometrial response to estrogen stimulation. In both the long Lupron approach and the A/ACP, daily shots of antagonist or antagonist are continued up to the day of the hCG trigger. The egg retrieval (ER) is performed 35-37 hours following hCG administration.

Lupron Use in Embryo Recipient Cycles
Cases of egg donation, embryo donation, gestational surrogacy, and frozen/thawed embryo transfers (FET) undergo a similar regime of BCP/agonist preparation as do those who undergo ovarian stimulation, except that instead of receiving gonadotropin injections, these women receive daily estradiol valerate injections. Thereupon, progesterone therapy (administered by intramuscular injection and/or by vaginal administration) is added for several days. The combination of estrogen and progesterone therapy prepares the uterine lining for embryo implantation. Lupron therapy is discontinued 5-7 days prior to Embryo Transfer (ET) in such cases.

There is really no need to be overwhelmed by what at first might seem to be a complex treatment regimen. Extensive studies on non-human primates, as well as limited human evaluations, indicate that Lupron is relatively harmless to both mother and baby. The drug is eliminated from the system within hours of discontinuing its administration. At SIRM we discontinue Lupron therapy at least 5-7 days prior to transferring embryos/blastocysts to the woman's uterus. The administration of subcutaneous or trans-nasal agonist is rarely associated with significant side effects. Some women experience temporary fluctuations in mood, hot flashes, nausea, and symptoms not similar to PMS. No serious long-lasting side-effects have been reported.

The subcutaneous injection of Lupron is relatively painless. Unfortunately, the drug will incur a modest additional financial burden. Lupron administration as described above spares women the inconvenience and frustration of unnecessary cancelled treatment cycles with gonadotropins. As such, the use of Lupron in reality reduces the overall cost of ovulation induction.