The International Council on Infertility Information Dissemination, Inc

The Site That Changed My Life by M. Tufts

In 1994 I miscarried twins. I went on to have a healthy baby but when I tried to have another, I miscarried again. In desperation for answers (there seemed to none in the medical world with the exception of the hurtful 'it was meant to be' or 'it was probably for the best') I did an on-line search for information regarding miscarriage.

What I kept coming to was a site called which was originally a site devoted to infertility awareness. I found more answers there than I could imagine exisited. I was able to learn things that even my obstetrician was unaware of. I was pointed in the right direction for treatment (sometimes finding the right specialty and someone who practices it in your area is the most difficult part of seeking a treatment) and I am happy to say I am now 7 months pregnant. An additional benefit of the site, because it has numerous bulletin boards, it that you can hook up with and befriend many other people with similar histories. This support aspect is unequaled in 'real life' where you may never meet someone with the same disorder The site has many medical moderators. These individuals, leaders in thier fields of specialty, volunteer their time and do not prescribe medicine, although they do give out much needed advice.

The site has clearly changed my life and I shudder to think where I would be had I never found the information I needed so badly. The site is free, and staffed predominently by volunteers, They are always strapped for funds which they richly deserve for all the good they do, and often request small donations from users. I wish I was a millionaire so that I could give them the donation I think they deserve.


Originally printed by ZDNet AnchorDesk:

The Risks of Multiple Pregnancy Associated with IVF By Angie Beltsos, M.D.

In-Vitro fertilitization (IVF) is an exciting therapy that offers many infertile couples the opportunity to achieve pregnancy that would not otherwise exist.  It’s important for couples to remember that as they consider IVF, they need to know it has played a significant role in increasing the incidence of high order multiple pregnancies (triplets or more) since its introduction in 1978.

The goal of infertility treatment is the delivery of a full-term, healthy infant.  Multiple pregnancy – especially high order multiple pregnancy – clearly puts this goal at risk. Maternal complications of high order multiple pregnancy include:

  • pre-eclampsia
  • excessive weight gain
  • anemia
  • chronic back pain
  • possible damage to the anterior abdominal wall


More importantly, fetal complications include prematurity and the resulting increase in infant morbidity and mortality.  Furthermore, the rearing of high order multiples creates physical, emotional and financial stress for the family with a reported increase in the incidence of maternal depression and anxiety.  For these reasons, reducing the number of high order multiples has become an essential goal of most successful IVF programs.    

Two relatively new developments in the art and science of IVF appear to significantly decrease the need to transfer a large number of embryos and therefore, offer the promise of decreasing the incidence of high order multiple pregnancies.  In 1990, preimplantation genetic diagnosis (PGD) became a reality.  Embryos created through IVF can now be tested for age-related genetic abnormalities.  This screening allows the clinician to transfer fewer PGD screened embryos in women 35 years of age and older, while still maintaining high rates of pregnancy.

The second significant development has been the ability to keep embryos in culture for 5 days (blastocyst stage) instead of 2 or 3 days (cleavage stage) prior to transfer.  Blastocysts are more likely to implant and lead to pregnancy.  Therefore, the fewer blastocysts (usually only 2) need to be transferred in order to maintain good pregnancy rates.  Fertility Centers of Illinois is one of the few practices in the nation that is able to offer patients both of these procedures.


Angie N. Beltsos, M.D. is board certified in both obstetrics and gynecology

and reproductive endocrinology.  Dr. Beltsos completed her residency in obstetrics and gynecology at LoyolaUniversity followed by a two-year fellowship in reproductive endocrinology and infertility at WashingtonUniversity in St. Louis, MO.  Dr. Beltsos is currently a Clinical Assistant Professor in reproductive endocrinology at Loyola Medical School, Chicago, IL, and has participated in numerous research projects.


Phone: 847-215-8899






Genetic Counseling by Michael Doyle, M.D.


Genetic Counseling

by Michael Doyle, MD
From the 2007 Resource Directory



While the vast majority of babies are born healthy, approximately 2-3% of all babies are born with some type of birth defect or genetic condition. Genetic counseling is the process of providing individuals and families with information and support on the nature, inheritance and implications of genetic and related conditions. Genetic counseling offers tests to assess the risks for passing on various genetic diseases.


Those benefiting from genetic counseling would be women who are age 35 or older, couples with recurrent miscarriages, individuals with family histories of birth defects and/or genetic conditions, patients planning fertility treatments such as intrauterine inseminations (IUI), in vitro fertilization

(IVF) and pre-implantation genetic diagnosis (PGD). Couples with male factor infertility, patients with questions regarding genetic screening or gender selection, prospective egg donors and directed semen donors, as well as newly pregnant patients who are over age 35 or who have questions regarding prenatal testing options, would also benefit. 


Using PGD, healthy, chromosomally normal embryos can now be distinguished from nonviable and diseased ones. This is particularly helpful for women over 35, since chromosomal problems account for a large percentage of miscarriages and infertility in these women. This is chiefly due to the fact that as a woman ages, her eggs decrease in both number and quality. Consequently, over time, a couple’s chances of becoming pregnant with a healthy baby decrease, and the rate of miscarriage climbs. In fact, if a healthy 40 year-old woman in excellent health does conceive, her chances of having a chromosomally abnormal embryo are over 50% without PGD, resulting in infertility, inevitable miscarriage, or fetal abnormality.


Traditionally, the overall appearance of embryos conceived by IVF have been assessed microscopically to predict their chances of implanting. Pre-implantation genetic diagnosis (PGD) takes fertility treatment to a new level. By screening the genetic information contained within the embryo prior to deciding which embryos to transfer, genetically normal embryos can be selected and transferred back to the patient. These pre-screened embryos are much more likely to implant and when they do, the chance of a problem is much lower.


The optimal time to perform genetic testing is before a couple begins trying to conceive. Genetic Counselors, with a specialized graduate degree in the areas of medical genetics and counseling, meet  with patients to determines which genetic conditions are the most appropriate  to screen for based on family history and ethnicity.


Most of the genetic screening tests are for conditions which are inherited in an autosomal recessive manner, which means that both parents would need to be carriers in order to have an affected child. It is common for the female partner to be tested initially, and if she is found to be a carrier for a particular genetic condition, it is recommended that the male partner consider testing. If both members of the couple are carriers for the same genetic condition, a genetic counselor will review the implications of these results, and discuss appropriate testing options.

Some of these options include preimplantation genetic diagnosis (PGD) and prenatal diagnosis. Testing during pregnancy may involve chorionic villus sampling (CVS), usually done between 10 and 12 weeks of pregnancy, or amniocentesis which is typically performed between 16 and 18 weeks of pregnancy.


Screening for the following genetic disorders are available: Cystic Fibrosis, Sickle Cell Disease, Alpha Thalassemia, Beta Thalassemia Fragile X Syndrome, and for conditions with increased frequency in the Ashkenazi Jewish population: Tay-Sachs disease, Canavan disease, Familial Dysautonomia, Fanconi Anemia group C, Bloom syndrome, Gaucher disease, Niemann-Pick disease type A, Glycogen storage disease type 1A , Maple syrup urine disease, and Mucolipidosis type IV.


Genetic counseling can provide individuals and families with the information and support on the nature, inheritance and implications of genetic and related conditions. Genetic counselors can offers tests to assess the risks for passing on various genetic diseases to assist patients in achieving the goal of having a healthy baby.



Michael Doyle M.D. is the founder and medical director of the Connecticut Fertility Associates. His specific areas of expertise include
microsurgery, advanced laser laparoscopy and hysteroscopy, treatment of severe endometriosis, management of male fertility, and in vitro fertilization.

Connecticut Fertility Associates
4920 Main Street
Bridgeport, CT 06606
Phone: (203) 373-1200 Fax: 203-365-6516


Thinking Out-CIID the Box!

In 1994. three women who had been told their infertility was intractable, went out on the internet and found solutions to their issues.

They thought OUT-CIID the box.  These same three women met in cyberspace and formed the organization INCIID to help others on their family building journeys.  Folks told them the Internet was full of misinformation and the thing would never work.  13 years later, INCIID ‘s community continues to grow and provide reliable and cutting edge information and support to tens of thousands of families.  These women once again thought OUT-CIID the box. In 2002, Nancy Hemenway and her board of directors decided it was time to find a way to provide some help for those unable to afford IVF and the From INCIID the Heart Program came about. This year, over a dozen a babies have been born as a result of this OUT-CIID the box thinking .

Before we ask you for a contribution, we would like to say a big thank you to all of our 2006 donors. Without your thinking outciid the box with us, our heart scholarship program would not be able to function. We appreciate your generosity.

Now, INCIID is going to ask you to do some OUTCIID the box thinking.  Yes, we are asking for your financial support to continue our mission.  (

As has been said, “infertility is no one’s national emergency” and funding opportunities are few and fiercely competitive. But all of you know how personal and painful infertility can be and you know how important it is to support one another. We know many of you are counting pennies to pay for treatment and we want you to know we value small contributions as well as larger ones.  We have a monthly giving plan to help spread the payments over the year. INCIID is asking you to find a way to financially support our organization with the same enthusiasm you bring to supporting one another.

Please help INCIID to continue to think OUTCIID the box in pursuing new and exciting technology to deliver information and support through on-line chats with experts in the field of infertility treatment , Webinars, Pathways to Parenthood, Twitter, Facebook and INCIID Insights Community Newsletter
INCIID provides 24 hour on-line access to support and information boards to help you in your family building journey.

Give a  tax deductible donation to support INCIID Programs.

You are not alone! INCIID is there for you. Help us continue to think OUTCIID the box and give generously with a year-end tax deductible contribution!

With Thanks,
The INCIID Staff and Volunteers

Fax your credit card information directly to INCIID:

We need your Name as it appears on the card
Address, City, State and Zipcode
Credit card number
Expiration Date
Signature giving us permission to process your card.
Fax directly and securely here:
(703) 379-1593

SECURE Online contributions here:

IVIg Trial

Intravenous Immunoglobulin for Treatment of Recurrent Pregnancy Loss



Intravenous Immunoglobulin for the Treatment of Recurrent Pregnancy Loss , C.B. Coulam, L. Kyrsa, J. J. Stern, M. Bustillo, Genetics & IVF Institute, Fairfax VA.

Objective: To evaluate the efficacy of intravenous immunoglobulin for treatment of individuals experiencing unexplained recurrent pregnancy loss.

Design: Prospective randomized, placebo-controlled clinical trial.

Materials and Methods: 95 women experiencing 2 or more consecutive spontaneous abortions (SA) with no known cause were randomized and received either intravenous immunoglobulin (IVIG) 500/mg/kg/mo or placebo (albumin)

Results: Of 95 women participating in he study, 47 received IVIG and 48 received placebo. Medication was discontinued in 34 women who failed to conceive within 4 cycles. The remaining 61 women achieved pregnancy. Pregnancy outcomes included 29 delivery and 32 recurrent SA. Among women delivering live births 18 (62%) received IVIG and 11 (33%) received placebo. By contrast 21 (67%) women experiencing SAs received placebo and 11 (33%) received IVIG. Among 61 women who conceived, 29 received IVIG and 32 received placebo. Of the 29 women who conceived and received IVIG 18 (62%) delivered live births and 11 (33%) experienced recurrent SA. Of the 33 women who conceived and received placebo, 11 (33%) delivered live births and 22 (67%) had recurrent SA. The difference in live birth rates between women receiving IVIG and placebo was significant
(P = 0.01, odd ratio 0.2)

Conclusion: IVIG is effective in enhancing the percentage of live births among women experiencing unexplained recurrent SA.



Recurrent spontaneous abortion is a common complication of pregnancy for which there is no known cure.1 An immunologic cause has been suggested for more than 80% of otherwise unexplained recurrent spontaneous abortion and various immunotherapies have been proposed as treatment for these couples.2 White blood cell immunization has been the most widely used immunotherapy.3 The efficacy of this treatment is low, with an absolute reduction of risk of another abortion between 8% and 10%. Thus, the number of cases needing to be treated in order to prevent a single pregnancy failure was between 9 and 13.4 Because of the low treatment effect, alternative treatments for recurrent spontaneous abortion have been sought. Among alternative treatments reported to result in successful pregnancies is intravenous immunoglobulin.7,15 None of the studies reporting successful pregnancies after treatment with intravenous immunoglobulin included control subjects. We therefore undertook a prospective randomized placebo-controlled double-blinded clinical trial to define the efficacy of intravenous immunoglobulin in the treatment of recurrent spontaneous abortion. We now report the results of this randomized placebo-controlled trial.


Materials and Methods


Women experiencing two or more consecutive spontaneous abortions with the same partner were offered the opportunity of participating in an Institutional Review Board (IRB) approved randomized placebo controlled trial using intravenous gammaglobulin (IVIg) or albumin (placebo) from January 1991 to March 1994. The obstretrical histories of each of the women were obtained and the number of total pregnancies, live births stillbirths, abortions, ectopic pregnancies, and hydatidiform moles and the number of partners for each pregnancy were recorded. All couples were investigated with chromosome analysis, hysterosalpinography, and hysteroscopy, luteal phase endometrial biopsy, and serum progesterone timed with ovulation documented by ultasonic monitoring of folliculogenesis, anticardiolipin antibody (ACA) and activated partial thromboplastin time. All couples with a diagnosis of chromosomal, anatomic, endocrinologic and autoimmunologic etiology of recurrent pregnancy loss were excluded from the study. Also excluded were women less than 18 years or greater than 45 years of age, and women with a history of IgA deficiency or hypersensitivity to immunoglobulin. Each woman had blood screened for the presence of HIV antibodies and the Hepatitis B antigen.


Sample-Size Consideration

The major determinant of sample size for this type of study is the expected proportion of subsequent pregnancies to end in a spontaneous abortion among the nonintervention group. Estimates provided in the literature suggest 40% as a reasonable expected proportion of third to sixth spontaneous abortions.1,14,16 The next major consideration is the level of reduction to be achieved by the intervention (therapy). If the causes of recurrent spontaneous abortion differ from the causes of isolated spontaneous abortions and can be eliminated by the intervention, the base line risk for subsequent abortion would be about 12%.16 Thus the maximum effect of the treatment would be a decrease in risk of abortion from 0.40 to 0.12. According to traditional parameters for sample size computations, including type 1 error of 0.05, type 2 of 0.2 and a one sided test, 25 pregnancies would be required in the treated and untreated groups. This sample size requires that all of the patients conceive. Previous data indicate 73% of women with three spontaneous abortions and no viable pregnancies have a subsequent pregnancy.16Therefore both the treated and untreated groups should consist of a minium of 43 patients. Since the reduction of the excess risk of spontaneous abortion due to "recurrent causes" might not be complete due to heterogeneity of the causes of spontaneous abortion and /or effectiveness of the intervention, a sample size of 45 in each group would ensure reliable data (Graph PAD, InStat Version 1.12a, Graph PAD Software, 1990.)



A total of 95 women were randomized using computer-generated random number, on half receiving intravenous immunoglobulin (IVIg) and the remaining one half albumin infusions. Each patient received an intravenous infusion of the follicular phase of the cycle when pregnancy was desired. Patients were randomized in a double-blinded fashion to receive either (IVIg 500 mg/kg per month of albumin 0.5% in an intravenous infusion. The patient received the infusion every 28 days until pregnant or for 4 months. If the patient was not pregnant in 4 months, she was dropped from the study and replaced with another patient. Once conception occurred, the patient received an infusion every 28 days until delivery or until 28-32 weeks gestation.




Ninety-five women participated in the study. Their mean age was 35 years (range 27-44) and gravidity 5.7 (range 2-18). Forty-six women experienced recurrent spontaneous abortion after a previous live birth (secondary recurrent spontaneous abortion), and

49 women lost two or more pregnancies with no pregnancy progressing beyond 20 weeks of gestation (primary recurrent spontaneous abortion). Of 95 women participating in the study 47 received IVIG and 48 received placebo. The mean age of women receiving IVIg was 35 years (range 27-44), mean gravidity was 5 (range 2-11), 27 women were primary aborters, and 20 were secondary aborters. No differences in age, gravidity, parity, or proportion of primary and secondary aborters existed between the group receiving IVIg and placebo. Medication was discontinued in 34 women (18 receiving IVIg and 16 placebo) because of lack of conception.

Among 61 women who conceived, 29 received IVIg and 32 received placebo. Of the 29 women who conceived and received IVIg, 18 (62%) delivered live births and 11 (38%) experienced recurrent spontaneous abortion. Of 32 women who conceived and received placebo, 11 (34%) delivered live births and 21 (66%) had recurrent spontaneous abortion. The difference in live birth rates between women receiving IVIg and placebo was significant (P=0.04, odds ratio 3.1)


Pregnancy Outcome

Pregnancy outcomes included 29 deliveries and 32 spontaneous abortions (Table 1). Among women delivering live births, 18 (62%) received IVIg and 11 (38%) received placebo. By contrast, 21 (66%) women experiencing recurrent spontaneous abortions received placebo and 11 (34%) received IVIg.

TABLE I. Out come of 61 pregnancies randomized to receiving intravenous immunoglobulin (IVIg) or placebo (albumin)

Pregnancy Outcome

























Blighted Ovum







Intrauterine Death














Thirty-two women experienced recurrent spontaneous abortion (Table I.) Ultrasonographic finding of the 32 pregnancy losses included 15 (47%) empty embryonic gestational sacs or blighted ova and 17 (53%) intrauterine deaths after establishment of cardiac activity in the first trimester of pregnancy. Eight of the blighted ova occurred in women receiving IVIg and 17 in those receiving placebo. Of 17 intrauterine embryonic deaths, 3 (18%) occurred in women receiving IVIg and 14 (82%) in women receiving placebo. Among the 11 pregnancy losses occurring in women receiving IVIg, 8 (73%) were blighted ova, and 3 (27%) were intrauterine embryonic deaths. Twenty-one pregnancy losses occurred in women receiving placebo; 7 (33%) were blighted ova, and 14 (67%) were intrauterine embryonic deaths. The difference in intrauterine embryonic deaths between women receiving IVIg and placebo was significant (P<0.004, odds ratio 0.1)



No reactions to study medications occurred. One infant was born with Mosaic Down syndrome and one pregnancy was complicated by an umbilical cord accident at 30 weeks gestation. Both women received IVIg.



Analysis of results from this randomized, double blinded placebo-controlled clinical trial suggests that IVIg us efficacious in the treatment of recurrent spontaneous abortion. Another randomized, placebo-controlled trial has been performed in Germany as a multicenter study.17 A significant specific effect of IVIg on live birth rate could not be demonstrated. However , success rates for both IVIg and albumin were in the same range as allogeneic leukocytes.17 The difference in interpretation of results in the current study and the German experience 17 has at least three explanations. The first explanation involves patient selection. The women included in the studies could represent different populations with different risk factors for pregnancy loss. More sensitive and specific markers are needed to identify individuals most likely to respond to immunotherapy before differences in study populations can be prepared. The second explantation involves the differences in the study design between the two studies. In the current study, therapy was begun before conception, whereas the German study instituted all treatment after a positive pregnancy test was obtained.17 Preconception treatment for recurrent spontaneous abortion using various forms of immunotherapy has been shown to be more effective than postconception treatment.17 The third exception for differences in success rate is co-intervention by the control treatment. The reason the German study showed no treatment effect of IVIg is that the effect seen was the same as that of albumin. Both effects were the same as the treatment effect seen by IVIg in the current study and by leukocyte immunization in the worldwide prospective collaborative study.4 The concentration of albumin in the German study17 was a 5% solution in contrast to the current study in which 0.5% albumin was used. Little is known about the immunomodulating effects of albumin. Recently, soluble HLA molecules have been detected, not only in IVIg19 but also in smaller amounts, in albumin preparations.20

Intravenous immunoglobulin therapy has been previously reported to be effective in prevention of recurrent spontaneous abortion (5-13). The mechanism of this antiabortive effect is not known. Immune modulation by IVIg has been speculated to result from passively transferred blocking or antiidiotypic antibodies,22 blockage of Fc receptors,23 enhancement of suppressor T-cell function,24 down regulation of B-cell function,25 and/or reduction of activation of complement components, 13,26,27 natural killer cell function, and cytokine production.28

Whatever the mode of action, the mechanism does not maintain pregnancies associated with blighted ova29 but does maintain pregnancies that are lost as a result of intrauterine demise after the establishment of embryonic cardiac activity (Table I.).

The majority of pregnancies (73%) lost after treatment with intravenous immunoglobulin are blighted ova (Table I.). Limited data in the literature suggest that ultrasonographic demonstration of an empty sac is associated with an abnormal analysis of the chorionic villus sampling .30,31 If these observations can be confirmed in women experiencing recurrent pregnancy loss, then pregnancies lost after treatment with intravenous immunoglobulin will be those with abnormal chromosome complements. IVIg is effective in enhancing the percentage of live births among women experiencing unexplained recurrent spontaneous abortion. Since IVIg preparations are free of cells and can be quarantined for prolonged periods, IVIg provides a safer alternative for treatment of recurrent pregnancy loss than white blood cell immunization.



The authors should like to thank the following physicians who provided patients who participated in the study: S. Alexander, D. Fein, J. Langley, A. Toofanian, G. Janneck, M. Liptak, D. Koepping, G. Shuster-Haynes, M. Hinton, K.Duprey, A. Haney, J. Eberhardy, A. Hough, R. Zold, R. Nehls, D. Mullaney, R. Suarez, M. Maloney, M. Aiken, M. Jones, M. Freedman, J. Davidson, P. Taylor, C. Whitworth, D. Ross, S. Marynick, B. Wassell, L. Beard, M. Utley, S. Reager, R. Chopyck, S. Collins, C. Calvello, M. Turner, T. Markus, A. West, A. Gonzales, J. Thompson, L Underwood, J. Jones, K. Fischer, R. Reinsch, D. Bewall, A. Peters, and R. Lloyd.


Coulam, CB. Unification of immunotherapy protocols. Am J Reprod Immunol 1991: 25:1-6

McIntyre JA, Coulam CB, Faulk WP. Recurrent spontaneous abortion. Am J Reprod Immunol 1989; 21:100-104

Mowbray JF, Lidlee H, Underwood JL, et al. Controlled trial of treatment of recurrent spontaneous abortionby immunization with paternal cells. Lancet 1985; 1:941-949

Fraser EJ, Grimes DA, SchultzKF, Immunization as therapy for recurrent spontaneous abortion; a review and meta-analysis. Obstet Gynecol 1993; 82:854-859

Coulam CB, Peters AJ, McIntyre JA, Faulk WP. The use of intravenous immunoglobulin for the treatment of recurrent spontaneous abortion. Am J Reprod Immunol 1990; 22:78.

Mueller-Eckhardt G, Heine O, Neppert J, Kunzel W, Mueller-Eckhardt C. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin. Vox Sang 1989:56:151-154

Mueller-Eckhardt G, Huni O, Poltrin B. IVIg to prevent recurrent spontaneous abortion. Lancet; 1991; 1:424

Berstein RM, Crawford RJ. Intravenous IgG therapy for anticardiolipin syndrome: A case report (abstract). Clin Exp Rheumatol 1988; 6:198

Scott JR, Branch DW, Kochenour NK, Ward K. Intravenous immunoglobulin treatment for pregnant patients with recurrent pregnancy loss caused by antiphospholipid antibodies and Rh immunization. Am J Obstet Gynecol 1988; 159:1055-1056

Carreras I.O., Perez GN. Vega HR. Casavilla F. Lupus anticoagulant and recurrent fetal loss: Successful treatment with gammaglobulin. Lancet 1988; 2:393-394

Francois A. Freund M. Daffos F. Remy P. Risch M. Jacquor C. Repeated fetal losses and lupus anticoagnulant. Ann Intern Med 1988: 109:993-994

Parks A. Maer D. Wilson D. Andreoli J. Ballow M. Intravenous gamm-globulin, anti-phospholipid antibodies and pregnancy. Ann Intern Med 1989: 110:495-496

Christriansen OB. Mathiesen O. Lauristen JG. Grunner N. Intravenous immunoglobulin treatment of women with multiple miscarriages. Human Reprod 1992; 7:718-722.

Parazzini F.Acais B. Ricciardeiello O. Fedele L. Liata P. Candiani GB. Short-term reproductive diagnosis when no cause can be found for recurrent miscarriage. Br J Obstet Gynaecol 1988; 95:654.

Risch HA. Weiss NB. Clarke EA. Miller AB. Risk factors for spontaneous abortion and its recurrence. Am J Epidemiol 1988; 128:420.

Poland BJ. Miller JR. Jones DC. Trimble BK. Reproductive counseling in patients who have had spontaneous abortion. Am J Obstet Gyencol 1977; 127:685.

The German RSA/IVIG Group. Intravenous immunoglobulin in the prevention of recurrent miscarriage. Br J Obstet Gynecol 1994; In press.

Kwak JYH. Gilman-Sachs A. Beamen KD. Beer AE. Reproductive outcome in women with recurrent spontaneous abortions of alloimmune and autoimmune causes: preconception vs. postconception treatment. Am J Obstet Gyencol 1992; 166:1787-1795.

Gross-Wilde II. Blasczyk R. Westhoff U. Soluble HLA class I and II concentrations in commercial immunoglobulin preparations. Tissue Antigens 1992; 39:74-77.

Sancoso S. Kiefel V. Voiz H. Mueller-Echardt C.Quantitation of soluble HLA class I antigen in human albumin and immunoglobulin preparations for intravenous use by solid-phase immunoassay. Vox Sang 1993; 62:29-33.

Hay CRM. The effect of chronic exposure to clotting factor concentrates on the immune system. In Coagulation and blood transfusion. Smit Sibings (T. Das PC. Mannucci PH(eds). Dordrecht. Boston. London; Kluwer Academic Publisher. 1991:227-240

Brand A. Wirvliet M. Claas FHJ. Benificial effect of intravenous gammaglobulin in a patient with complement-mediated autoimmune thromboeytopenia due to IgM-anti-platelet antibodies. Br J Haemarol 1988; 69:507-511.

Kimberly RP. Salmon JE. Bussell JB. et al. Modulation of mononuclear phagocte function by intravenous gammaglobulin. J. Immunol 1987; 132:745-750.

Delfraissy JF, Tchernia G. Laurian Y. et al. Suppressor cel function after intravenous gammaglobulin treatment in adult chronic idiopathic thrombocytopenic purpura. Br J Haematol 1985; 60:315-322.

Nydegger UE. Hypotheric and established action mechanisms of therapy with immunoglobulin G. In immunotherapy with intravenous immunoglobulin. Imbach P (ed). Academic Press. London. 1991. pp 27-36.

Kulies J. Rajnavolgya E. Fust G. Gergely J. Interaction of C3 and C3h with immunoglobulin and complement concentration. Nephron 1985; 40:253-254.

Zielinski CC. Pries P. Eibl MM. Effect of immunoglobulin and complement concentration. Nephron 1985; 40:253-254.

Newland AC. The use and mechanisms of action of intravenous immunoglobulin: An update. Br J Haematol 1989; 72:301-305.

Coulam CB. Stern JJ, Bustillo M. Ultrasonographic findings of pregnancy losses after treatment for recurrent pregnancy loss: intravenous immunoglobulin versus placebo. Fertil Steril 1994; 61:248-251.



To:       Medical Director Name
            Insurance Company Name

            Patient Name:
            Patient Policy & Group Numbers:
            Policy Holder Name:

Dear ______________________________,
            The ability to successfully host a pregnancy is largely dependent upon complex immunologic interactions designed to promote orderly accommodation of the invading trophoblast (developing embryo).  Peer-reviewed studies provide compelling evidence that functional failure of these intricate immunologic interactions during implantation lead to infertility, failure of IVF, recurrent miscarriage, and late pregnancy fetal loss, and pirimarily involve  immunologic factors including anti-phospholipid antibodies (APA), anti-thyroid antibodies (ATA), and activated Natural Killer Cells (NKa).  These immunologic markers are measured via blood tests analyzed by specialized reproductive immunology laboratories.
            An increased incidence of detectable APA’s has been reported in women with pelvic endometriosis, unexplained infertility and repeated IVF failure (1-5).  Recent evidence strongly suggests that the presence of APA’s in cases of non-male factor infertility resulting in immunologically-associated implantation failure is likely mediated by activation of a sub-population of lymphocytes known as Natural Killer (NK) cells, in particular, CD 56 lymphocytes, that comprise more than 80% of the lymphocyte population in the late secretory and early pregnancy endometrium (6).   NK cells contain / produce a variety of TH-1 cytokines [tumor necrosis factor alpha (TNFa), interferon gamma and interleukins (IL) 1&2] and TH-2 cytokines (IL 3,4,6,7,8,11,12). Excessive release of TH-1 cytokines, particularly TNFa, is cytotoxic to trophoblast and endometrial glandular cells, causing unregulated apoptosis and subsequent failed implantation. Orderly, controlled release of TH-1 cytokines, occurring in association with an appropriate production of TH-2 cytokines, is vital to proper placentation.  This TH1/TH2 homeostasis creates an environment fostering implantation and optimal intrauterine development.
Endometrial NK cells are normally predominantly of the CD56+ and CD16- variety. However, in some situations NK cells may become sensitized and express the cell surface marker CD16+. These include:  (1) inappropriate HLA signaling (possibly due to allogeneic compatibility between the conceptus and the maternal organism) and (2) occult or overt organic pelvic disease where the female tests positive for APA, particularly for anti-phosphoethanolamine (PE)/anti-phosposerine (PS) (e.g., endometriosis).  CD56+ and CD16+ NK cells are highly susceptible to activation by TH-1 cytokines such as IL2, transforming them into lymphokine activated killer cells (LAK) which in turn, release large amounts of TH-1 cytokines that threaten implantation.  Because these activated NK cells (NKa) can migrate into the peripheral blood their cytotoxicity can readily be assayed.
IVIG is thought to offset or counter the anti-implantation effects associated with APA positivity and NKa because:
(1) IVIG is a potent suppressor of NKa;
(2) IVIG contains anti-idiotypic antibodies which counter the effects of harmful APA’s; and
(3) IVIG also suppresses activated T-cells and polyclonal B-cells. Studies suggest that this may explain why IVIG therapy improves reproductive performance in females who test positive for antithyroid antibodies (ATA) (7).
IVIG has a profound ability to down-regulate and deactivate endometrial/decidual LAK cells over a period of one to two weeks, therefore, the assay used to measure NK cell activity--the administration of titrated dosages of IVIG to NK cells--determines the amount of IVIG necessary to neutralize NK cell activation.  It has been recently demonstrated that IgG or IgM antibodies to PE or PS in non-male factor infertility cases is often accompanied by increased peripheral NK activity and that IVIG therapy selectively benefits this group of patients (6,8) as well. This suggests that APA’s, rather than being causally related to IVF implantation failure, may act as markers of an underlying abnormality of cellular immunity and shows that appropriate IVIG dosing improves outcome in this patient population. Because the immunologic expression of the fetoplacental unit converts from an atypical Class I (i.e. HLAG) expression to a typical Class I type, it becomes much less susceptible to immunologic injury. This change in HLA antigenicity confers improved immunologic protection to the trophoblast.  Therefore, it is probably unnecessary to continue IVIG therapy beyond the 6th week of gestation, the time at which this conversion occurs.
In conclusion, patients undergoing assisted reproduction may experience failed IVF cycles, implantation failure, clinical miscarriages, or other pregnancy wastage on the basis of pathologic immune processes. Clear evidence now exists to support the fact that patients with serologically demonstrable levels of APA’s and NK’s may benefit from immunotherapy in selected cases.  Further, other perturbations of the immune system, including activation of T cells and polyclonal B cells, and ATA’s, if associated with NKa, may represent an additional indication for IVIG treatment (7).
            In pursuit of optimizing the outcome of IVF, we have a profound responsibility to make every effort to enhance implantation, and hence the chance of pregnancy.  We believe that it is appropriate for you, as the insurer, to recognize that IVIG therapy for this patient is medically prudent and cost-effective in light of the potential alternative need for repeat treatment and/or third-party assisted reproduction in the event of IVF failure, and to authorize benefits for this patient accordingly.


Physician and/or Patient


1.   Fisch B., Rikover Y., Shohat L., Zurgil N., Tadir Y., Ovadia J., Wik I., and Yron I.: The relationship between in vitro fertilization and naturally occurring antibodies; evidence for increased production of antiphospholipid antibodies. Fertil. Steril. 56(4), 718-724, 1991.
2.   Gleicher N., Liu H.L., Dudkievicz A., Rosenwaks Z., Kaberlien G., Pratt D., et al.: Autoantibody profiles and immunoglobulin levels as predictors of in vitro fertilization success. Am J Obstet. Gynecol. 170:1145-1149, 1994.
3.   Birkenfeld A., Mukaida T., Minichiello L.., Jackson M., Kase N.G., Yemini M.: Incidence of      autoimmune antibodies in failed embryo transfer cycles. Am. J Reprod. Immunol.  31:65-68, 1994
4.   Kaider B.D., Price D.E., Roussev R.G., Coulam C.B.: Antiphospholipid antibody prevalence in patients with IVF failure. Am. J Reprod. Immunol. 35:383-393, 1996.
5.   Bustillo M. Goodman C.: Assisted reproductive technologies and immune infertility. Am. J.      Reprod. Immunol., 35:205-289, 1996.
6.   Matzner W. Presentation at Pacific Coast Infertility Meeting, 1998.
7.   Sher G., Maassarani G., Zouves C., Feinman M., Sohn S., Matzner W., Chong P., Ching W. The Use of Combined Heparin/Aspirin and Immunoglobulin-G Therapy in the Treatment of In Vitro Fertilization Patients with Antithyroid Antibodies. Amer. J. of Reprod. Immunol. 39: 223-225, 1998.
8.   Sher G., Matzner W., Feinman M., Maassarani G., Zouves C., Chong P., Ching W.: The selective use of heparin/aspirin therapy, alone or in combination with intravenous immunoglobulin G, in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization. Am. J of Reprod. Immunol., 40:74-82, 1998.

SIRM Shares new Egg Freezing Breakthroughs

Freezing the Biological Clock


The proverbial “biological clock” is not just a myth. 

A woman’s fertility begins to decline around age 27.   In fact, even in her late 20’s and early 30’s, more than half of a woman’s eggs are chromosomally abnormal.  Egg quality declines with age so that in the early 40’s, the percentage of “competent” eggs decreases to less than 5% on average.  This is an irrevocable fact.

Though we can’t change the rate at which a woman’s reproductive system ages, we are now much closer to stopping the biological clock via another route: egg freezing and banking. 

There are numerous reasons for a woman to preserve her fertility through egg freezing/banking.  These include fertility-threatening cancer treatment, postponement of child bearing for career purposes, lack of a suitable partner, and various other issues of timing and choice. 


Obstacles to Successful Egg Freezing

Women seeking viable options for fertility preservation have long faced a difficult barrier due to the poor success rates for egg freezing.  Pregnancy rates for women using frozen/thawed eggs have historically been less than 4% for each individual egg frozen.  This is due to several factors:

First, at least 60% of eggs frozen are chromosomally abnormal from the outset and therefore cannot produce a normal embryo.  Second, traditional (slow) egg freezing techniques cause ice crystal formation within the structure of the egg, reducing viability or destroying the egg in the process. 


The Solution

A recent breakthrough by researchers at the Sher Institutes for Reproductive Medicine (SIRM) and its affiliate, ReproCure Genetics, addresses both of these issues, yielding a promising advance in the viability of egg freezing/banking. 

First, using a proprietary process known as CGH (Comparative Genomic Hybridization), each egg is tested for its chromosomal integrity prior to freezing, ensuring that only the “competent” ones are frozen. 

Second, a new method of ultra-rapid freezing (modified by ReproCure) called Vitrification is used, allowing much more successful freezing without ice crystal formation. 

The combination of chromosome analysis through CGH and Vitrification to preserve the eggs has resulted in post-thaw pregnancy rates that are more than 8 times higher per egg stored than previously reported methods. Initial studies at SIRM/ReproCure have already resulted in many births from frozen eggs using this technique.  These exciting breakthroughs promise to finally open the door to viable fertility preservation for women.

Do you have more questions about egg freezing and how it might relate to the way eggs are fertilized and to IVF?  Come over to the INCIID Community Forums where Dr. Saleh (a reproductive endocrinologist) who will answer your questions online daily.


SEE the Video Web Cast with Geoff Sher, MD: New Breakthrough in IVF. Study Doubles IVF Success

NEW STUDY --- Doubles the IVF Success Rates -- Geoffrey Sher will be coming to INCIID to chat about this breakthrough
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Download the free media player here.



A process that could markedly improve pregnancy rates from In Vitro-Fertilization (IVF) was reported in a
study published in the prestigious medical journal Fertility and Sterility (F&S). 
This was presented on Feb. 15, 2007 - 9:30 PM ET


      "This very exciting breakthrough could more than double IVF pregnancy success rates while reducing the risk of multiple births. We are now much closer to the goal of one IVF attempt, one egg, and one embryo, yielding one healthy baby," said Dr. Geoffrey Sher, who along with Levent Keskintepe PhD , both of ReproCure, LLC and the Sher Institutes for Reproductive Medicine(SM) (SIRM) developed the process and conducted the study.

Dr. Geoffrey Sher will come back to INCIID and do a follow up chat with us. TBA  

Start sending your questions ahead of time, please email them "WebCast" using the INCIID Contact Form
Subject of your email should be IVF Breakthrough Question
Check back here for time and date of this chat.


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