Recurrent Pregnancy Loss

As seen in the previous blog post, infertility can lead to unwanted stress and/or depression in an already fragile situation. Recurrent pregnancy loss (RPL) only adds more questions and concerns for couples battling infertility and trying to give birth to a healthy baby. It is important to note that approximately five percent of the population have had two consecutive pregnancy losses. While this is certainly an upsetting situation, in no way does it mean that these couples will never achieve a pregnancy that will result in a healthy birth. There are multiple etiologies of RPL and the typical textbook breakdown is as follows: Infectious (0.5-5%), Genetic (2-5%), Anatomic (10-15%), Endocrine (17-20%), Autoimmune (20%), and Unexplained (40-50%). In the following paragraphs, we will explore these various reasons known to cause RPL and the potential for therapy of each.
Infectious: The role that infections play in RPL is speculative. In fact, the American College of Obstetricians and Gynecologists Practice Bulletin on RPL states that infections are known to cause sporadic pregnancy loss but no infectious agent has been proven to cause recurrent loss. The reason this etiology is speculative is because in order for an infectious agent to be implicated in RPL, it must persist in the genital tract with few, if any, symptoms. Nevertheless, the infectious agents thought to play a role include Toxoplasmosis, Rubella, Cytomegalovirus, Herpes Simplex Virus, and Listeria. The proposed mechanism of action is either by direct infection of the womb and/or embryo or placental problems. Bacterial vaginosis has also been implicated but there are inconsistent reports. It has been suggested by some that perhaps the most prudent approach would be treatment of an infection early in pregnancy if the patient has a history of preterm birth. The bottom line is that population screening for these is not recommended.
Genetic: Normal human development is directed by our genetic make-up. If there is too much or too little genetic information, problems with development occur. When an egg and sperm meet at fertilization, they each bring the respective genetic make-up from the parents-to-be. One can imagine that if there is an imbalance of genetic information, either too much or too little, from one or the other (egg or sperm), the future of that embryo can be compromised. This can occur when either member of the couple has a rearrangement of their genetic code, called a chromosomal translocation. This can be detected by a blood test called a karyotype that looks at the number and structure of a person’s chromosomes. While there is no “fix” for this, in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD) can offer couples the ability to have embryos that don’t have the genetic translocation be transferred into the uterus in hopes that a successful pregnancy will result in a healthy birth.
Other genetic reasons can include blood disorders, such as sickle cell anemia, or other inherited conditions. In particular would be those inherited conditions such as Marfan’s Syndrome or Ehlers-Danlos Syndrome that may disrupt the integrity of the cervix. As with a translocation, there is no “fix” for these conditions but knowing that the patient has them can allow for the obstetrician to better prepare the patient and hopefully the outcome of the pregnancy.
Anatomic: When we talk about anatomic factors that can lead to RPL we are mainly talking about anatomic factors within the uterus. While development of the uterus typically follows the normal path of one cervical opening with one clear uterine cavity (where a baby grows), there are many variations on the theme. Developmental abnormalities can lead to a uterine septum, unicornuate uterus, bicornuate uterus, or a uterine didelphys. (See picture) A uterine septum is the most common of these and, fortunately, is the one that can be corrected with a relatively simple surgical procedure.

Other uterine factors that can be involved with RPL, and are able to be corrected, include fibroids, polyps, or intrauterine adhesions (called synechiae, or Asherman’s Syndrome). Pelvic ultrasounds can aid in the diagnosis and therefore management of these factors.
Endocrine: The main disorders that fall under this category are polycystic ovarian syndrome (PCOS), thyroid disease, and diabetes. In PCOS, which occurs in approximately 40% of women with RPL, there is often insulin resistance leading to elevated levels of insulin circulating in the blood (hyperinsulinemia). This hyperinsulinemia can not only lead to problems with embryonic development but also embryo implantation which can then result in a failed pregnancy. Much the same can be said for patients with diabetes where it has been shown that poor diabetic control increases the miscarriage rate in the individual. Thyroid disease, hypothyroidism in particular, can also lead to an increased chance of miscarriage. The bottom line is that if you do have any of these conditions, there are simple blood tests that can help your doctor manage you appropriately and therefore optimize your chances for a successful pregnancy.
Autoimmune: This category mainly has to do with clotting disorders that a person can have through autoimmunity, which, simply put, means your body has made antibodies to certain things that can cause an increase in blood clotting to occur (called an acquired thrombophilia). The main antibodies involved, and therefore tested, are lupus anticoagulant and anticardiolipin antibody. While there are others, collectively they are called Antiphospholipid Antibodies, and they play a role in RPL due to their propensity to increase clotting and affecting a number of factors important in embryo implantation and development. Antiphospholipid Antibody Syndrome (APA Syndrome) is a known etiology of pregnancy loss, and depending on your history, can be treated accordingly to best optimize the uterine environment for a pregnancy.
Celiac sprue is also an autoimmune disease that has known implications in RPL. It too can be tested with blood tests, and possibly follow-up biopsy, and if found can be treated with a gluten free diet.
Unexplained: It is a given that couples going through RPL want to have answers, and hopefully solutions, to their problem. Unfortunately, however, there will be a number of couples who fall into the “unexplained” category because even though our current technology is excellent, it is not without limits. There are new avenues of exploration that include immunology at the cellular level and possibly manipulating the balance of certain immunological cell types but any such treatment is yet to come.
As a group, my partners and I feel that a large portion of patients that fall into this “unexplained” category may in fact have endometriosis. It has been shown that those women with endometriosis also have fertility issues and that surgical resection can potentially improve fertility outcomes. However, the only definitive way to diagnose endometriosis is with surgery. A detailed menstrual history can help your gynecologist decide if surgery for potential endometriosis is right for you.
There are also inherited genetic disorders that can lead to increased blood clotting (called congenital thrombophilias) which can lead to RPL and these are collectively called the non-APA Syndrome thrombophilias. Include in this group are Factor V Leiden, Prothrombin Gene mutation, Protein C or S deficiency, Antithrombin III deficiency, and MTHFR mutation. There are blood tests to determine if you have these and, based on your history, you can be treated accordingly in hopes of sustaining a healthy pregnancy.
While RPL is undoubtedly a difficult diagnosis to have, it does not mean that there isn’t hope of delivering a healthy baby in the future. The different etiologies listed above are the most commonly seen, but are certainly not an exhaustive list. If you are in this situation it is important to sit down with your gynecologist or reproductive endocrinologist to explore the different possibilities of treatment.

Creighton E. Likes, III, MD

Depression and Infertility

I saw an infertile couple today and the wife was mentioning the symptoms of stress she was having and also wondered if she was depressed.  If she is depressed, she is not alone. Depression is a frequent, unwelcomed guest in the lives of infertile couples. Major depressive disorders (MDD) and associated conditions such as anxiety are common in women with infertility and are often not adequately addressed by the primary care providers.  Depression is not well understood, nor is it known how infertility causes depression, but logically there are complex psycho-dynamics at play that might contribute to the onset and maintenance of MDD (1).

Reasons for depression are many but might be exacerbated in the setting of infertility due to feelings of isolation, both from society, friends, and parents but also isolation from one’s spouse. Normal joyful relationships become strained and the act of love-making can become a repetitive opportunity for failure rather than being part of the normal relationship building that couples share.  Not knowing where to place blame often results in individuals blaming themselves.  Loss of control and feelings of anger also contribute to an emotional disorientation, making it difficult to negotiate the normal social interactions that we all face and deal with on a daily basis.  The anger is often occult and displaced with no place to be appropriately directed. Someone said that depression is anger turned inward, which I believe is true in many cases. If we could get to the bottom of that “anger well” and release those feelings can often improve those feelings of depression. Talk therapy can be quite helpful in the right setting, but this also takes time and trust, since many of the defenses that we establish to maintain our inner emotional equilibrium are there to protect us (prevent us) from delving too deeply into our own pockets of despair.  While these feelings may be irrational, they often have a basis far removed from current events, established by earlier relationships, particularly involving parents and siblings.  Finding time to discuss those feelings with one’s partner is important, especially since he or she may also be experiencing similar feelings of isolation and self-blame. Finding other sources of help is equally important especially when hopelessness becomes a dominant feature of ones daily experience.

Prevalence of depression in the infertile population, reflects the higher rate of depression in women in general during their reproductive years. The risk of developing MDD is higher for women than for men (1). In the infertile couple, men have a reduced role to play both during the diagnostic workup but also the treatment phase of infertility. Men don’t have the dramatic changes in hormones that women experience, made worse by the fertility treatments involving hormone stimulation. Except in certain circumstances, many treatments involving needle injections, dye instillation, surgery, ultrasound and biopsy all fall to the female partner, many involving pain or apprehension. Fear of miscarriage or birth defects can contribute to the anxiety a woman experiences. In unexplained infertility, the physician or nurse may attribute the lack of success to “bad eggs” or “poor uterine environment” casting unintentional blame to the female partner for factors that are completely out of her control. The other side of this coin is whether  emotional problems such as anxiety and depression might in themselves contribute to the reduced fertility. Finances to fund fertility treatments are a major factor in the dynamics that drive emotional dysequilibrium, especially has more 3rd party payers reduce their support for infertility treatments.  It is no wonder why some women feel helpless and hopeless as their situation seems to spiral out of control, without clearly defined endpoints or answers.

The treatment of mood disorders is increasingly being handled by the pharmacist rather than by the psychiatrist or psychologist. Pills are becoming the first line of therapy depression or anxiety. Pharmaceutical agents used to treat depression can complicate the treatment of infertility. The use of antidepressants has been associated with an increase in miscarriage (2). Small studies have suggested a decreased pregnancy rate for IVF in women taking serotonin reuptake inhibitors (3,4).  Some antidepressants can reduce sex drive (libido) further reducing the enjoyment and frequency of sex.  The American College of Obstetricians and Gynecologists (ACOG) cautions about low birth weight, lung problems and neonatal irritability in neonates in women taking antidepressants, and some drugs such as Paroxetine have recently been implicated in cardiac anomalies, leading many clinicians to advise against its use in pregnancy.

Group or individual psychotherapy may be the safest and perhaps the best approach to this particular mood disorder, given that it is confined to a specific medical condition or situation and may therefore be amenable to improvement  through increasing self-awareness of the impact of isolation and anger surrounding the state of infertility itself. Group session like the ones we host at GHS as part of the Mind-Body program are one example that not only attempt to reduces stress but allow the establishment of new avenues for communication between partners but also between other individuals or couples sharing similar feelings and problems.

A blog on depression in women would not be complete without some mention of clinical depression and its link to post-partum depression. This complication of pregnancy can be serious and affect not only the mother but the other family members including the child or his or her siblings. Women with a history of post-partum depression or serious depressive symptoms going into pregnancy would be advised to let their obstetrician know about their condition, as SRIs may have a benefit in reducing or eliminating these symptoms after delivery.

Source material included from Catapano The Female Patient, Vol 35, 2010

References cited

1. Williams et al., Mood disorders and fertility in women: Critical review of the literature and implications for future research. Hum Reprod  Update 13:607-616, 2007.
2. Hemels et al., Antidepressant use during pregnancy and the rates of spontaneous abortions: A metaanalysis. Ann Pharmacother. 39:803-809, 2005.
3. Klock et al., A pilot study of the relationship between selective serotonin reuptake inhibitors and in vitro fertilization outcome. Fert Stert 82:968-9, 2004
4. Friedman et al., Effect of selective serotonin reuptake inhibitors on in vitro fertilization outcome. Fert Stert 92:1312-14, 2009.

Lyme Disease and Pregnancy

We had an interesting dilemma this week that got us thinking about Lyme disease and pregnancy.  An infertile patient who is in the midst of an ovulation cycle to conceive tested positive for Lyme disease. The question she had was should she continue the therapy and what if she gets pregnant? Truthfully, this rarely comes up and even our specialty OB doctors did not know immediately what the risks of having Lyme disease would be on a pregnancy. This becomes the subject of today’s blog.

Lyme disease is a bacterial illness that is caused by a spirochete, named Borrelia burgdoferi. Common vectors for transmission of this bacteria are deer ticks that maintain the pathogen in their gut and transmit it to the host  when they attach to the skin. Interestingly, the transmission of disease from person to person does not occur. The symptoms can be vague and non-specific but can be serious and involve joints, heart, and the nervous system, if left untreated. Lyme disease was first discovered in Connecticutt and is endemic to the Northeast, from Maine to Maryland. Here in South Carolina, it is very uncommon unless contracted elsewhere by the affected person.

The stages of infection include an early period localized to inflammation of the skin, a second disseminated phase that can affect the heart and nervous system (including meningitis) and a late phase of disease associated with arthritis, sensory nerve damage and brain inflammation.  The initial redness of the skin can last up to a month and then gradually disappears. Diagnosis can occur during the earliest phases of the disease but often Lyme disease is diagnosed later after the afflicted person gets tested for antibodies against the Spirochette. The test can be wrong and incorrectly indicate that the person has been exposed when in fact they have not (‘false positive”). The best test and a confirmation of Lyme disease requires a Western Blot (a test involving antibodies and gel electrophoresis).  Treatment of Lyme disease involves antibiotics. Doxycycline or tetracycline are effective but cannot be used in pregnancy. Late disease may require IVF antibiotics including penicillin G or Ceftriaxone.

So, should a woman suspected of having Lyme disease get pregnant? Probably not, until the diagnosis is firmly established and treatment initiated. That was my advice anyway. The problem for fertility patients, especially those in a cycle, its very difficult for them to stop trying to get pregnant given their intense need and drive to accomplish this biological imperative. In a pregnant woman, newly diagnosed, avoiding doxycycline would be important, especially since alternative therapies are available. Treatment is also vital since there have been cases reported of the bacterium crossing the placenta and causing fetal death.  The liklihood of this happening is very small, but why take that risk?  Given the difficulty in making a firm diagnosis and the reduced liklihood of getting this disease in South Carolina, it would be important to see a specialist who can make sure this is the actual diagnosis.

For those of us living in the South, Lyme disease is not the only tick-borne disease to worry about. The CDC lists Babesiosis, Southern Tick-associated rash illness (STARI) and Tick-borne relapsing fever. Rocky Mountain spotted fever is the most severe disease associated with ticks caused by the organism Rickettsia rickettsii. So, all those outdoors people beware and take notice of tick bites as they can have some nasty consequences.

What to do until the doctor arrives

Infertility is a highly personal problem that affects 1 in 5 couples. Many people who are confronted with this problem start with high hopes that they will be able to start a family just like everyone else.  There may be a certain amount of denial and also misconceptions about what constitutes a problem with fertility. To be sure there is a blame game that occurs, either on the surface or below, that may get in the way of relationships or communication. Couples may also find that the very act of trying to conceive becomes stressful rather than enjoyable and some partners may withdrawal or even avoid sex to stop having to confront the problem that they just never thought they’d have to deal with in the first place.

First of all, infertility is common and in most cases not absolute. A decreased chance of conceiving is different that no chance (sterilitiy) and for most couples time will heal all wounds. We don’t usually see couples for infertility problems until they have tried for a year or more. There are times when waiting would be inappropriate, including older couples or couples that have clearly identifiable problems that preclude achieving a pregnancy. Examples would include women approaching the late 30s who wish to start a family or men with ejaculatory problems or women who don’t ovulate. In most cases, however, everything seems fine but that pregnancy test just never turns positive.

So, first let’s list the causes of infertility in general terms and see what can be done without making an appointment with your doctor:

1) Male factor – low sperm number, motility or morphology (the way the sperm look under the microscope)

      Men with a history of mumps, undescended testes, testicular injury or lack of a sex drive or erection should probably go ahead and see their doctor who can order a semen analysis (SA). For most men, there are tests that they can use at home that will reassure them that they have sperm (CheckMate is an example). If a man has fathered a child in another relationship that would be presumptive evidence that he is OK.  In up to 40% of cases it is the man who has the primary defect leading to infertility. We would add that most of the work up for couples is conducted on the female partner and since these tests are often more invasive, we like to do the SA first. It doesn’t hurt, guys, honest.

2) Cervical issues – problems with the lower portion of the uterus that is at the top of the vagina can cause infertility

Women with human papilloma virus (HPV) exposure are increasingly being offered “cryotherapy” or “leep” procedures to remove the infected portion of the cervix that shows up as an abnormal pap smear. One thing we tell women, especially young women, is that the virus will often be cleared by your immune system.  If the doctor finds an abnormal pap smear, he or she will often recommend a closer look at the cervix (colposcopy) and possibly a biopsy. Ask if they can screen for the high risk HPV while they are there. This might help you avoid surgical trauma to the cervix. The removal or freezing of cervical tissue may be important to fight cervical cancer but it reduces cervical mucous, interferes with fertility and may even lead to preterm birth or endometriosis. Advice is cheap but here there is some merit in being informed about your condition before having anything done to your cervix.  The vaccine against HPV is available and many women are taking that to avoid HPV infections. Women that are just staring out might also remember that HPV can be avoided by using condoms and just one unprotected sexual encounter with an infected individual may be enough to have transfer of those viral strains.

With regard to the cervix, a discharge usually is normal at the time of ovulation and is usually clear and stringy. It is the cervical mucous that helps guide sperm into the cervix and uterus. This may be something a couple can monitor to know when to time intercourse. The mucous usually dries up after ovulation. Cervical mucous throughout the menstrual cycle can indicate a lack of ovulation. Finally abnormal discharge with an odor or other symptoms can indicate cervicitis or vaginitis that can interfere with getting pregnant. That may require antibiotic or anti-fungal therapy to treat.

3) Timing of intercourse is important.

The time of maximal fertility is usually mid-cycle (day 14 of a 28 day menstrual cycle). If a woman’s cycles are longer, then count back 14 days from the average length of the menstrual cycle and that’s when she is likely to be ovulating. Cycles that vary greatly or menstrual cycles with heavy or unpredictable blood loss is another indication of no ovulation (anovulation or PCOS).  After the egg is released the cervical mucous gets much thicker and the sperm can no longer travel through the cervix into the uterus. Intercourse after ovualtion is not useful for conception purposes.  Spotting before the period starts is an indication of problems with hormone levels or response to hormones. The first person to mention this was Ann Wentz in 1980 who made the connection between premenstrual spotting and endometriosis. That is a good indicator of endometriosis in my opinion.

4) Fallopian tubes – Women require at least one open fallopian tube in order to conceive. Those with a history of gonorrhea or chlamydia or other sexually transmitted diseases are at increased risk for tubal blockage. The test for tubal patency is a hysterosalpinginogram done by a doctor under an X-RAY source. Ultrasound can sometimes detected blocked tubes and they are often found at the time of surgery (laparoscopy).  Couples with a history of STDs might want to check the tubes earlier in the process than couples without that history. Interestingly, one blocked fallopian tube is almost as bad as 2 blocked tubes. We found that if the bad tube was surgically removed, almost 85% of women conceived, without the need for other infertility procedures (Sagoskin et al., 2003 Hum Reprod 18:2634-7).

5) Endometriosis – We written about endometriosis on this blog before. Up to 40% of infertility is due to endometriosis. 30 to 50% of women with endometriosis are infertile. The signs are protean but center around pain, bladder or bowel symptoms or just infertility or pregnancy loss. For the couple trying to improve their chances at pregnancy, there are things you can do including attention to diet, excercise and the use of preventative measures prior to trying to conceive. For example, we see women with painful periods that get much better on oral contraceptive pills (OCPs). If a woman has a history of painful periods as an adolescent, the use of OCPs might improve the chances at conception later.  Unfortunately, endometriosis is often suppressed but is still there, so it can get worse over time if pregnancy does not occur quickly off the pill. The Endometriosis Association in Waukesha WI has alot of information about endometriosis and I encourage you to read their source book.

Finally, what can the average couple do to improve the time to conception? Here are some hints:

1) Reduce stress when possible

2) Maintain a healthy lifestyle and avoid becoming overweight

3) Men – avoid hot tubes, saunas and keep the lap top off your lap

4) Monitor your menstrual cycles for regularity, timing of ovulation (LH kits) and symptoms of endometriosis around the time of menses

5) Time intercourse every other day around the middle of the month

6) Seek help if you need to by someone with experience in treating infertility

7) Don’t wait too long to start trying to get pregnant. Women approaching 40 years of age may have a much harder time conceiving than women 35 and younger. You may feel young but your ovaries have a limited supply of eggs that begins to decline in the mid-thirties.

8) Read books on fertility – many good books are out there.

Getting pregnant should be a fun and rewarding time. Good luck but come to see us if you get frustrated.

Cystic Fibrosis Testing

Cystic fibrosis testing for couples contemplating pregnancy – what are the issues

Cystic fibrosis (CF) is the most common autosomal recessive genetic disorder in Caucasian populations.  CF is a disease that affects the lungs and intestines of those who carry it.  Not everyone has the same severity of symptoms.  Affected individuals may have significant health issues, and shortened life expectancies.

CF affects approximately 1/3300 Caucasians, 1/8000 Hispanics, and 1/15000 Blacks.

CF is inherited when an asymptomatic genetic carrier adult passes on the gene to an offspring who also gets a CF mutated gene from the other parent.  Each carrier parent will pass the gene onto 50% of their children.  When a child has two copies (one from mom, one from dad) then they are no longer a carrier, but have the disease.  Testing for CF carrier status is done by drawing a tube of tube of blood.

The disease causes high levels of chloride in the sweat and thick mucus in the lungs and pancreas which causes most of the symptoms of the disease.  Diagnosis is made during the first year of life in most cases.  Men who have cystic fibrosis are usually infertile due to an absence of the vas Deferens which connects the testicles to the penis and serves as the conduit for sperm.

Most patients with CF die from complications of their pulmonary (lung disease).  Medical therapy has increased the average life expectancy to the 30’s.

IN 1989 the gene for CF and the most common gene that causes CF were discovered (Delta F508).  In 1997 the National Institutes of Health Consensus Development Conference on Genetic Testing for CF recommended that CF screening should be offered to adults with a family history of CF, to partners of people with CF, to couples planning a pregnancy, and to pregnant couples seeking prenatal care.

In 2001 the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG) convened a committee to ensure that information about genetic screening for CF was disseminated to health care providers and patients in a useful and meaningful way.  They also refined the recommendations of the NIH as follows:

The following groups should be offered CF screening:

• Individuals with a family history of CF
• Partners of individuals with CF
• Couples in which one or both partners are Caucasian and are planning a pregnancy or seeking prenatal care.
• Screening can be offered to individuals from other ethnicities, although the results will be less sensitive.

Ideally, couples would be screened before a pregnancy occurs to allow for reproductive options to be considered.  While no test is perfect, detection rates are very high amongst highest risk populations.

		Estimated Carrier Risk
Ethnic Group	Detection Rate	Before Test	After Negative Test
Ashkenazi Jews	97%	1/29	Approx. 1/930
Caucasian	80%	1/29	Approx. 1/140
Hispanic	57%	1/46	Approx. 1/105
African American	69%	1/65	Approx. 1/207

This means that 1/29 Caucasians are carriers of the cystic fibrosis gene.

Typically, screening is done in sequence.  The partner who is a greatest risk of being a carrier is screened first, and only if the result is positive is the other partner tested.

Treatment choices are better and more options exist if testing is done before pregnancy.  If one parent is a carrier and the other is not, then couples can attempt pregnancy normally.  If both partners are positive for the CF mutation, options include contraception, donor gametes (sperm or eggs) from a non-carrier, or in vitro fertilization with Preimplantation Genetic Diagnosis (PGD) to identify embryos that are affected with the disease and selection of only healthy embryos for transfer into the uterus.

So what got me interested in CF screening?  Two events came together in short order that caught my attention. First, when I was in high school I knew three brothers who all had CF.  All three had died by the time I was in my 40s, from complications of their disease.  Second, my son Jake was sick when he was only 2 years of age. He was not growing at the appropriate rate, and one of the concerns was that he might have CF.  My family was lucky, his CF test came back negative and we found he had a severe allergy to milk that caused his symptoms.  Just by changing his diet we have reversed his problem and he is a now healthy 9 year old.  I remember the days between his blood test and diagnosis well.  Not only were we worried that he might have CF, we were also worried what that diagnosis would mean for his two sisters and all his cousins.

Today we offer CF screening to all couples when they come in for their initial visit.  About 50% of couples choose to have screening done and detection rates are as expected – 1/29 Caucasians, and 1/46 Hispanics, and 1/65 African Americans turn out positive.  When this happens we screen their spouses. Luckily, it is very rare that both partners are positive for the CF mutation and no treatment is needed.  But when we do find the 1/900 Caucasians (much rarer in other ethnicities) couples where both are positive for the CF mutation, it is comforting that we can offer treatments that will eliminate the risk of an affected child before they become pregnant.

David Forstein –

The Mind Body Program

  Guest Blog from:                                     

Cynthia K. Whitaker, LISW/CP &

The Department of Obstetrics and Gynecology

Reproductive Endocrinology & Infertility

Introduces the Mind/Body Approach to Infertility

INFERTILITY PROGRAM

Research has shown that women who experience infertility can report higher than normal levels of physical and psychological symptoms including: insomnia, headaches, fatigue, abdominal pain, depression, isolation, anger, frustration and anxiety. This is complex and not well understood. Some scientists believe that negative emotions may negatively impact conception. Often, these feelings are the result, not the cause, of infertility. In either case, a reduction in stress and tension clearly is beneficial.

The Mind/Body Approach to infertility is a comprehensive, complementary program designed to decrease physical and psychological symptoms, reduce isolation, and educate participants on the potential impact of positive changes to lifestyle behaviors for improved reproductive health. Recent research has demonstrated that past participants in this program experienced significant improvements in psychological health as well as increased pregnancy rates following completion of the program.

Program Components

• Elicitation of the relaxation response, a physical state of deep rest that changes the physical and emotional responses to stress (decreased heart rate, blood pressure, and muscle tension)
• Cognitive-behavioral strategies to enhance skills for coping with negative emotions
• Up to date information about the impact of exercise, nutrition and other lifestyle choices on reproductive health
• Practice of effective communication and good self care

Program Goals

• Increase your sense of control and well-being
• Reduce/manage physical symptoms such as insomnia, fatigue, headache or abdominal pain
• Examine factors such as lifestyle, diet, stressors that directly affect health
• Broaden understanding of relationship between stress and infertility
• Develop skills to ease the process of infertility treatment

Research Demonstrates

• Infertile women are significantly more depressed than fertile women
• Infertile women have equivalent levels of anxiety and depression as women with cancer, heart disease or HIV status
• Depression can have a correlation with poor response rate in IVF treatment
• Participants in the program experienced decreased levels of depression, anger, and anxiety
• Women who had been trying to conceive for 1-2 years prior to beginning mind/body treatment experienced a 55% take home baby rate compared to a 20% rate in women receiving standard medical treatment alone

Clinical Visits, Costs and Insurance Coverage

• The infertility program will meet at the Life Center from 5:00 – 8:00 PM
• There will be an initial evaluation with the clinical counselor
• There will be 10 weekly 2 ½ hour session ( 3 of  these will include husbands/partners)

All of the sessions will be held on Thursday evenings with the exception of one Sunday session, which is for couples from 10:00AM – 4:00PM.)

• There will be a discharge session with the clinical counselor

In most cases, billable claims are submitted directly to your insurance carrier as a medical office visit. The first, the seventh and ninth sessions of the 10-week program will require self-payment. You will be responsible for your co pay at the remainder of the sessions. You will need to contact one of our financial coordinators Stephanie Brown at

455-1600, or Allison Fowler at 454-2219 and they will also schedule an initial evaluation counseling session with Cynthia Whitaker, LISW/CP. Your checks should be made payable to The Center for Women’s Medicine. Those checks will be collected at each weekly session by your counselor.

• There will be a one-time materials charge of $35.00 payable at the first session.
• For Session 1 you will have an out of pocket expense of $50.00; this is in addition to materials fee.
• Your insurance co pays will be due at Sessions 2, 3, 4, 5, 6, 7, 8, and 10.
• For Session 7, you will pay your co pay in addition to a $25.00 check made payable to

Ross Muller, LPC, the male therapist who will meet with the men’s group.

• For Session 9 there will be an out of pocket cost of  $140.00, which will pay for the massage therapists teaching the art of couples massage.

The initial evaluation should be scheduled with Cynthia Whitaker at The Center for Women’s Medicine (864-455-1600). The initial evaluation session must be scheduled prior to the 10-week program. The discharge session will also be with Ms. Whitaker and will be scheduled at the end of the 10-week program. In most cases, if your insurance provides mental health coverage, the charges will only involve your co pay.

 In the event where insurance reimbursement is not available, the patient will be responsible for the cost of the initial evaluation at $176.00, the discharge session at $114.00, as well as a fee of $70.00 for each weekly session.

Mind/Body Infertility Weekend Retreats

For those who live too far from the Greenville area or live out of state, weekend retreats for women and couples coping with infertility will be help periodically. The retreats will present most of the skills taught in the 10-week Mind/Body Approach and will be strictly self-pay. Call the facility for further information.

Who Would Benefit

• All women having difficulty conceiving, including those currently involved with IVF programs

For Further Information

The Infertility staff includes Cynthia K. Whitaker, LISW/CP, Director of Mind/Body Program,

Paul Miller, MD, Medical Director, Bruce Lessey, MD, and David Forstein, MD.

Department of Obstetrics and Gynecology

Reproductive Endocrinology & Infertility

890 W. Faris Road, Suite 470

Greenville, SC 29605

(864) 455-1600

When is enough, enough?

With advances in reproductive technologies it seems that there is no shortage of things we can do to (for) infertile couples trying to start or extend their family. Nothing seems to be out of reach anymore. We have an alphabet soup of procedures including IUI, HSGs, L/S and H/S, SOIUI, IVF, ICSI, GIFT, ZIFT, PGD, etc., etc. If a woman doesn’t have eggs, we can get some from someone else. If a man doesn’t have sperm, ditto. Testicular biopsy or epididymal aspiration with intracytoplasmic sperm injection (ICSI) has changed the outcomes for men with azospermia or after vasectomy. Women without a uterus can find a gestational carrier. Serious gene defects can be weeded out and eliminated from the gene pool of the next generation using preimplantation genetic diagnosis (PGD).  The number of things we can do is astounding, but so is the cost.

Living in SC, I’ve felt a reluctance on the part of certain couples to go to the extremes, even to IVF, when other plans don’t pan out. There are concerns about creating life that they won’t be able to nurture and protect. These couples may have the financial ability to make use of our latest miraculous cures, but choose not to go there for other more personal reasons. Even here concessions can be made and explanations given that can ameliorate concerns and provide avenues that are more acceptable, such as freezing oocytes (eggs) instead of fertilizing them with a sperm.

The second group that stops short of taking advantage of the most advanced techniques are those that don’t have health insurance, or have insurance without infertility benefits.  Financial capital, like emotional capital is not an infinite resource and boundaries should be discussed so that couples know when enough is enough. When all else fails, there is still adoption, which also can be very expensive.  Donor egg cycles continue to excalate in price as donors get more and more for donating their eggs. Keeping resources set aside  for this choice is an important consideration as well.

Finally, there are those that have done it all and still are not pregnant. Sometimes, these couples have skipped a step along the way, heading straight to IVF and IVF hasn’t worked. My first patient that I diagnosed with implantation failure and endometriosis had spent her $25K of insurance on 3 IVF but had never had a laparoscopy. She now has three beautiful children after laparoscopy found and treated her underlying problem and she was able to conceive naturally. Fast forward 20 years and its still happening (http://www.ghsumc.org/FertilityCenter/wilmas_story.htm). Even so, we see couples occasionally who baffle the experts and have no known reason for their infertility. They’ve submitted their bodies to all available tests and procedures and still don’t conceive. Nothing seems to work. There comes a time in the relationship when I know its time to stop. Being an optimist, I find it hard to admit defeat. Still, it is our duty to our patients to recognize in them when it is time to stop trying or to take a break. Sometimes they agree and sometimes they don’t. A second opinion is always OK to recommend as well.

I hope that all patients with infertility seeing specialists can maintain some control over their journey through infertility and have the type of relationship with their doctor where they can have this discussion, if necessary. Not everyone gets pregnant but everyone should be allowed to stop, even when enough is not  enough.

Polycystic ovary syndrome (PCOS) Part I

PCOS is the most common endocrinopathy in reproductive aged women, affecting 8 to 10% of the population. While present in both lean and overweight patients, obesity is a common feature of PCOS.  Difficulty losing weight is a common complaint as well as the characteristic evidence of too much male hormone (androgens) and ovulatory dysfunction. Finally, the appearance of the ovary on ultrasound with many small follicular cysts filling the ovarian cortex  gives PCOS its name. (The picture above is an exploding supernova star but reminded me of the PCOS ovary). Infertility is also a common feature of PCOS which is primarily due to lack of ovulation, but reproductive outcomes can be poor, even once ovulation is restored.

PCOS usually develops after puberty, but serum markers are being studied that predict the onset of PCOS even prior to menarche.  Many women with PCOS report always having had irregular cycles. The menstrual “cycles” are frequently unpredictable with heavy and prolonged bleeding coming at irregular intervals. Some women go years without a period and because of the convenience often do not seek medical help. Such a prolonged state of anovulation (no ovulation) can eventually lead to endometrial polyps, hyperplasia and even endometrial cancer. The endometrium of women with PCOS is different from normal women, expressing more steroid receptors for estrogen, androgen and steroid receptor coactivators, all resulting in a hypersensitivity to estrogen and androgens. Normal proteins involved with implantation may not be expressed in PCOS endometrium.

Hirsutism and acne are common complaints of the PCOS patient. Young PCOS patients that I see often lack their feminine persona and can have redistribution of body fat and muscle. Appropriate treatment, including medications to block the androgen receptor, oral contraception to reduce ovarian function and androgen production, and diet and excercise can transform these young ladies back to their desired state, often to the great relief of their parents. Aggressive behavior and social difficulties along with depression can afflict young PCOS women.  Women initiating treatment for hirsutism can expect to see results lag 3 to 6 months behind the start of the medications but ultimately the results are usually gratifying.

Androgens and anovulation go hand-in-hand. People speak of a “vicious cycle” that is difficult to break. Elevations in insulin may be an initiating event, stemming from insulin resistance (a pre-diabetic trait).  Overproduction of insulin leads to stimulation of androgen production from the ovarian stroma. The high circulating androgens stimulate hair growth in the skin, but also change the pituitary response to ovarian steroids making the pituitary produce too much LH (luteinizing hormone) compared to FSH (follicle stimulating hormone). LH, in turn produces more androgen from the ovary, thus completing the vicious cycle. The androgens also affect the liver, which produces less sex hormone binding globulin (SHBG), so more of the ovarian androgens are available to act on target tissues.  The high LH and androgen and lack of normal FSH leads to anovulation leading to a lack of progesterone, essential hormone for endometrial health.  Thus, the woman becomes stuck in a perpetual proliferative phase which leads to endometrial build up, bleeding and infertility.

Which comes first, androgens or insulin? If you give insulin to a woman with PCOS the androgens go up. Administration of glucose makes both insulin and androgen levels rise. Weight loss will decrease androgens and insulin, and experimental reduction of insulin will lower androgen levels. Correction of androgen levels does not correct the high insulin levels. So it appears that hyperinsulinemia is the primary cause of PCOS in many women.

If its not PCOS, what is it? Physicians diagnose PCOS using an agreed set of criteria, including ovulatory dysfunction, hyperandrogenism and polycystic ovaries. Two make the diagnosis, but other conditions need to be ruled out, including 21 hydroxylase deficiency, Cushings disease, hypothyroidism and hyperprolactinemia.  PCOS can go undiagnosed for years as well. Insulin resistance and a family history of diabetes are commonly found in the PCOS patient. Treatment now with medication and exercise can reverse many of the features of PCOS.

Treatment depends on what the patients wants. For pregnancy, getting a healthy lifestyle before getting pregnant is always advisable. Drugs to reduce the insulin resistance can be helpful, like metformin, although the jury is still out regarding it’s true benefit. For some, metformin helps with weight loss; for others it just causes indigestion. Fertility drugs like clomiphene citrate can be used successfully to induce ovulation. Femara (Letrozole) is also a very useful drug, but it needs to be used carefully to avoid taking it during pregnancy.  Ovulation agents that are injectable, like Gonal-F and other gonadotropins are useful but powerful and can lead to multiple pregnancies. The ovaries of women with PCOS make many more follicles and eggs than the normal ovary so care needs to be taken when using these powerful drugs.

If a woman does not desire pregnancy, oral contraception  (OCPs) and spironolactone (an anti-androgen) is a great combination to reduce the side effects and symptoms of the syndrome. Women with PCOS benefit by having less androgens, more SHBG, and progestins that prevent endometrial build up.  Another choice is the Mirena IUD, to prevent the endometrial changes but avoid the systemic effects of OCPs. Women can also opt just to take intermittent progesterone (Prometrium) every other month to make sure cycles occur on a regular and predictable basis and avoid endometrial cancer.

There are serious consequences to the woman with PCOS. Heart disease and stroke are more common in women with PCOS, especially later in life. Bad cholesterol levels may be part of the syndrome with elevated cholesterol and reduced HDL. C-reactive protein, associated with heart disease and atherosclerosis is sometimes present in the blood and combined with hypertension, obesity, sedentary lifestyle and diabetes can lead to premature death from heart attack and stroke. A large percentage of PCOS women have metabolic syndrome, a serious condition that puts them at risk for early heart disease and stroke. Endometrial cancer is more common in PCOS women.

Even after pregnancy is established, women with PCOS have problems. They don’t keep their pregnancies as well as normal women, having more miscarriages than the general population. Women with PCOS may have more endometriosis than normal women due to their frequent and heavy menses and lack of progesterone.  Preeclampsia (elevated blood pressure and early delivery) and gestational diabetes are more common as well as admissions to the neonatal intensive care nursery. Getting weight under control, changing diet and excercising prior to pregnancy will go a long way to correcting these risks.

PCOS can be a life-long challenge for those affected. Support groups for PCOS have not been as accessible as those for infertility or endometriosis, for example. Today’s dietary choices that are high in processed foods and carbohydrates may be driving more women into PCOS due to obesity and insulin resistance. Finding the right health care provider can be one key to success and finding a support group to motivate and encourage the type of lifestyle changes that are required to truly succeed. And while fertility is easier to restore than in days past, the challenges faced in pregnancy suggest that women may wish to delay pregnancy until a time when they are healthier to provide the best possible environment for the baby.

References

1.            Homburg R. Polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2007 Sep 4.

2.            Apparao KB, Lovely LP, Gui Y, Lininger RA, Lessey BA. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol Reprod. 2002 Feb;66(2):297-304.

3.            Arumugam K, Mahmood TA, Kong YF. The association of anovulation and endometriosis in the infertile female. AustNZJObstetGynaecol. 1989;29:350.

4.            Dor J, Itzkowic DJ, Mashiach S, Lunenfeld B, Serr DM. Cumulative conception rates following gonadotropin therapy. Am J Obstet Gynecol. 1980;136:102-5.

5.            Gregory CW, Wilson EM, Apparao KB, Lininger RA, Meyer WR, Kowalik A, et al. Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium. J Clin Endocrinol Metab. 2002 Jun;87(6):2960-6.

6.            Liddell HS, Sowden K, Farquhar CM. Recurrent miscarriage: screening for polycystic ovaries and subsequent pregnancy outcome. Aust N Z J Obstet Gynaecol. 1997 Nov;37(4):402-6.

7.            Donaghay M, Lessey BA. Uterine receptivity: alterations associated with benign gynecological disease. Semin Reprod Med. 2007 Nov;25(6):461-75.

8.            Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update. 2006 Nov-Dec;12(6):673-83.

Meet our people

Fertility Center of the Carolinas has maintained a stable group of highly motivated, professionals  that stand behind our high success rates. Our patients love the way our nurses call them back immediately and visitors to FCC can sense how well we function as a team. We thought it would be nice to show you who we are.

Our nurses

IVF nurses: Noreen Denham and Lynn DeGraf

REI nurses: Meagan Vanzant, Amy Sakofsky, Katy Johnson, Donna Martin, Leslea Greenwood, Susan Kay

Our ART Staff: William Boone PhD, H. Lee Higdon, III PhD

Jane Johnson, Julia Butler, Angela Houwing

Our Physicians:

Bruce A. Lessey MD, PhD

Paul B. Miller, MD

David A. Forstein DO

Financial Counselor: Stephanie Brown

Front Desk:  Joann Sammons, Nicole Watkins, Gail Featherstone and Amy Butler

Clinical Research Nurses : Crystal Prader, Barb Strickland, Cheryl Myers, Allison Moore, Karen Nichols

Society for Gynecologic Investigation – Day 3

This is the most scientific meeting that OBGYN’s go to, in my opinion. This meeting in Orlando  emphasized Epigenetics and Reproduction. On this last day, there are some important presentations that I will summarize.

From the posters, a very important study that develops (for the first time) a urine test for endometriosis. Tokushige et al., with Ian Frasier from Australia found that cytokeratin 19 is highly upregulated in the urine of women with endometriosis with a specificity and sensitivity of close to 90 to 95%. This is an very important discovery if it pans out, since surgery is the only available test for endometriosis at the present time and this disease is often missed, especially in adolescent women with pelvic pain.

Nerve fibers in endometriomas (endometriosis in the ovaries) was reported by the same investigators. It is often difficult to understand why endometriosis causes so much pain; the ingrowth of nerve fibers into the ovary surrounding the endometrial cysts could explain why.

The active ingredient in red wine, resveratrol, inhibits stromal cell proliferation in a mouse model of endometriosis suggesting a benefit for women. This came from the Vanderbilt group including Kevin Osteen and Kaylon Bruner Tran. We reported similar findings and won the Donald F. Richardson award at the ACOG meeting last year for similar experiments with Sheri Amaya doing that work.

A study of LibiGel, a testosterone gel, showed a low cardiovascular risk in post-menopausal women. This first long term study by Snabes et al, is in keeping with other reports in men that low testosterone is associated with increased risk of heart attack. Safety studies in women are encouraging and may help this product become approved for use in women.

Selective progesterone receptor modulators, including Proellex and CDB4124 were shown to limit the growth of fibroids. Two abstracts, one from Duke (Phyllis Leppart) and one from Chicago (Serdar Bulun’s group) show contradictory findings regarding a medical treatment of fibroids.

Lower serum Vitamin D appears to be a risk factor for uterine fibroids in African-american women according to a study by Halder et al., from Galveston, TX. The same group had an oral presentation today showing that adding Vit D to the diet of special Eker rats reduced growth of fibroids in this animal model.

Predicting preterm birth would save lives and improve outcomes by allowing early intervention. This study by D’Addio et al, from University of Pennsylvania, reported on biomarkers of early white blood cell activation and cellular adhesion molecules.

Bisphenol A (BPA) a component of plastic, is higher in women with infertility, as reported by Aldad et al., (Hugh Taylor’s group at Yale). This molecule acts as an estrogen and may contribute to endometriosis.

Unexplained infertility does not appear to mean poor egg quality, as reported by Droga et al, from Cincinnati OH. This goes along with what we find, that most unexplained infertility is due to implantation defects due to endometriosis.

Polycystic ovary syndrome and early onset preeclampsia are at risk for future cardiovascular problems, suggesting these diagnoses should trigger lifestyle modifications to avoid future heart attack or stroke, reported by Veltman et al from the Netherlands.