Geoffrey Sher, M.D.

Educated in South Africa, Dr. Sher was a Senior Specialist of Obstetrics and Gynecology at the prestigious Groote Schuur Hospital (the teaching institution for the University of Cape Town), where the world's first human heart transplant was performed. In 1975, he was recruited by the University of North Carolina in Chapel Hill to assume a faculty position in the Department of Obstetrics and Gynecology. In 1979, Dr. Sher entered private practice in Nevada where he is currently a Clinical Professor of Obstetrics and Gynecology at the University of Nevada School of Medicine. In 1982, Dr. Patrick Steptoe, the father of In vitro Fertilization (IVF), afforded Dr. Sher an opportunity to study under him at Bourn Hall in England. Dr Sher returned to the United States and in January 1983 opened the nation's first private, non-university based IVF center (the fourth IVF program in the USA), in Reno, Nevada. He is Board Certified in Obstetrics and Gynecology in South Africa, England and in the United States and also has Sub-specialty Board Certification in Maternal-Fetal Medicine.

Between 1987 and 1998, Dr. Sher opened the California based Pacific Fertility Medical Centers (PFMC) with three locations. During his tenure with PFMC, Dr. Sher was largely responsible for the Group's emergence as one of the leading IVF programs in the nation. In ten (10) years he propelled PFMC into the forefront of clinical performance and research, introducing several major medical break-throughs that impacted positively on the treatment of infertility. In 1990 Dr. Sher was the first to point to the fact that ultrasound evaluation of the uterine lining prior to IVF, allows for prediction as to the likelihood of a subsequent pregnancy. In 2000 he demonstrated that the administration of Sildenafil (Viagra) to women with poor endometrial linings, improves uterine blood flow and enhances hormonal thickening. In the field of reproductive immunology, Dr Sher was the first to link immunologic problems causally, to female-related resistant infertility and repeated IVF failure, introducing immunotherapies that have virtually doubled the IVF birthrates in such cases.

In 1995, Dr. Sher and his team introduced a novel consumer-friendly concept in fee structuring for IVF. This so called Outcome-Based Pricing (OBP)-arrangement granted eligible patients a 70-100% refund of medical fees, if they did not have a successful outcome after IVF treatment. In the absence of IVF insurance coverage, this risk- sharing financial arrangement was welcomed by IVF patients across the board, but was strongly criticized by almost all IVF physicians who felt that widespread introduction of such an arrangement would place them at financial risk. After waging a relentless and often single-handed crusade, Dr. Sher was successful in getting this plan accepted by SART, the IVF medical governing body, as well as by the IVF medical community. Currently, more than 50 of an estimated 350 IVF programs in the nation offer it as an option, in one form or another, to their patients.

Dr Sher is a strong proponent of accountability on the part of IVF programs for the success rates they report to consumers, favoring the establishment of an accreditation process for all centers that provide IVF and related services. He believes that in order to render IVF treatment affordable to all Americans, regardless of their socioeconomic status government should mandate insurance coverage for couples undergoing IVF through providers who meet well defined, validated outcome-based performance standards.

Dr. Sher was a founding Board Member of SART. He has more than 200 accredited scientific publications and abstracts to his credit and has co-authored two consumer-oriented medical books; "Your Pregnancy," published by Simon and Schuster in the 1980's and "In vitro Fertilization, the A.R.T. of Making Babies", published by Facts on File. The latter is currently one of the most widely read consumer books on the subject of IVF, in the USA. "In vitro..." was written to assist infertile couples in evaluating their options with regard to the various advanced fertility procedures.

In 1998, Dr. Sher separated from PFMC to found the Sher Institute for Reproductive Medicine (SIRM), a state-of-the-art facility that offers advanced fertility treatment and research. SIRM programs are located in programs in: Las Vegas, Los Angeles, Sacramento, St. Louis, Central IL, Chicago and soon to be in New York City (Spring 2004).

Dr Sher has been influential in the births of more than 6,000 of an estimated 100,000 IVF babies born in the United States, to date.

Important links:
  > Basic Comprehensive General Infertility Work-up
  > The influence of age and the severity of endometriosis on fertility treatment options
  > Male factor infertility

Infertility is generally defined as the inability to conceive after a year of unprotected intercourse in women under 35, or after six months in women 35 or over, or the inability to carry a pregnancy to term. There are a variety of conditions and diagnosed problems such as anovulation, tubal blockage, low sperm count, endometriosis and immunological problems that may affect the ability to conceive. Unfortunately, infertility is a common problem affecting 15 to 20% of couples, some of which are members of our StorkNet community.

We are very proud to present our guest, Geoffrey Sher, M.D. Please take a moment to read his bio in the left column. Member questions and Dr. Sher's answers follow.

Stephanie: I have been diagnosed with re-occurring Complex Hyperplasia without atypia. It will show up, I'll do progesterone treatments and then it's gone. I'm wondering if Hyperplasia plays any roll in TTC. Is it possible for me to get pregnant and then carry to term? Thank you!

Dr. Sher: It can interfere with implantation but the bigger issue is to decide whether this is a premalignant form of adebnomatous hyperplasia and if it is safe to try and conceive.

preggowanttobe: Does an underactive thyroid cause infertility?

Dr. Sher: The immunologic cause can interfere with implantation.

Patti: I had a laparoscopy performed to remove severe scaring from an appendix in order to conceive my first child by clomid and IUI. I have been trying to have a second child with no success, is it possible the corrective surgery done 26 months ago be voided by the scar tissue reforming? I have low count progesterone too.

Dr. Sher: Patti, this is most likely attributable to peritubal adhesions.

Jessica: I delivered my baby early at 35 1/2 weeks. The first thing that happened before I felt contractions was that my water broke, and I ended up with a C-Section because of a partial placenta previa that was just barely in the way. I know for sure that my dates were correct. My baby was fine... she had no problems and weighed 5 pounds 12 ounces.

I am aware that the cause for her early birth will never be known. My provider has told me that in my next pregnancy it likely will not happen again, and that they won't do anything differently to monitor me.

My question for you is: Is there ANYTHING at all that they can do? My main fear is that my cervix was dilating unbeknownst to me, and that is what caused my water to break. If that was the case, I am afraid that my cervix is weak and that I will deliver even earlier next time. Because I was not quite 36 weeks, I never had my cervix checked before my water broke, and it was never checked at the hospital because I warned them of my previa, which was verified by ultrasound that day. So I have no way of knowing this.

How would you handle my next pregnancy if I were your patient? Would you run any tests, etc.? Thanks in advance for your opinions and advice. Jessica

Dr. Sher: The important thing is to exclude cervical incompetence because this is the most common cause of "passive cervical dilatation." The diagnosis of cervical incompetence is usually strongly suspected on the basis of the following history:

• Recurrent second trimester miscarriages or premature births, in which both bleeding and painful contractions are minimal and the process is completed rapidly
• Few prior warning symptoms or signs
• Where the bag of bulging membranes often breaks followed by a sudden gush of water per vagina that heralds the onset of miscarriage or premature birth
• A physician inadvertently detects a partially dilated and shortened cervix with routine pelvic examination performed in the mid-trimester of pregnancy.

Once the diagnosis of cervical incompetence is suspected, it can and indeed should be confirmed on the basis of one or more of the following:

1. A hysterosalpingogram (HSG-dye x-ray test) to evaluate for a well demarcated anatomical transition from endocervical canal to the uterine cavity (without evidence of "funneling") and to detect a deformity (congenital or acquired) of the uterus, that can also lead to mid-trimester miscarriage and premature birth.

2. A vaginal ultrasound examination to measure the length of the cervical canal (it should measure more than 2.5 cm) and to exclude pathology of uterine wall(e.g.; fibroids)

3. A diagnostic hysteroscopy to carefully evaluate uterine scarring, fibroid tumors protruding into or distorting the uterine cavity and for the congenital deformities such as a uterine septum.

Treatment:

Cervical incompetence is routinely treated by the placement of a temporary circumferential non-absorbable tape or suture around the neck of the cervix at the 12th-14th week of pregnancy per vagina ("McDonald cerclage"). The advantage of this approach is that the cerclage can readily be removed a week or two before delivery, thereby allowing a subsequent spontaneous vaginal birth to take place The disadvantage of placing a McDonald cerclage is the ever present risk of puncturing the fetal membranes while inserting the stitch. This sometimes prompts the overcautious OB/GYN to place the stitch well below the cervical-uterine junction, thereby increasing the likelihood that it will slip or tear and thus fail to prevent cervical shortening and dilatation.

After undergoing a preliminary assessment to confirm the diagnosis of cervical incompetence, non-pregnant women in whom a McDonald cerclage has failed, should be considered for the elective placement of a permanent, non-absorbable cerclage "Shirodkar suture," prior to undertaking another pregnancy. In fact, we believe that this should be considered as the primary (initial) approach. The reason is that in the absence of a pregnancy, it is possible, through careful surgical dissection, to ensure the correct placement of the suture (usually a double strand of #2 nylon is used), and in so doing, maximize its effectiveness. The one relative disadvantage to this approach is that the completely buried Shirodkar suture, is sometimes not amenable to removable before delivery. Accordingly, such women would require delivery by Cesarean section. Notwithstanding this, we hold that a Cesarean delivery, is a relatively small price for a woman who has usually experienced recurrent pregnancy loss, and/or repeated premature deliveries, to pay to have a healthy baby.

Paula: How will Gonal-f/Pregnyl affect thyroid function? Also, has it been determined what TSH level works best for achieving pregnancy?

I'm 40 year old with Hashimoto's diagnosed Nov '02. Currently taking Armour thyroid. TSH level spring 2003 was 1.36/1.68. Early Dec '03, TSH was 2.46. I began Gonal-f (150iu) 12.26.03 and completed course in eight days. TSH increased to 4.53 on 1.8.04. My general MD has increased my Armour to 90mg/day. As you know, the injectables are quite costly and I want to maximize my chances during use. Thank you.

Dr. Sher: The gonadotropins will not affect Thyroid function. However, it is important to keep your hypothyroidism under control by adequate hormone replacement, as I am sure you are doing. Hashimoto's disease is associated with the presence of antithyroid antibodies. About 50% of women who have autoantibodies to their own thyroid tissues (antithyroglobulin and/or antimicrosomal antibodies) regardless of whether or not there are clinical signs or symptoms of reduced thyroid hormone activity (hypothyroidism) have activated Natural Killer cells (NKa+ and/or activated T-cells in their blood. Such women often present with reproductive failure manifesting as infertility, recurrent IUI and IVF failure or repeated pregnancy loss. The antithyroid antibodies (antimicrosomal and/or antithyroglobulin antibodies) do not cause the problem. They act as markers pointing to an underlying immunologic implantation problem that occurs when NKa or T-cell activation is present. Here, as soon as the embryo starts to burrow into the uterine wall, "toxins" are produced (locally) that impair implantation. In some cases, the pregnancy is lost before a blood test can detect it, while in other cases a miscarriage occurs. (Some pregnancies escape the "toxic gauntlet" and proceed.)

One of the most significant hints that a non symptomatic woman might have antithyroid antibodies is a family history of hypothyroidism (under performance of the thyroid gland requiring thyroid hormone therapy).

We were among the first to demonstrate that women who have reproductive failure associated with antithyroid antibodies and NKa+/T-cell activation can have successful IVF outcomes following administration of intravenous gammaglobulin (IVIG). Women who are antithyroid antibody positive who do NOT have NKa+ and or T-cell activation do not require or benefit from IVIG therapy.

Lori Ann: I have been diagnosed with immunological problems. I have been trying to have a baby for the past four years (after a tubal reversal). I have gotten pregnant four times (last time was 1 1/2 years ago) but cannot carry past 7.5 weeks. I have elevated Antinuclear, AntiOvarian and Antiphospholipid antibodies.

My RE now has me taking prednisone, 5mg cd 3 till trigger shot then 60 mg for 4 days, then 10 mg's till pregnancy test, if positive then 20 mgs, if negative then stop. (This is along with my baby aspirin, folic acid, Follistim and IUI treatment). My question is, does this really work? What kind of chances does a 32 year old, with children aged 12 and 14 who has lost her last 4 pregnancies have of carrying a healthy baby to term? Thank you for your input.

Dr. Sher: National statistics indicate that only one out of four women under the age of 40 achieves a live birth following treatment with in vitro fertilization IVF). While most IVF laboratories report a similar egg fertilization rate (I.e., 60-70%), program-to-program IVF birth rates still range from below 10% to greater than 50% per embryo transfer. To improve IVF success rates, the cause(s) of this discrepancy, must be recognized and addressed.

Compelling evidence suggests that an abnormally functioning maternal immune system often leads to poor reproductive performance (i.e., IVF failure, recurrent abortion, poor intrauterine growth and even fetal and that identification and selective immunotherapy results in a significant improvement in IVF birth rates, intrauterine development and fetal survival.

Almost across the board physicians who provide services in the field of Assisted Reproductive Technology (ART) tend to attribute recurrent unexplained treatment failures to sub-optimal embryo quality and then advise such patients that the only way to improve their subsequent chance of a successful outcome, is by changing clinical and laboratory protocols involved in ovarian stimulation, gamete and embryo preparation and/or the transfer of gametes or embryos to the woman's reproductive tract. Such logic fails to take into account the fact that it is "implantation failure" rather than poor egg/embryo number or quality that is often the root of the problem. A rational approach to subsequent treatment requires that a clear distinction be made between those factors that cause "true infertility" (defined the absence of normal fertilization and/or embryogenesis), and those that lead to "failed implantation," (namely; immunologic rejection of the embryo, local inflammation and pathology involving the uterine cavity). Only treatment directed at an identifiable probable cause of prior ART failure, can justify providing patients with renewed hope of success in a subsequent cycle of ART treatment.

The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblast), which later becomes the placenta, begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a "cross talk" through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus is able to foster the embryo's successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby. In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

Considering its importance, it is not surprising that failure of proper function of this immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes: anti-phospholipid antibodies (APA), antithyroid antibodies (ATA), and, perhaps most importantly, activated natural killer cells (NKa). Presently, these immunologic markers can be adequately measured by only a few (less than a half dozen) highly specialized reproductive immunology laboratories in the United States, from patient blood samples.

Antiphospholipid Antibodies (APA)

A large body of literature has confirmed that patients who experience repeat IVF failures often have increased levels of circulating APAs. Compelling evidence has also demonstrated that up to 50% of women with pelvic endometriosis and unexplained infertility harbor APAs in their blood. Despite this information, the role of APAs in reproductive outcome is still controversial. In 1995, we proposed that in cases of non-male factor infertility, women who test positive for APAs be treated with mini-dose heparin and low-dose aspirin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of trophoblast cells, thus enhancing their development. Aspirin, by inhibiting platelets from adhering to the early trophoblast, might prevent clot formation in the early utero-placental vasculature. We subsequently demonstrated that heparin/aspirin therapy improved IVF outcome only for women whose APA testing was positive for antibodies other than those directed against two specific phospholipids, i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS), and that only women who had IgG/IgM-related anti-PE or anti-PS antibodies experienced a significant improvement in IVF implantation and birth rates when IVIG therapy, instead of heparin/aspirin, was initiated more than one week prior to embryo transfer.

Notwithstanding the above, the following recent observations suggest that APA's rather than being causally linked to implantation failure, might serve to identify a population at inordinate risk of implantation failure and that NKa, through the unregulated release of embryo toxins, are in fact the real culprits.

• The presence of APAs in male factor cases appears to bear no relationship to IVF outcome
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with IVIG.
• More than 75% of APA+ women who have increased NK cell activity also harbor aPE and/or aPS antibodies

Natural Killer Cell cytotoxicity

After ovulation and during early pregnancy, NK cells comprise more than 80% of the white blood cell population seen in the uterine lining. NK cells produce a variety of local hormones known as TH-1 cytokines. Uncontrolled, excessive release of TH-1 cytokines is highly toxic to the trophoblast and endometrial cells, leading to their programmed death (apoptosis) and, subsequently to failed implantation. In the following situations these NK cells (and also T-cells) can become abnormally activated (Nka+), and thereby over-produce these TH-1 cytokines:

In female patients that have both pelvic disease (especially endometriosis--regardless of severity) and abnormal APA testing

• In about half of the cases where the woman forms antibodies
• Against her own thyroid gland (i.e., antithyroid antibodies.)

Activated NK cells (NKa) can spill over from the uterine lining into the peripheral blood where their toxicity can be measured. IVIG therapy, initiated more than 1 week prior to embryo transfer, can subdue activated NK cells, thereby reducing the risk of implantation failure.

Antithyroid Antibodies (ATA)

A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility). We have previously reported on the ability to double IVF birth rates through the administration of IVIG to ATA+ patients. IVIG therapy should be initiated prior to initiation of treatment with fertility drugs, and should be administered one more time after pregnancy is diagnosed. About 50% of women who harbor ATAs also test Nka-positive The risk of implantation failure in ATA+ women appears to be confined to cases where ATAs coexist with Nka. IVIG therapy should be confined to such cases.

TREATMENT OPTIONS:

Heparin/Aspirin
There is compelling evidence that subcutaneous heparin (administration at a dosage of 5000 U twice daily to women undergoing IVF for female causes of infertility who test positive for APAs, but negative for NK activation), significantly improves IVF birth rates. Heparin administration is withheld on the day of egg retrieval until immediately following embryo transfer, whereupon it is recommenced and continued until the 8th week of pregnancy. Heparin is thought to act by repelling APAs from the surface of the trophoblast (early "root system" of the embryo). Provided that platelet counts are normal, are checked on a regular basis and heparin is withheld on the day of egg retrieval, its administration is virtually risk-free.

The administration of aspirin in combination with heparin, offers no benefit over treatment with heparin alone, for the management IVF patients with immunologic implantation failure. As such, with the notable exceptions of women with primary APA-related autoimmune diseases (e.g., lupus erythematosis, rheumatoid arthritis, etc.) and cases associated with recurrent pregnancy loss, we no longer prescribe aspirin to women undergoing treatment for reproductive failure.

Intravenous Immunoglobulin G (IVIG)
IVIG is a sterile protein preparation derived from human blood. Every effort has been made to ensure that it is free of bacterial and viral contamination. There are basically three ways in which IVIG may offset or counter the anti-implantation effects associated with reproductive immunologic deficiencies.

First, it is a potent suppressor of activated (toxic) NK cells (see above). Second, it contains anti-idiotype antibodies that combat the effects of harmful antibodies, thereby protecting the embryo/fetus from rejection. Third, IVIG deactivates activated T-cells and polyclonal B-cells that may be involved in poor reproductive performance associated with the presence of antithyroid antibodies (Sher, et al, American Journal of Reproductive Immunology, 1998). Unfortunately, IVIG has had some undeserved bad press. Since it is a blood derivative, the thought of administering it in an era where HIV is rampant, is frightening to most; but consider the following: The IVIG products available in the United States and the United Kingdom, according to the manufacturers, have not resulted in a single HIV viral transmission in more than two million administrations. Moreover, IVIG is derived from the very same blood pool used for transfusion purposes, and since millions of units of blood have been administered in the United States over the last 7 years without any reports of HIV transmission, and since the product is thoroughly tested in this country, it is safe to say that US produced IVIG is untainted by viral contamination. IVIG therapy for increased NK activity/APA positivity is initiated at least 10 days prior to embryo transfer, and for ATA positivity is initiated 7 to 14 days prior to the initiation of gonadotropin therapy. The infusion is repeated once pregnancy is diagnosed. We do not recommend repeating IVIG administration subsequently during the pregnancy.

Corticosteroid Therapy (Prednisone, Prenisilone and Dexamethazone)
Steroid therapy is a mainstay of most IVF programs. Some programs use daily oral methyl prednisilone while others prescribe oral Dexamethazone commencing about ten days prior to initiating ovarian stimulation with gonadotropins, and continuing until the diagnosis of pregnancy, whereupon, in the event of a negative test (Beta HCG or ultrasound), the dosage is tapered over a period of seven to ten days, and then discontinued. Pregnant patients continue treatment through the first trimester. Steroids are believed to act by inhibiting the cellular immune response.

The selective use of immunotherapy as outlined above has, on numerous occasions, has enabled us to achieve successful pregnancies in-patients who had previously suffered repeated IVF failures (4 or more). Many such patients had previously been advised not to try again with their own eggs. We are able to report IVF births occurring in more than a dozen cases, after more than ten (10) prior IVF failures. One such case involved a 42-year-old woman who had a baby (using her own eggs) following 22 consecutive prior IVF failures. It is indisputable that such results would not have been achieved without access to selective immunotherapy. In a recent study, we were able to show that Nka+ women who do not receive IVIG/heparin therapy have a 10 times lower chance of successful IVF.

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Endometriosis (about 30% of cases are associated with increased Nka+ activity requiring IVIG/heparin)
• Unexplained infertility
• Infertility following recurrent miscarriage
• A positive personal or family history of autoimmune disorders such as Rheumatoid arthritis, Lupus erythematosis and hypothyroidism (Hashimoto's disease) which is rather common in women.

The controversy relating to the use of selective immunotherapy in IVF has been spawned by issues other than those related to science. Political one upmanship, the competitive nature of the ART field and lack of understanding with regard to the complex issue of reproductive immunology, has led a lot of misinformation. This issue will be laid to rest by a large randomized and controlled study we have been able to undertake due to a >1 million dollar grant given to us by a large pharmaceutical company.

CONCLUSION:

The immunologic contribution to successful reproduction is a complex puzzle that is still being assembled one piece at a time. Clear evidence now exists to support the view that women with non-male factor related infertility, who harbor IgG/IgM, APAs, can selectively benefit from immunotherapy with heparin or IVIG. Rather than being causally linked to implantation failure, APAs, probably serve as markers that point to a population at risk and that this risk is greatly increased when such antibodies are specifically directed against PE and/or PS are present and/or when Nka are detected. APA positive/Nka negative women should be treated with heparin, while all Nka positive women, regardless of their APA/ATA status should receive IVIG.

Gina: I am a 35 year old woman who has been trying to conceive my second baby for a year. I have had two miscarriages, one before my son and one after. My TSH was a bit high (one at 6.4 and the other 4.5) at the time of my miscarriages. My TSH at the time of my only successful pregnancy was .06. Did my TSH play a factor here? What is your opinion on TSH levels and successful pregnancy outcomes?

Dr. Sher: Gina, raised TSH levels may point to Thyroid dysfunction . . . either hyperthyroidism or Hypothyroidism. Both may have an immunologic basis and increase the risk of immunologic implantation failure. Please read my responses above. Best of luck.

Kimber1773: Is there any link between IF tx and pre-eclampsia? I had a successful IUI with a vanishing twin. Horrible morning sickness and I threw up the whole pregnancy. I started getting Pre-eclampsia symptoms at 24 weeks and delivered at 26 weeks 3 days with eclampsia, HELLP, Kidney Failure, Liver Failure and a Grand Mail seizure. I just wondered if there have been any links to IF tx with my problems. Thank you.

Dr. Sher: Possibly so, Limber, because we now are beginning to see a link between pregnancy induced complications such as pre-eclampsia and abruptio placentae and perhaps hyperemesis on the one hand and immunologic implantation problems and thrombophylia on the other.

Thrombophylia is the inherited tendency to develop blood clots too easily. Thrombophylias are due either the presence of too much of certain blood-clotting factors or too little of anti-clotting proteins in the blood. As many as one in five people in the United States has a thrombophylia.

Pregnant women in general are more likely than non-pregnant women to develop a venous thrombotic episode (VT), or development of a blood clot in a vein. This is due to normal pregnancy-related changes in blood clotting in order to limit blood loss during labor and delivery. And pregnant women with a thrombophylia are at a higher risk than other pregnant women of developing a VTE. Studies suggest that more than half of pregnant women who develop a VTE have an underlying thrombophylia.

All pregnant women who have had a blood clot should be offered testing for hereditary thrombophylias. In addition, women with a family history of blood clots, pulmonary embolism (blood clot in the lung), or strokes that occurred prior to age 60; or a history of pregnancy complications, including stillbirth, early or severe pre-eclampsia, placental abruption, or poor fetal growth due to undetermined causes may be considered for testing.

Some pregnant women with thrombophylia are treated with one or more daily injections of low dose heparin, a blood-thinning drug, which does not cross the placenta and is safe for the baby. In some cases, physicians may recommend low doses of aspirin along with heparin. Low-dose aspirin with the B vitamins folic acid, B6 and B12 can be given to women who have one of the milder thrombophylias and a history of pregnancy complications, but not a history of blood clots.

Not all pregnant women with a thrombophilia need heparin treatment during pregnancy.. Regular heparin can be supplanted with a newer form of heparin, called low-molecular-weight heparin, that appears to pose a lower risk of side effects such as bone loss and can be injected once instead of twice daily (as with regular heparin) and which reduces the risk of local bruising, significantly.

Generally, treatment is not recommended for most pregnant women with one of the less severe thrombophilias (such as factor V Leiden or prothrombin mutation) and no history of blood clots or pregnancy complications. This is because the risk of blood clots or pregnancy complications due to thrombophilia appears to be less than 1 percent in these women. However, treatment may be recommended for about six weeks after birth, when the risk of blood clots may be highest, if the woman has a strong family history of blood clots or if she has had a cesarean delivery.

Heparin treatment is recommended throughout pregnancy and the postpartum period for women who have one of the more severe thrombophylias ( e.g MTHFR genetic mutations and factor II G20210A) , even if they have not experienced any blood clots or pregnancy complications. Women with a thrombophilia (regardless of severity) who have a past history of blood clots are usually treated with heparin during pregnancy and the postpartum period. Warfarin (also a blood-thinning drug) may be used safely in addition to, or instead of, heparin in the post-partum period and during breast feeding. However, it is not recommended during pregnancy because it can cause birth defects.

As yet, no proven cause and effect relationship has been shown to exist between thrombophilia on the one hand and failed embryo implantation, poor IVF outcome, and/or early recurrent miscarriages, on the other.

Jane: I have been charting for 8 months now and my LP is never any longer than 10 days. That is the average. What can I do to lengthen this in order to sustain a pregnancy? Here are my charts for your perusal. http://circles2.fertilityfriend.com/home/downunderjane/ Thank you very much.

Dr. Sher: Jane, you could have luteal phase defect.

Following ovulation, the remainder of the dominant follicle transforms itself into a structure called the Corpus Luteum (CL) which produces progesterone. The purpose of progesterone is to prepare the uterus to accept and support an early pregnancy until it is able to sustain itself at around 8-10 weeks of gestation.

The life span of the CL is predetermined to be 12-13 days, unless rescued by a signal from the early pregnancy. If no pregnancy occurs, the CL stops making progesterone and menses ensues 1-2 days later. For most women the length of the second half of the menstrual cycle (the luteal phase) is constant at 14 days. A small percentage of infertile women (3-4%) have a shortened luteal phase. This may result in the loss of pregnancy support before the budding pregnancy has a chance to signal the ovary that it is there.

The lining of the uterus (the endometrium) has a specific appearance that changes throughout the menstrual cycle, such that a biopsy of the lining a few days prior to expected menstruation, can accurately date endometrial development. A three or more day difference between endometrial dating by biopsy and cycle day as determined by the start of the next menstrual period is indicative of a luteal phase defect (LPD). Sequential mid luteal progesterone levels < 10 ng/dl can also be used to diagnose a LPD. Luteal phase defect can be treated with Clomiphene Citrate, Progesterone supplementation or hCG injections.

LottaGriffin: My husband and I have a 3.5 year old that was conceived on our "first try." We now want to add another baby to our family, but we have tried for nine months now without any luck. Since we have one child we know that we can have children, but I want to ask you what some of the reasons for me not getting pregnant again could be. Thank you!

Dr. Sher: There could be many possible reasons for secondary infertility. You need to see an RE and have a thorough evaluation as outlined here.

Sherri: I am 36 year old and have been ttc for 2.5 years. Lap in August revealed asymptomatic endometriosis on uterus which was removed. Also fibroids within uterine walls which were not removed. Having a less than great response to follistim, should I move on to IVF or try one more cycle at six vials/night? Should fibroids within the uterine wall be removed? Thank you for your time!

Dr. Sher: With endometriosis at 36, IVF is probably the best alternative. Read here.

Jodi: My question has to do with male infertility. I am really curious on your opinion regarding the lack of research on this cause for infertility. The "solution" seems to be IVF with ICSI which is not actually a solution but a work-around. Male infertility seems to be so far behind female infertility. Do you have any thoughts as to why this is the case? Insurance will often pay for treatment of the causes, but in the case of male infertility, there are seldom such treatments available! I am just curious on your thoughts or experiences. Thank you.

Dr. Sher: Jodi, the amount of research and knowledge on MF infertility is growing exponentially. Read on...

Jodi: Can you share more about your opinion about Viagra assisting with blood flow to the uterus and lining thickness? Is it similar to baby aspirin or more effective? How can one introduce the idea to an RE who may be unaware of this treatment option? Thank you!

Dr. Sher: It is far more effective. BUT alas "there are none so blind as those that will not see!"

In 1989, we were among the first to show that in normal and "stimulated" cycles, pre-ovulatory endometrial thickness and ultrasound appearance, is predictive of embryo implantation (pregnancy) potential following In Vitro Fertilization/Embryo Transfer (IVF/ET). With conventional IVF (where the woman receives fertility drugs and has her own fresh embryos transferred to her uterus), here needs to be a 9mm sagital thickness (Grade 2) and a triple line appearance (Grade A) accordingly, a Grade 2A lining is optimal in such cases. Anything less is associated with about a five- (5) fold reduction in live birth rate per ET. An exception to this rule seems to apply for third party embryo Recipients (Ovum donation, IVF-Surrogacy) and in cases of frozen embryo transfers (i.e., where the recipient receives supplementary estrogen/progesterone and not gonadotropins, to prepare the uterine lining. Here, a lining of 8mm thickness seems to be adequate.

A "poor" endometrial lining most commonly occurs in women with a history of unexplained recurrent IVF failures or early recurrent miscarriages and is usually attributable to: 1) inflammation of the uterine lining (endometrium), i.e., endometritis (occurring following a septic delivery, abortion or miscarriage, 2) adenomyosis (gross invasion of the uterine muscle by endometrial glandular tissue), 3) multiple fibroid tumors of the uterine wall) 3) prenatal exposure to the synthetic hormone, diethylstilbestrol ( DES) and, 4) in women who have received clomiphene citrate (Clomid, Serophene) for at least 3 months in a row without a resting cycle (this effect is self-reversible within 4-6 weeks of discontinuing clomiphene).

Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.

In 1995/96, we began to recognize that it was possible to improve endometrial development in women who had "poor uterine linings," by the daily application of nitroglycerine skin patches during ovarian stimulation with fertility drugs. We believed that the therapeutic effect was probably attributable to the local action of nitric oxide (NO) on the uterine vasculature, leading to improved endometrial blood flow and enhanced delivery of estrogen to the uterine lining. About 75% of our IVF patients with compromised uterine linings so treated with nitroglycerine skin patches, showed a marked improvement in estrogen-induced endometrial growth and many went on to achieve viable pregnancies. Unfortunately the lack of access to ultrasound color flow Doppler (UCFD) to measure uterine blood flow at the time precluded us from confirming that the observed enhancement in endometrial development was directly attributable to enhancement of uterine blood flow. Accordingly we did not publish these findings.

The high incidence of unpleasant side effects associated with nitroglycerine therapy (e.g. severe headaches, nausea, and light-headedness brought about by fluctuations in blood pressure) resulted in poor patient tolerance. Accordingly, when Sildenafil (Viagra) was shown to facilitate penile erection through increasing penile blood flow, without eliciting bothersome side effects, we decided to investigate whether this drug could replace nitroglycerine for the improvement of endometrial development. This time, with ready access to UCFD, we set out to examine for a cause and effect relationship between Viagra-induced enhancement of uterine blood flow and improved endometrial growth in women with poor endometrial development.

We elected to incorporate Viagra into vaginal suppositories in an attempt to improve local uterine absorption and minimize the incidence of systemic side effects .To this end, we enlisted the services of a compound pharmacist and began testing the effect of vaginally administered Viagra on uterine blood flow and on estrogen-induced endometrial development. Four women with chronic histories of poor endometrial development and failure to conceive following several advanced fertility treatments were evaluated for a period of 4-6 weeks and then underwent IVF with concomitant Viagra therapy. Viagra vaginal suppositories were administered four times daily for 8-11 days and were discontinued 5-7 days prior to embryo transfer in all cases.

We reported on our findings in a preliminary study, published in the prestigious journal, "Human Reproduction" (April 2000). The findings clearly demonstrated that vaginal Viagra produced a rapid and profound improvement in uterine blood flow and that this was followed by enhanced endometrial development in all four cases. While three of the four women subsequently conceived, the study is too small to prove that these pregnancies can be attributed to the Viagra therapy. Larger independent and controlled studies will be needed to demonstrate this.

In a manuscript which appeared in "Fertility & Sterility" (The official journal of The American Society of Reproductive Medicine) in October 2002, we reported on the administration of vaginal Viagra to 105 women with repeated IVF failure due to persistently thin endometrial linings. All of the women had experienced at least two (2) prior IVF failures attributed to intractably thin uterine linings. About 70% of these women responded to treatment with Viagra suppositories with a marked improvement in endometrial thickness and 45% of these achieved live IVF- births following a single cycle of treatment with Viagra. 9% miscarried. None of the women who had failed to achieve an improvement in endometrial thickness following Viagra subsequently and underwent embryo transfers in the same cycle during which Viagra was administered, achieved viable pregnancies.

Our very first patient (Rene Danford)to achieve a live birth following Viagra treatment subsequently again conceived following IVF where Viagra was administered and has since delivered a healthy baby (a girl this time), at full term.

Lynette: My husband and I got pregnant back in 1995 but miscarried at 11 weeks, and we have been trying ever since. I have gone to a few doctors and had tests done and they seem to come back fine. Could my weight be what the problem is? I have been heavy all my life but what is the largest some one can weigh and still get pregnant? Thanks, Lynette.

Dr. Sher: Weight should not be a major factor in getting pregnant, but it can cause problems in pregnancy. Diabetes of pregnancy, pre-eclampsia, prolonged/dysfunctional labor, large babies, obstructed labour, post partum hemorrhage and infection etc are all more common.

Allison: My husband and I have been trying to conceive for almost 2 years now. I am 28 and he is 30. We've had many fertility tests done (SA, HSG, hormone levels drawn, and PCT) and they all are normal (besides a low LP progesterone). I'm normally anovulatory, so my doctor put me on Clomid eight months ago. After five months on Clomid, we moved onto injectables (Bravelle-FSH) and HCG trigger. After eight months of medicated cycles (five which were ovulatory and three which were anovulatory), I never became pregnant. I'm wondering, do you suggest I get a laparoscopy done before we move onto IUI? I have no symptoms of endometriosis, but I know that many women who have it don't. Thanks in advance for taking time out of your busy day to chat with us here on StorkNet!

Dr. Sher: You probably will be best advised to consider IVF. Call Sharon Benzel at 800-780-743 and set up a free medical telephone consultation with me so we can talk.

Traci: I am a 35 year old woman (divorced and recently remarried) who already has two children ages 12 & 8. My new husband and I want to have a baby, however, in the last couple of years, my menstrual cycles have become either extremely irregular, short or non-existent. My former OB-GYN diagnosed it as just stress based the results of a laparoscopy, hysteroscopy, and a D&C. My new OB-GYN has decided to try some medication to get me back on track. Does this mean that I have stopped ovulating completely or just that the time that I am ovulating is drastically shortened? Is there hope for us to conceive a child? Explain to me the different medications used to resume ovulation? Side effects? Thank you so very much, Dr. Sher.

Dr. Sher: Could be stress, abnormal hormone balance, or you may be moving more quickly to a menopause ( hopefully not). Either way it sounds a s if you are not ovulating functionally or at all. You need to be properly evaluated ASAP and then move on to the most appropriate treatment.

Amy: Hi, Dr. Sher, I appreciate you being available for questions! My question is what is the probability of infertility after giving birth to one child (via c-section)? We have been actively trying for six months now and haven't gotten pregnant. We didn't try at all for our first child. I visit a family doctor and he said he won't intervene until we'd been trying for a year. I guess I'm impatient and I just want to make sure everything is okay. I know when I'm ovulating and so we plan sex for that time and I'm still not getting pregnant. Any suggestions on what we can do? Should I see an ob/gyn about this problem? Thanks so much for any help! Amy

Dr. Sher: Amy, by definition infertility is the inability to conceive after 1 year of regular trying . You may indeed be best advised to give it another six months. Try not to stress out; it only makes matters worse.

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