Infertility is by far the most common reason why patients seek treatment at the Alta Bates IVF Program. Traditionally, infertility has been defined by lack of a live birth after 12 months of unprotected intercourse. Recently, in recognition of the major impact of female age factor, the interval has been shortened to 6 months for women at 35 years and beyond. Patients often think that they need to either monitor ovulation or otherwise “actively try” to get pregnant, but this is not the case. In the absence of using contraception, the “default setting” for the woman is to get pregnant without any special efforts beyond intercourse.

With the advent of third party treatments, which rely upon use of donor sperm, egg donation, donated embryos and gestational surrogates, the very concept of parenthood has come under close legal scrutiny and elucidation. The crucial role of the Intended Parent(s) was established in a landmark decision by the Supreme Court of California in 1988 (Buzzanca v. Buzzanca). This ruling states that the Intended Parent(s) are “the first cause, prime movers, of the procreative relationship." Therefore, a parental relationship is established when medical procedures are initiated and consented to by the Intended Parent(s), even in the absence of any genetic or gestational relationship between them and the children thus created.

Basic Workup

While multiple factors can result in sub-fertility, the three major ones pertain to the sperm, the eggs and female pelvic anatomy. Many patients start their infertility workup before coming to the Alta Bates IVF Program but frequently not all the essential tests have been completed. A thorough review of past evaluation and treatment, however, helps avoid unnecessary re-testing and associated expenses.

Below is a list of the minimum screening tests:

I. Ovarian Factors: AMH (Anti-Mullerian Hormone), Cycle day 3 FSH and Estradiol, Cycle day 21 progesterone. Ultrasound assessment of antral follicle count (AFC).

II. Male Factors: Semen Analysis to determine if male infertility is a factor.

III. Tubal and Uterine Factors: HSG (hysterosalpingogram).

On the basis of these few tests most couples can be assigned to broad categories depicted on the pie-chart below.

However, this type of categorization is of limited value inasmuch as many infertile couples have multiple factors simultaneously and no allowance is made for female age or reduced ovarian reserve which often presents the single greatest challenge.

Egg Factors

Eggs are essential to the success of reproduction because they make a much greater contribution to the developing embryo than the sperm. Women are born with all the eggs they will ever have. Of the approximately half-million eggs in the ovaries of a newborn female, only about 300-400 will be ovulated during a woman’s reproductive years from puberty to menopause. The vast majority of eggs undergo degeneration through a process known as atresia which occurs regardless of pregnancy, breastfeeding or the use of hormonal contraceptives.

The three major areas of egg dysfunction are:

1. Aging which lowers egg viability

2. Diminished ovarian reserve which reflects low number of eggs in the ovaries

3. Irregular ovulation which is the hallmark of polycystic ovarian syndrome (PCOS)

What Is Age Factor?

Successful pregnancy and delivery of a healthy child becomes more difficult as women become older. The reproductive aging process is complex and multi-faceted but the aspect which comes into play relatively early (in the mid-30s) pertains to decreasing viability of eggs and embryos (fertilized dividing eggs).

This decrease in viability reflects higher frequency of errors in chromosome number (aneuploidy). These errors arise during the development of immature eggs found in small ovarian follicles (fluid-filled sacs containing the eggs) into mature eggs found in the large follicles at ovulation. Chromosome number errors (i.e. too many or too few chromosomes) arise in each individual egg and are not inherited from either parent both of whom have the correct number of chromosomes.

The primary adverse effect of aneuploidy is on embryo development after 3 days and especially on implantation (attachment of the 5-7 day old embryo to the uterus). The earlier steps of ovulation and fertilization progress normally. Early division of the embryo is pre-programmed by the mother’s genes but subsequent development and implantation require activation of the embryo’s own genes at which point the errors manifest themselves. Needless to add, we do not currently have the ability to either prevent or repair such abnormalities albeit embryo biopsy permits their detection (Embryo Testing).

Clinically, these chromosomal abnormalities lead to one or more of the following:

1. Infertility

2. Sub-fertility with infrequent conception

3. Early miscarriages

4. Elective terminations prompted by finding an abnormality on amniocentesis or chorionic villus sampling (CVS).

The graph below portrays the decline in live births with advancing age in all women undergoing embryo transfers after in vitro fertilization (IVF) with their own eggs in the United States in year 2005 as reported by the CDC.

While the IVF data are best documented, the same decline occurs in spontaneous conceptions in fertile couples as well as with other infertility treatments. You may want to note that the steep declining slope begins as early as the age of 33 years.

 

Since there are no direct interventions to counteract the age factor, the available therapeutic approaches are indirect and limited. One such strategy is to increase the total number of eggs being ovulated within a given period of time, such as a cycle or a year, by using FSH hormone to induce ovarian stimulation with simultaneous release of multiple eggs.

This strategy is central to IVF (IVF Primer) but it can also be used as a standalone approach in conjunction with intrauterine insemination (IUI) in couples where the woman’s tubes are open and the sperm is likely to fertilize the eggs in vivo. The success of this strategy is dependent upon the ability of the ovaries to respond to FSH by producing multiple follicles containing healthy eggs which is known as ovarian reserve. Ovarian stimulation does not create new eggs or follicles within the ovaries but merely induces simultaneous growth of several follicles thus overcoming the body’s natural tendency to select a single dominant follicle containing just one egg.

Women who have infertility associated with both age factor and reduced ovarian reserve typically derive little benefit from ovarian stimulation because their ovaries have few follicles and FSH does not result in the maturation of multiple eggs. In addition women above the age of 43 have generally low live birth rates with IVF and ovarian stimulation even if their ovaries are capable of producing multiple eggs at the same time. Patients in these categories are much more likely to achieve live birth with egg donation than with their own gametes as shown in the graph below adapted from the 2005 national CDC report.

The graph above also demonstrates that the primary effect of aging is upon the ovaries and eggs rather than the uterus which is capable of carrying pregnancy long after the ovaries cease to function. While there is a mild decline in outcome of donor eggs cycles due to uterine factors its magnitude is relatively small and it does not occur until about 48-50 years of age.

Are men affected by age factor? While the effect of age on male fertility is slight by comparison to women, there is evidence of increased frequency of point mutations in chromosomes of men above the age of 45 years. By comparison with aneuploidy associated with advanced female age, such small mutations rarely cause a problem because most of time their effect is obscured by the presence of the other normal chromosome.

How Do We Test Ovarian Reserve?

Ovarian reserve refers to the number of ovarian follicles (fluid-filled sacs) containing healthy eggs. In a spontaneous ovulatory cycle a single dominant follicle containing a single mature egg normally ovulates. However, ovaries of reproductive age women also contain a number of smaller follicles which can potentially grow and produce mature eggs. In general women with better ovarian reserve have higher IVF success rates.

Women whose ovaries possess good ovarian reserve typically respond to ovarian stimulation with FSH by developing multiple growing follicles and mature eggs capable of establishing a healthy pregnancy. Women with reduced reserve typically develop very few follicles even with higher doses of FSH injections. Even more importantly, multiple studies have established that women with diminished ovarian reserve (DOR) are much less likely to achieve a live birth than women with other infertility factors when undergoing the IVF process and other fertility therapies.

The graph below clearly illustrates that women with diminished ovarian reserve (low reserve in red bar) had about half the live birth rates achieved by patients with most other diagnoses (adapted from the national CDC Reports on ART for 2004-08). Thus, next to the age factor, which itself is closely related to ovarian reserve, reduction in ovarian reserve is the greatest determinant of the success of infertility treatments in women using their own eggs.

 

Live birth rate per IVF cycle start in couples with different infertility factors

Accurate assessment of ovarian reserve may involve multiple hormonal tests as well as a high resolution vaginal ultrasound. Traditionally a baseline cycle day 2, 3 or 4 FSH and Estradiol blood tests have been used to estimate ovarian reserve. FSH levels above 10 mIU/mL and/or Estradiol levels above 80 pg/mL are indicative of reduction in ovarian reserve. However, FSH/Estradiol levels tend to vary from one cycle to the next making interpretation tricky.

AMH (Anti-Mullerian Hormone) is secreted by the small follicles in the ovaries so it is more constant on different days of the menstrual cycle and and thus can be measured on any day in the cycle. AMH can be determined even in patients taking oral contraceptives, during pregnancy or breastfeeding. Thus AMH has rapidly gained popularity and is particularly useful in identifying women with PCOS who are at risk of ovarian hyperstimulation during the IVF process. AMH is of great value in women considering fertility preservation procedures such as egg cryo-preservation (egg freezing).

High resolution vaginal ultrasound of the ovaries provides the antral follicle count (AFC) which is an anatomical correlate of ovarian reserve. Unless small antral follicles are present within the ovaries, fertility drugs cannot make them grow and the woman will not exhibit the multi-follicular response which is key to the success of IVF and other fertility treatments.

 

Ovary with several small follicles (normal reserve)

Ovary without small follicles (reduced reserve)

The main reason for ovarian reserve testing is to define the exact likelihood of successful conception for each infertile couple so that they have best information in order to make an informed decision about different treatment options. In addition, the information is of value in selecting ovarian stimulation regimen best suited for an individual patient. Women with severely reduced ovarian reserve, especially if it is associated with advanced age, are much more likely to achieve a successful birth using egg donation.

What Is PCOS?

Polycystic ovary syndrome (PCOS) is the most common disorder of reproductive hormones occurring in 5-10% of women. Its key feature is irregular ovulation and menstruation, typically dating from the onset of menses in adolescence. Hence PCOS frequently results in infertility. Other common problems include extra facial hair, acne and obesity but relatively few patients have all the features of the full-blown syndrome. Most women seeking help to conceive have a mild variant of PCOS manifesting itself as infertility with irregular menses.

While the diagnosis of PCOS is based on clinical assessment not laboratory tests, a number of different hormonal irregularities occur in subsets of women with PCOS. Very few women manifest all of these laboratory abnormalities which can include higher levels of LH than FSH, more male hormones (testosterone) relative to female hormones (estradiol and, especially, progesterone) and elevated fasting glucose and/or insulin. Women with more severe PCOS are at an increased lifetime risk of developing diabetes, hypertension and heart disease. Young PCOS patients who are overweight may achieve remarkable success with even modest weight loss.

When conception is the goal, oral ovulatory meds are the accepted first step. Obviously, it is important to ensure that no other factors, such as abnormal sperm (male infertility) or tubes, contribute to the infertility. Clomiphene pills (Clomid, Serophene are the brand name fertility drugs) are usually tried initially. Whereas many general Ob-Gyns prescribe clomiphene, they often fail to perform the follow-up tests necessary to monitor its effectiveness. If no regular ovulation or conception is achieved with clomiphene alone, adrenal suppression or insulin-sensitizing medication, metformin, may be added with good results. Letrazole is another option available, albeit ovulation induction is an off-label use for this medication. Once regular ovulation is established, IUIs are typically added to maximize the per cycle pregnancy rate..

Ultrasound showing multiple small follicle cysts in PCOS ovary

If oral fertility drugs do not establish pregnancy, then gonadotropin injections or the IVF process need to be selected. The use of injectable gonadotropins in PCOS is risky because women with such a multitude of small follicle cysts (after which the condition is named) are particularly prone to hyper-stimulate. Successful management of infertile women with PCOS remains a clinical challenge. At the Alta Bates IVF Program women with PCOS receive particularly close monitoring and such attention to all details of their care usually leads to a successful pregnancy. While there is no simple cure for PCOS, Dr. Chetkowski’s long experience and maximal continuity of care offered by our program have resulted in outstanding results.

How to Avoid OHSS

Ovarian hyper-stimulation syndrome (OHSS) is the most common serious complication of the injectable fertility drugs occurring in 2-3% of IVF and FSH/IUI cycles. The syndrome results from ovarian enlargement with ovulation of multiple follicles and accumulation of large quantity of fluid within the abdomen. The symptoms include distension, nausea, pain and shortness of breath.

The severity of OHSS varies widely. A mild degree of abdominal distension occurs in virtually all women given gonadotropin injections. Young age, presence of PCOS (What is PCOS?), development of many small follicles, small body habitus and high levels of estradiol are among the major predisposing factors toward moderate and severe forms of OHSS. Mild and moderate OHSS frequently respond to bedrest and supportive measures. Severe cases may require a minor operation to drain excess fluid from the abdominal cavity, intravenous fluids and even hospitalization. The severe OHSS may lead to such life-threatening complications as formation of clots, stroke, kidney failure and pulmonary embolism.

There are two types of severe OHSS: 1. early which occurs in response to hCG trigger within 5-7 days of ovulation; 2. late which is caused by the rising hCG hormone levels produced by the placenta in conception cycles. Over the years many strategies have been developed to prevent the occurrence of severe OHSS but most of them are not always effective. The single best technique to avoid early severe OHSS is to substitute LH trigger for hCG trigger while the single best strategy to eliminate the risk of late severe OHSS is to freeze all the embryos and delay the frozen embryo transfer until the next cycle. Other approaches include reduction in dose of hCG trigger, “coasting” to allow estradiol levels to fall, administration of volume expanders during egg retrieval and cycle cancellation before hCG.

Avoidance of severe OHSS has become a major goal at the Alta Bates IVF program and it plays a major role in selecting the individualized stimulation protocol for each patient. Combination of close monitoring of ovarian response, use of LH to trigger ovulation and the strategy of freezing of all fertilized eggs for transfer in the subsequent cycle have allowed us to eliminate all cases of severe OHSS in IVF patients over the past several years.

Male Factors

Sperm abnormalities take a variety of forms and stem from different causes. When considering sperm production it is important to keep in mind that sperm are generated throughout a man’s lifetime and that the process takes about 70 days. Thus exposure to high temperature, which is harmful to sperm production, or another insult may manifest itself as low count or motility several weeks later.

Semen analysis is the primary test done to check for male infertility. The normal sperm parameters are: volume above 2 mL, concentration (“count”) above 20 million/mL, initial motility above 50% and normal morphology above 4% by strict criteria. These numbers calculate to a minimum of 10 million moving sperm per ejaculate. Men whose ejaculates contain 5 or more million moving sperm per ejaculate are candidates for intra-uterine artificial insemination (IUI). Men who ejaculate less than 4 million moving sperm at a time are more likely to require ICSI-IVF.

While semen analysis is the cornerstone of diagnosis, what really matters is the ability of sperm to fertilize eggs, which is much harder to assess. History of prior pregnancies may be helpful but, in its absence, IVF represents the ultimate “test” of sperm fertilizing capacity. ICSI is the primary treatment for sperm which cannot fertilize eggs on their own.

Sperm concentration and motility are the most common form of male factor. Some of these cases are associated with the presence of a varicocoele which is a dilated plexus of veins draining the testes. Surgical ligation or radiologic occlusion of a varicocele may improve sperm parameters and lead to conception provided there are no complicating female factors. Medical therapy has not usually been of help although an empirical trial of clomiphene has few downsides.

If the ejaculate lacks sperm, the condition may be due to either obstruction, such as following a vasectomy procedure, or failure of sperm production in the testes. The former condition is known as obstructive azoospermia and it is the primary indication for MESA procedure.

Tubal Disease

Tubes pick up the egg at ovulation, permit sperm to reach the egg after intercourse or insemination and transport the dividing fertilized embryo into the uterus to permit normal implantation within the uterine cavity. HSG (hysterosalpingogram) is the initial step in evaluation tubal status, but further evaluation may require laparoscopy which is a minor outpatient surgery.

Tubes are exquisitely susceptible to damage by sexually transmitted bacteria such as Chlamydia trachomatis and Neisseria gonorrhea. Pelvic infections (PID) are notoriously “silent” so only about 50% of women with damaged tubes are aware of having had an episode of PID in the past. Pelvic infections are most common in women in their teens and 20s but their consequences last for years.

Pelvic infections can result in distal closure of the tube near the ovaries with dilation of the tube by accumulated secretions. Whereas in the past tubal surgery was frequently performed, its results have been generally disappointing with re-occlusion of tubes, ectopic pregnancies and low live birth rates. IVF represents a much more successful approach to distal tubal occlusion, but for best results the occluded tube(s) should be removed before IVF is initiated. If only one of the tubes forms a hydrosalpinx, Dr. Chetkowski and others have reported high pregnancy rates with removal of the diseased tube without requiring IVF.

Occlusion of the tubes proximally near insertion into the uterus is much less ominous than distal occlusion and requires no intervention before the IVF process. This portion of the tube is very narrow and can easily become closed by a mucus plug, debris or even transient tubal spasm. Select patients with proximal tubal occlusion may benefit from opening them up by cannulation which is usually performed by an interventional radiologist with x-ray guidance.

What Is a Hydrosalpinx?

If tests of tubal patency, such as an HSG (hysterosalpingogram), indicates that you have dilated distally closed tube(s), known as a hydrosalpinx, the advisability of surgical removal or ligation of the tube(s) by laparoscopy will be discussed with you.

HSG showing a large hydrosalpinx

Hydrosalpinx is most commonly caused by an old pelvic infection which may have been caused by a sexually transmitted disease. Other causes include previous surgery or severe scarring.

Hydrosalpinx fluid interferes with embryo implantation decreasing pregnancy rate by as much as 60%. The larger hydrosalpinges, which are often visible on ultrasound, are more likely to interfere with embryo implantation than smaller closed tubes. The presence of hydrosalpinges also increases the risks of severe pelvic infection and ectopic pregnancy.

Some women with hydrosalpinx may have constant or frequent pain in their lower belly or abdomen. A vaginal discharge can also be associated with this condition. Most women have no symptoms.

 

Large right hydrosalpinx at laparoscopy

 

Frequently, tubal occlusion occurs on both sides. While surgery can open up the tubes, they seldom function normally and recurrence of hydrosalpinx is common. In some cases, the hydrosalpinx is just on one side and the other tube is normal and open. Dr. Chetkowski and collaborators have reported high spontaneous pregnancy rates after removal or ligation of the diseased tube. Since most conceptions happened shortly after laparoscopy, it is reasonable to try this approach first before starting IVF.

Uterus

Uterine fibroids and endometrial polyps are frequent findings which may interfere with embryo implantation regardless of how conception occurs. The diagnosis of uterine abnormalities relies upon pelvic examination and several imaging tests: 1. ultrasound; 2. HSG x-ray; 3. saline infusion sonohysterogram (SIS); 4. MRI.

The location of fibroids is often more important than their size or number. Fortunately, the most problematic fibroids occur within the uterine cavity and can usually be removed with hysteroscopy, a minor surgical procedure performed on an outpatient basis.

Fibroids arise from the muscle layer of the uterus. The pictures below show a large submucous fibroid being resected with an electric loop. The patient had a successful spontaneous conception shortly after surgery.

Removal of a submucous fibroid

With regard to fertility the location of a fibroid matters the most. Intramural fibroids within the wall of the uterus are most common but their exact impact on the cavity may be the key consideration for pregnancy. Subserosal fibroids, as pictured below at laparoscopy, have little, if any, impact on the chance of a successful pregnancy.

Two subserosal fibroids outside the uterus

In rare cases multiple fibroids and surgeries to remove them may damage the uterus to the point that a successful pregnancy cannot be achieved. In such situations gestational surrogacy may be advisable.

Endometrial polyps arise from the gland layer lining the uterine cavity. Large polyps can be apparent on vaginal ultrasound (upper picture) while smaller polyps usually are readily seen on saline infusion sono-hysterogram (SIS, lower picture). Hysteroscopic removal of all polyps is recommended before IVF and other advanced treatments.

Inborn (congenital) abnormalities of uterine shape are relatively common. Septate uterus contains 2 small cavities within a unified uterine body (see images below) and is associated with recurrent miscarriages. Uterus unicornis is another congenital abnormality in which only one half of the womb develops in association with a single tube and frequently a kidney abnormality as well.

Other uterine abnormalities include scarring (Asherman’s syndrome) from infection in conjunction with pregnancy and narrowing of the cervical canal (stenosis) which can make embryo transfer difficult. Most of these conditions can be corrected through outpatient hysteroscopy.

Ultrasound of a septate uterus (S=septum, C=cavities, M=uterine muscle)

Hysteroscopic view of septum at arrow and 2 cavities in upper panel; unified uterine cavity after incision of septum in lower panel

 

Our fertility patients come to us from San Francisco, the Bay Area, Berkeley, Oakland, Sacramento and bordering locations.