October 22, 2011
BlueCross BlueShield of Illinois
RE:
Patient:
Provider:
Service: IVIG
Date of service: Prior authorization for IVIG (proposed start date 10/21/2011)
Dear Medical Director:
I am writing to initiate an appeal of BCBS-IL’s denial of coverage of Intravenous
Immunoglobulin (IVIG) for treatment of recurrent pregnancy loss related to autoimmune
disorders, as detailed in the predetermination letter dated October 11, 2011.
BCBS-IL’s initial denial was based on the fact that there is insufficient evidence in support of the
use of IVIG for these purposes in the peer-reviewed literature. However, the basis for this
conclusion is both outdated and not applicable in this case. In addition, there is a large amount of
medical literature supporting the use of IVIG in this case; this evidence comes from a wide
variety of peer-reviewed journals. I have taken the time to compile a subset of this research
literature, including references and summaries of the methods and results; you can find this
information in the pages that follow.
I have undergone three attempts at in vitro fertilization (IVF). I have been pregnant three times
and five heartbeats have been recorded during those pregnancies. The first pregnancy was the
result of a natural conception; since then I have been unable to conceive naturally and I have had
one failed IVF cycle and two IVF cycles that resulted in pregnancy. Though no live birth
followed the natural conception, infertility can be considered secondary, as the first pregnancy
occurred naturally and within average latency. Missed miscarriages have followed each
conception, all of which required dilation and curettage (in fact, one miscarriage required two
D&Cs to remove all products of conception); testing results on the products of conception
have indicated normal karyotypes, ruling out aneuploidy as the cause of embryonic/fetal
demise. Moreover, male factor infertility has been ruled out, as have physical problems with my
anatomy such as fibroids, uterine septum, and blocked fallopian tubes (documentation of these
medical results available upon request).
After the third pregnancy loss, I underwent a battery of immunologic tests. I tested positive for
antinuclear antibodies (ANA) and my natural killer cell (NK) level and cytotoxicity
were elevated. Increased killing activity is associated with implantation failure and
pregnancy loss. Natural Killer cell activity or activation assay (NKa) measures the killing
activity (cytotoxicity) within each cell, as well as the ability of IVIG to suppress the killing
activity. Patients with high NK cell activity that suppress with IVIG in the NKa will respond
very well to intravenous immunoglobulin (IVIG) therapy. In fact, the live birth rate with
preconception IVIG is more than 80%, compared to 20% without treatment. My test
results indicated that the NK cell in vitro response to immunoglobulin G was adequate.
Additionally, I was found to have increased T Helper 1, inflammatory immune response. T
Helper 1/T Helper 2 cytokine ratio reflects the ratio between two opposing T Helper immune
responses. My elevated ratio reflects the dominance of TH-1 cells (represented by secreting
TNF-alpha and INF-gamma), which are cytotoxic and pro-inflammatory; as against the TH-2
cells (represented by secreting IL-10) which are important for implantation and successful
pregnancy. TNF-alpha is considered a major inflammatory mediator; it is a T-Helper 1 cytokine
produced by activated macrophages, T cells, and other cells, and has many biological activities
on the immune and reproductive system.
My medical records and test results support Dr. Kwak Kim’s clinical judgment that future
natural and IVF attempts at pregnancy will continue to fail unless I am able to be treated with
IVIG, as does evidence found in the peer-reviewed literature. For these reasons, I ask that BCBSIL reverse its decision and permit me to undergo IVIG prior to my next and final attempt at IVF.
In contrast to BCBC-IL’s claim that there is insufficient evidence to support the use of IVIG for
these purposes, research has supported the effectiveness of this treatment in achieving and
maintaining pregnancy and live birth. Historical and recent articles have shown that IVIG is
effective, especially in cases of immunologic IVF failure like mine.
Other treatments, such as prednisone therapy, are not appropriate in this case because of my
predisposition to glucose sensitivity. Moreover, “Corticosteroid therapy has been shown to be
ineffective for [spontaneous abortion] and this treatment is associated with numerous
complications during pregnancy, especially preterm delivery” (Stricker, Steinleitner, Bookoff, &
Weckstein, 2000). Thus, Dr. Kwak Kim feels that the presence of NK cells and ANA and
cytokine ratios point strongly in favor of IVIG (see Doctor’s letter requesting pre-authorization
for IVIG). Several authors, whose articles can be found below, explain how effective IVIG can
be for a patient like me, who has failed IVF repeatedly and experienced recurrent pregnancy loss.
Several other articles also indicate that a trial with IVIG is indicated at this point. Clark, Coulam,
and Stricker (2006) found that “IVIG significantly increase[s] the probability of taking home one
or more babies by patients undergoing IVF for infertility and/or early pregnancy loss.” They
explain that, “increased numbers and/or activity of circulating bloodtype NK-related cells can
translate into an unfavorable environment at the feto-maternal interface,” and add that “a
common theme in patients with IVF failure/infertility and/or recurrent miscarriages has been
increased NK activity, increased TH1/Th2 cytokine ratios, and presence of autoantibodies, and
patients undergoing IVF have an increased miscarriage rate which . . . appears to be countered by
IVIG.”
van den Heuvel and colleagues report very convincing results (van den Heuvel, Peralta, Hatta,
Han, & Clark, 2007). In their study “eight of thirty infertile women presented with high numbers
of CD56+ CD3+ NKT cells, which declined after treatment with IVIG. The elevated NKT cell
group with or without concomitant autoimmunity achieved a significantly higher successful
pregnancy rate over the course of the study, as compared to women with average numbers of
NKT cells and no evidence of autoimmunity (p = 0.018). Elevated NKT levels alone was an
independent predictor of success on treatment (p = 0.003).”
Stricker and colleagues (2000) findings also are impressive. Of the 47 women participating in
this study, 36 received initial IVIG treatment, and 24 subsequently became pregnant. Of these
women, 20 continued IVIG treatment through 26–30 weeks of gestation, and 19 (95%) had a
successful term pregnancy. Four women discontinued IVIG therapy after 10–12 weeks of
gestation, and 3 (75%) had a successful pregnancy outcome. Of the 11 women who refused
IVIG therapy, 7 became pregnant, and all 7 miscarried. The difference in pregnancy success
rate between the IVIG-treated and untreated groups was significant (p < .001). Authors also
discussed problems with the design of other studies that that did not find such a beneficial effect.
Those problems included poor patient selection that deliberately excluded older women and did
not adequately screen for immunologic abnormalities. “The resultant comparison between
younger women who have a high pregnancy success rate without any treatment significantly
biased the outcome of these studies against IVIG therapy. Other problems include irrational or
excessive IVIG regimens and inadequate patient screening for immunologic abnormalities.”
Furthermore, Hutton and colleagues recently conducted a meta-analysis and found a significant
increase in live births following IVIG use in women with secondary recurrent miscarriage (OR
2.71, 95% CI 1.09-6.73) in randomized controlled trials evaluating IVIG for treatment of
spontaneous recurrent miscarriage (Hutton, Sharma, Fergusson, Tinmouth, Hebert, Jamieson, &
Walker, 2007).
For couples with immunological problems such as mine, the chances of losing a baby increase
with each successive pregnancy. The next round of IVF would be our fourth and most likely
final attempt. Our odds without IVIG are slim. Therefore, IVIG is the best remaining option for
me and my husband, whose chance to carry a child to term is running out. The medical literature
supports this use of IVIG as a safe and effective medication for treating immunological IVF
failure. All alternatives present significant risks that are not present with IVIG. Anticoagulation therapy has been tried in isolation and is not helping. Corticosteroid therapy is
ineffective and risky. Therefore, the best alternative is IVIG. Without effective treatment, my
medical bills for another IVF attempt and likely D&C surgery will continue beyond the cost of
IVIG. Thus, it is in both BCBS-IL’s interest and mine to try IVIG therapy.
For all of these reasons, along with the additional evidence I summarize below, I urge you to
reverse BCBS-IL’s noncoverage decision and give me a chance at the safe and effective
treatment that my treating physician deems most appropriate. Of course, if you would like any
additional information, please do not hesitate to contact me or Dr. Kwak Kim’s office.
Thank you for considering this request,
Selected References
Birkenfeld A., Mukaida T., Minichiello L.., Jackson M., Kase N.G., & Yemini M. (1994).
Incidence of autoimmune antibodies in failed embryo transfer cycles. American Journal
of Reproductive Immunology, 31, 65-68.
Summary: PROBLEM: The presence of antiphospholipid antibodies lupus anticoagulant (LAC),
anticardiolipin antibody (ACA) as well as antinuclear antibody (ANA) has been
associated with early spontaneous pregnancy loss and adverse pregnancy outcome. The
purpose of this study was to investigate the possible role of autoimmune antibodies
(LAC, ACA, and ANA) as a cause of implantation failure following embryo transfer
(ET) after in vitro fertilization (IVF). METHOD: Three groups were studied: Group I, 56
patients who failed to conceive following ET; group II, 14 patients who have conceived
following IVF-ET and delivered or are carrying an uncomplicated ongoing pregnancy;
and group III, 69 patients who were new candidates for IVF-ET. RESULTS: Eighteen out
of 56 (32.1%) of patients who failed to conceive following previous IVF-ET cycle (group
I) tested positive for one or more of the autoimmune antibodies. None of the 14 patients
of group II tested positive for autoimmune antibodies (P < .02). Seven out of the 69
patients (10%) of group III were found positive to one or more of the autoimmune factor.
This rate is significantly lower than the rate of positive autoimmune antibodies detected
in group I (P < .003). Fifteen patients of the 18 who tested positive for autoimmune
antibodies and who had previously failed to conceive following ET underwent a
subsequent IVF-ET cycle while being treated with prednisone and aspirin. Seven out of
the 15 (46.6%) conceived and were able to sustain a clinical ongoing pregnancy.
CONCLUSIONS: Patients receiving ET are carrying viable embryos within the
intrauterine environment. Therefore, in this unique group of patients, failure to
demonstrate a positive pregnancy test represents an implantation failure or a very early
postimplantation loss. The results of this study suggest that periimplantation events may
be affected by autoimmune antibodies. Very early miscarriage or implantation failure
may be related to the same pathophysiological mechanism that causes recurrent
miscarriages and is diagnosed incorrectly as infertility.
Carp, H.J., Toder, V., Gazit, E., Ahiron, R., Torchinski, A., Mashiach, S., & Shoenfeld, Y.
(2001). Further experience with intravenous immunoglobulin in women with recurrent
miscarriage and a poor prognosis. American Journal of Reproductive Immunology, 46,
268-273.
Summary: PROBLEM: Women with three or more unexplained miscarriages have a 60%
chance of a subsequent live birth. Intravenous immunoglobulin (IVIG) has not been
conclusively shown to improve this prognosis. This study assessed the effect of IVIG in
patients expected to have a poor outcome if untreated, i.e. women with five or more
abortions, who have aborted after paternal leukocyte immunization or who continue to
abort despite expressing anti-paternal complement dependent antibody. METHODS:
Seventy-six women received IVIG in a dose of 400 mg/kg body weight, in one day (total
30-45 g) in the follicular phase of a cycle in which pregnancy was planned. A booster
dose was administered when pregnancy was diagnosed. Their results were compared to
an untreated control group of 74 women. RESULTS: Thirty-five (49%) pregnancies in
treated women have resulted in live births or passed their previous stages of abortion
compared to 23 (31%) in control patients (P = 0.04). CONCLUSIONS: These figures
indicate that IVIG may prevent further miscarriages in this poor prognosis population.
These figures are especially significant considering the doubt concerning the efficacy of
IVIG in patients with three miscarriages and therefore a relatively good prognosis.
Christiansen, O.B., Pedersen, B., Rosgaard, A., & Husth, M. (2002). A randomized, doubleblind, placebo-controlled trial of intravenous immunoglobulin in the prevention of
recurrent miscarriage:Evidence for a therapeutic effect in women with secondary
recurrent miscarriage. Human Reproduction, 17, 809-816.
Summary: BACKGROUND: Previous trials of intravenous immunoglobulin (IVIG) treatment
of women with recurrent miscarriage (RM) have provided diverging results. This may be
due to different inclusion criteria and suboptimal treatment protocols in some trials.
METHODS: According to a computer-generated list, 58 women with at least four
unexplained miscarriages were randomly assigned to receive infusions of high doses of
IVIG or placebo starting as soon as the pregnancy test was positive. RESULTS: In the
intention-to-treat analysis, a 45% live birth rate was found in both allocation groups. In
patients with secondary RM, 50% in the treatment group and 23% in the placebo group
had successful pregnancies (P = not significant). When data from the present and a
previous placebo-controlled trial of the same treatment were combined, 15/26 (58%) of
the patients with secondary RM in the treatment group versus 6/26 (24%) in the placebo
group had successful outcomes (P < 0.02). Only 7% of the karyotyped abortuses were
abnormal. CONCLUSIONS: IVIG may improve pregnancy outcome in patients with
secondary RM.
Clark DA, Coulam CB, Stricker RB. (2006) Is intravenous immunoglobulins (IVIG) efficacious
in early pregnancy failure? A critical review and meta-analysis for patients who fail in
vitro fertilization and embryo transfer (IVF). Journal of Assisted Reproduction &
Genetics, 23, 1-13.
Summary: Problem: Intravenous Immunoglobulins (IVIG) are widely used off label in the
treatment of early reproductive failure. As IVIG is expensive, and may have side-effects,
evidence of efficacy is needed. Previous results have suggested that the pre-conception
treatment of primary recurrent abortion patients might be effective, but the data set has
been too small for adequate statistical power. More recently it has been suggested that
IVIG may improve the success rate of in vitro fertilization and embryo transfer (IVF) in
patients with prior IVF failures, but clinical trials have given conflicting results that need
explanation. Systematic reviews generating inconclusive results have focused on
methodological rigor to the exclusion of biological plausibility. Methods: Review of
current basic science of design, measurement, and evaluation of clinical trials and basic
science mechanisms providing a rationale for treatment. Meta-analysis of published
randomized controlled and cohort-controlled trials (updated with two unpublished data
sets) evaluating IVIG treatment in IVF failure patients. Live birth rate was used as the
most relevant endpoint. The ability of different sources of IVIG to suppress natural killer
(NK) cell activity was determined using a standard 51Cr- release assay in vitro. Results
and conclusions: Meta-analysis of three published randomized controlled trials (RCTs) of
IVIG in IVF failure patients shows a significant increase in the live birth rate per woman
(p = 0.012; Number Needed to Treat for 1 additional live birth, NNT = 6.0 women).
Using live birth rate per embryo transferred, and adding data from two cohort-controlled
trials to the meta-analysis further supports this conclusion (overall p = 0.000015, NNT =
3.7 women). Relevant variables appear to include properties and scheduling of the IVIG,
and selection of patients with abnormal immune test results. Different IVIG preparations
vary significantly in their ability to suppress NK activity in vitro. A rationale for use of
IVIG is provided by a review of mechanisms of IVIG action and mechanisms underlying
failure of chromosomally normal embryos.
Coulam, C. B., & Goodman, C. (2000). Increased pregnancy rates after IVF/ET with intravenous
immunoglobulin treatment in women with elevated circulating C56+ cells. Early
Pregnancy, 4, 90-98.
Summary: Intravenous (IV) immunoglobulin (Ig) has been previously shown to increase
pregnancy rates after previously failed in vitro fertilization (IVF) embryo (ET) attempts
in women who are efficient embryo producers (fertilize at least 50% of oocytes retrieved
and generate at least 3 embryos/cycle). Women experiencing implantation failure have a
higher frequency of elevated percentage of circulating CD56+ (natural killer) cells
(>12%) than fertile women (3-12%). To evaluate the effects of IVIG on pregnancy rates
in women with elevated percentage of circulating CD56+ cells, 32 women who had
previously failed IVF/ET (>12 embryos transferred without pregnancy) were studied.
Pregnancy and live birth rates with and without IVIG were compared in the same woman.
All 32 women had previously failed to conceive after at least 12 ET, were efficient
embryo producers and had persistently elevated plasma concentrations of CD56+ cells.
Each woman received IVIG 500mg/kg prior to ET. If serum hCG concentrations were
positive for pregnancy, IVIG was continued at 500mg/kg/mo until 28 weeks gestation.
Pregnancy rates with and without IVIG were 56% and 9% (P<0.0001). The rate of live
birth was 38% with IVIG and 0% without IVIG (P<0.0001). IVIG enhances pregnancy
and live birth rates in women with elevated circulating CD56+ cells who have a history
of implantation failure. Despite technologic advances leading to enhancement of
fertilization rates after in vitro fertilization (IVF) (1, 2) implantation rates after embryo
transfer (ET) have not increased significantly (3) over the last 20 years (4). Implantation
rates after IVF/ET are influenced by the quality of the embryos and receptivity of the
endometrium (3-9). Endometrial receptivity involves both hormonal (10-13) and
immunologic (14-29) factors. Among the immunologic factors that play a crucial role in
successful implantation are natural killer (NK) cells (14-18). NK cells present within the
decidua that express CD56(but lack CD 16) have been associated with successful
implantation (14-18). A deficiency of decidual CD56+ CD16- cells (18) and an increase
in circulating CD56+ cells (25, 26) have been observed in women experiencing
implantation failure. Women experiencing implantation failure after IVF and multiple ET
have been successfully treated with intravenous (IV) immunoglobulin (Ig) (27). IVIG
reduces activation of NK cells and NK killing activity both in vitro (29) and in vivo (30-
31). This reduction in activation of NK cells is essential for normal implantation to occur
(14). To further define the role of IVIG for treatment of implantation failure, pregnancy
and live birth rates were compared before and after IVIG treatment in women undergoing
IVF/ET who had elevated levels of circulating CD56+ cells.
Gleicher N., Liu H.L., Dudkievicz A., Rosenwaks Z., Kaberlien G., Pratt D., et al. (1994).
Autoantibody profiles and immunoglobulin levels as predictors of in vitro fertilization
success. American Journal of Obstetrics and Gynecology, 170, 1145-1149.
Summary: STUDY DESIGN: This was a blinded study in which laboratory evaluations were
performed on coded samples obtained from another institution. Codes were broken and
data were analyzed after results of all laboratory tests had been reported out. One hundred
five infertility patients who had undergone in vitro fertilization were randomly chosen.
Among those, 46 were considered low responders (six or fewer oocytes were retrieved)
and 59 as high responders (13 to 30 oocytes were retrieved). Total immunoglobulin G,
M, and A levels and 15 autoantibody levels (6 antiphospholipids, 5 antihistones, and 4
antipolynucleotides) were determined separately for immunoglobulin G, immunoglobulin
M, and immunoglobulin A isotypes. RESULTS: High and low responders demonstrated
an unusual incidence of autoantibody (25% and 30%, respectively) and immunoglobulin
(46% and 48%, respectively) abnormalities. They did not differ from each other,
however, in either immunoglobulin or autoantibody parameters. Autoantibody and
immunoglobulin abnormalities alone or in combination did not predict pregnancy success
(24% vs 16%), incidence of chemical pregnancies (15% vs 24%), or clinical pregnancy
loss (9% vs 11%) when such women were compared with those without either
abnormality. However, the occurrence of hypergammaglobulinemias, in contrast to
hypogammaglobulinemias, was associated with a significant decrease in the clinical
pregnancy rate (6% vs 24%, p = 0.05). CONCLUSIONS: Neither autoantibody
abnormalities nor total immunoglobulin abnormalities allow differentiation between high
and low responders in in vitro fertilization cycles. The presence of autoantibody and total
immunoglobulin abnormalities also does not predict low clinical pregnancy rates. Within
a group of women with immunoglobulin abnormalities, those with
hypergammaglobulinemias appear, however, at significant risk for low pregnancy rates
with in vitro fertilization. This observation suggests that high total immunoglobulin levels
may serve as a marker for an as yet to be determined immunologic factor that adversely
affects the chance of conception. The evaluation of total immunoglobulin levels may be
indicated as part of a routine infertility workup.
Graphou, O., Chioti, A., Pantazi, A., Tsekoura, C., Kontopoulou, V., et al. (2003). Effect of
intravenous immunoglobulin treatment on the Th1/Th2 balance in women with recurrent
spontaneous abortions. American Journal of Reproductive Immunology, 49, 21-29.
Summary: PROBLEM: The way by which intravenous immunoglobulin (IVIG) acts to prevent
immunlogically mediated recurrent spontaneous abortions (RSA) has not been clarified.
In the present study, a possible effect of IVIG on the T helper cell (Th1/Th2) balance was
investigated in abortions of either alloimmune or autoimmune abnormalities. METHOD
OF STUDY: The study included 21 women treated with IVIG before conception because
of a history of RSA characterized by alloimmune abnormalities (n = 15) or associated
with anti-phospholipid antibodies (APA) (n = 6). Peripheral blood samples, collected
before and 5 days after the first IVIG infusion, were stimulated, and Th1 and Th2 cells
were detected by flow-cytometric analysis using a combination of monoclonal antibodies
against T-cell surface markers and intracellular interferon (IFN)-gamma and interleukin
(IL)-4. The percentage of IFN-gamma-producing (Th1) and IL-4-producing (Th2) cells
and the Th1/Th2 ratio were compared between pre- and post-infusion samples.
RESULTS: A decrease of Th1 percentage in 66.6% of the cases and a concurrent Th2
percentage increase (47.61%) resulted in a decrease in the Th1/Th2 ratio in most of the
cases (76.1%) (p < 0.01). Similar results were found in Group A (Th1/Th2 decreased in
60% of the cases, p < 0.05), while in Group B the effect of IVIG was not clear (Th1/Th2
increased in three and decreased in another three cases). CONCLUSION: Our finding
suggests that IVIG administration in women with alloimmune RSA enhances Th2
polarization. This is not always the case with APA-associated abortions.
Hutton, D., Sharma, R., Fergusson, D., Tinmouth, A., Hebert, P., Jamieson, J., & Walker, M.
(2007). Use of intravenous immunoglobulin for treatment of recurrent miscarriage: A
systematic review. BJOG: An International Journal of Obstetrics and Gynaecology, 114,
134-142.
Summary: BACKGROUND: Intravenous immunoglobulin (IVIG) is a fractionated blood
product whose off-label use for treating a variety of conditions, including spontaneous
recurrent miscarriage, has continued to grow in recent years. Its high costs and short
supply necessitate improved guidance on its appropriate applications. OBJECTIVE: We
conducted a systematic review of randomised controlled trials evaluating IVIG for
treatment of spontaneous recurrent miscarriage. SEARCH STRATEGY: A systematic
search strategy was applied to Medline (1966 to June 2005) and the Cochrane Register of
Controlled Trials (June 2005). SELECTION CRITERIA: We included all randomised
controlled trials comparing all dosages of IVIG to placebo or an active control. DATA
COLLECTION AND ANALYSIS: Two investigators independently extracted data using
a standardised data collection form. Measures of effect were derived for each trial
independently, and studies were pooled based on clinical and methodologic
appropriateness. MAIN RESULTS: We identified eight trials involving 442 women that
evaluated IVIG therapy used to treat recurrent miscarriage. Overall, IVIG did not
significantly increase the odds ratio (OR) of live birth when compared with placebo for
treatment of recurrent miscarriage (OR 1.28, 95% CI 0.78-2.10). There was, however, a
significant increase in live births following IVIG use in women with secondary recurrent
miscarriage (OR 2.71, 95% CI 1.09-6.73), while those with primary miscarriage did not
experience the same benefit (OR 0.66, 95% CI 0.35-1.26). AUTHOR'S
CONCLUSIONS: IVIG increased the rates of live birth in secondary recurrent
miscarriage, but there was insufficient evidence for its use in primary recurrent
miscarriage.
Kwak Kim, J. Y., Gilman-Sachs, A., Beaman, K. D., & Beer, A. E. (1992). Reproductive
outcome in women with recurrent spontaneous abortions of alloimmune and autoimmune
causes: preconception versus postconception treatment. American Journal of Obstetrics
and Gynecology, 166, 1787-1795.
Summary: OBJECTIVES: The null hypothesis is that treatment of women with recurrent
spontaneous abortions with anticoagulation and immunosuppression will not increase the
reproductive outcome if it is started preconceptionally. STUDY DESIGN: Ninety-four
women with recurrent spontaneous abortion with autoimmune abnormalities comprised
the study group. Group I began autoimmune therapy 48 hours after ovulation: heparin
5000 U twice daily, aspirin 80 mg daily, and prednisone 5 mg twice daily, with an
increase to 10 mg twice daily when pregnant. Group II started the same medication after
a positive pregnancy test. Group III received no medication. Controls were 19 women
with no autoimmune abnormalities. The frequency of reproductive outcome was subject
to multiple comparison by the Duncan test. RESULTS: The percentages of live-born
children in groups I, II, and III were 74%, 44%, and 11%, respectively. CONCLUSIONS:
Preconception diagnostic work-up and treatment of autoimmune abnormalities in women
with histories of recurrent spontaneous abortion is advocated.
Kwak Kim, J. Y., Kwak, F. M., Gilman-Sachs, A., Beaman, K. D., Cho, D.D., & Beer, A.E.
(2000). Immunoglobulin G infusion treatment for women with recurrent spontaneous
abortions and elevated CD56+ natural killer cells. Early Pregnancy, 4, 154-164.
Summary: We aimed to investigate the clinical effect of intravenous immunoglobulin G (IVIG)
treatment in recurrent aborters with elevated peripheral blood CD56+ NK cell levels
while on lymphocyte immunization, anticoagulation and prednisone treatment, with
respect to subsequent live birth and reproductive outcome. Thirty-three women with
recurrent abortions achieved alloimmune recognition after lymphocyte immunizations.
All had autoimmune abnormalities and received preconception anticoagulation and
prednisone treatment. At the time of positive pregnancy testing, 18 women with normal
NK cell levels (<12%) and 6 with elevated NK cell levels (>12%) continued
anticoagulation and prednisone treatment, and 9 with elevated NK cell level initiated
additional IVIG treatment. The live birth rates of women with elevated NK cell level
(>12%) who initiated post-conception IVIG treatment in addition to anticoagulation and
prednisone (100.0%), women with normal NK cell levels (<12%) who continued
anticoagulation and prednisone (83.3%) and women with elevated NK cell level (>12%)
who continued anticoagulation and prednisone (33.3%) are significantly different
(P=0.0065). Prevalence of intrauterine growth retardation and preterm delivery among 3
study groups were not different. In conclusion, post-conception IVIG treatment
significantly improves reproductive outcome in women with elevated CD56+ NK cells
with pregnancy who received preconception lymphocyte immunization, anticoagulation
and prednisone treatment.
Kwak Kim, J. Y., Quilty, E. A., Gilman-Sachs, A., Beaman, K. D., & Beer, A. E. (1995).
Intravenous immunoglobulin infusion therapy in women with recurrent spontaneous
abortions of immune etiologies. Journal of Reproductive Immunology, 28, 175-188.
Summary: We have investigated clinical effectiveness of intravenous immunoglobulin G
infusion (IVIG) on antiphospholipid antibody titers in five women with evidence of
antiphospholipid antibody-associated recurrent spontaneous abortions and one with
antinuclear antibody who became refractory to conventional autoimmune treatment
during pregnancy and experienced pregnancy complications. Three women developed
intrauterine growth retardation and three had complicated twin pregnancies with rising
autoantibody titers. Antiphospholipid antibody and antinuclear antibody titers were tested
pre and 2 weeks after each IVIG infusion. We report that: (i) IgG antiphospholipid
antibody titers were significantly suppressed after each IVIG infusion (P < 0.05); (ii) IgM
antiphospholipid antibody titers were also significantly suppressed after each IVIG
infusion (P < 0.0001); (iii) decreased titers of autoantibodies paralleled increased levels
of maternal IgG which lasted for at least 30 days; the autoantibodies showed a definite
rise again prior to the next infusion; (iv) antinuclear antibody titers were effectively
suppressed; and (v) rising autoantibody titers combined clinical manifestation of
intrauterine growth retardation and women with complicated twin pregnancies. We
conclude that IVIG infusion effectively suppresses IgM and IgG autoantibodies to
phospholipids and antinuclear antibody in autoimmune women with a history of recurrent
spontaneous abortions and refractory to conventional anticoagulation or
immunosuppressive treatment.
Morikawa, M., Yamada, H., Kato, E.H., Shimada, S., Kishi, T., Yamada, T., Kobashi, G., &
Fujimoto, S. (2001). Massive intravenous immunoglobulin treatment in women with four
or more recurrent spontaneous abortions of unexplained etiology: down-regulation of NK
cell activity and subsets. American Journal of Reproductive Immunology, 46, 399-404.
Summary: The aims of this study were to investigate the efficacy of massive intravenous
immunoglobulin (MIVIG) treatment for women with recurrent spontaneous abortion
(RSA) of unexplained etiology, and to investigate changes in peripheral natural killer
(NK) cell activity and subsets. METHOD OF STUDY: MIVIG treatment was performed
in 18 pregnancies from 15 women with 4 or more consecutive RSA of unexplained
etiology. NK cell activity and subsets were assessed in 8 of the pregnancies. RESULTS:
14 pregnancies resulted in live births and 4 resulted in abortions with chromosome
abnormality. The pre-infusion NK cell activity (mean + SD. 40.9 + 17.0%) at 4.4 +/- 0.5
weeks of gestation (GW) decreased to 15.0 +/- 7.90% at post-infusion status (5.4 +/- 0.5
GW). Pre-infusion percentages of CD56+ CD16- cells (3.5 +/- 2.1%) and CD56+ CD16cells (16.8 +/- 8.8%) decreased to 3.0 +/- 2.2% and 11.1 +/- 6.9%, respectively, after
MIVIG treatment. CONCLUSIONS: MIVIG treatment was effective in all 14
pregnancies from RSA women of unexplained etiology, excluding 4 abortions with
chromosome abnormality. Peripheral NK cell activity and subsets were suppressed by
MIVIG treatment.
Morikawa, M., Yamada, H., Kato, E. H., Shimada, S., Sakuragi, N., Fujimoto, S., & Minakami,
H. (2003). Live birth rate varies with gestational history and etiology in women
experiencing recurrent spontaneous abortion. European Journal of Obstetrics and
Gynecology and Reproductive Biology,109, 21-26.
Summary: OBJECTIVES: The aims of this study were to assess pregnancy outcome in relation
to etiologic factors of recurrent spontaneous abortion (RSA). STUDY DESIGN: The
pregnancies from consecutive 216 RSA women were assessed for live birth rates (LBR)
according to etiology. The LBR in 110 pregnancies from RSA women with unexplained
etiology was investigated according to various therapies. An attempt to karyotype the
abortuses was made. RESULTS: Excluding pregnancies ending in abortion with
abnormal karyotype, the LBR in primary recurrent spontaneous aborters (68.8%) who
experienced three or more abortions was significantly lower than that in primary repeated
aborters (82.4%) who experienced two abortions. The LBR ranged from 50 to 100%
according to the etiology. In RSA women with unexplained etiology, the LBR in those
undergoing massive intravenous immunoglobulin (MIVIG) therapy (100%) was
significantly higher than those with low dose aspirin (57.1%) and luteal support therapy
(67.3%). CONCLUSIONS: Excluding pregnancies ending in abortion with abnormal
karyotype, we found that LBR varied with abortion history and etiologic factors of RSA.
Scher, J. & Salazaar, C. (2000). Clinical experience with IVIG Rx in patients with prior failed
IVF pregnancies: report of 30 consecutive patients. American Journal of Reproductive
Immunology, 44, 121-124.
Summary: PROBLEM: This study reviews one practitioner's experience with intravenous
immunoglobulin (IVIG) therapy in the in-vitro fertilization (IVF) cycles of 30 patients
with previous IVF failures. METHOD OF STUDY: Thirty patients had undergone 82
prior assisted reproductive technology (ART) cycles (mean 3.9 +/- 2 failed ART cycles,
median 3.0, range 1-8) yielding one term birth, one loss at 22.5 weeks, and five chemical
pregnancies. These patients underwent comprehensive clinical and laboratory evaluation,
including immunologic workup, and were accepted for IVIG therapy in their next IVF
cycle. RESULTS: A total of 40 cycles were treated. Twenty-four (60%) of the IVIGtreated IVF cycles showed a positive human chorionic gonadotropin test. Comparing the
IVIG cycles to the untreated ART cycles, there were no differences in the number of
embryos transferred, fertilized embryos, or eggs. Eighty-six percent of the cases with
confirmed implantation delivered; there was one chemical pregnancy, one 20-week
spontaneous fetal death, and one trisomy. Five (24%) of the 21 pregnant patients
delivered at 30-36 weeks. The remaining 13 delivered at term. Only three (11%) had no
positive immune test. CONCLUSION: In what may be a selected population of IVF
patients (with high incidence of abnormal immune testing), early IVIG therapy may be
associated with the improved success of IVF, and the high rate of live birth
Sipak-Szmigiel, O., Ronin-Walknowska, E., & Miklaszwicz, A. (2003). Application of
intravenous immunoglobulin therapy (IVIG) in pregnant patients with recurrent
spontaneous abortions. Ginekologia Polska, 74, 35-355.
Summary: OBJECTIVE: Clinical outcome of pregnancy in patients with recurrent pregnancy
losses treated with IVIG during their current pregnancy. MATERIAL AND METHODS:
The study group consisted of 10 pregnant women with 3-5 spontaneous abortions. Any
genetic, anatomical or infectious abnormalities were excluded as well as antiphospholipid
antibody syndrome and negative lymphocytotoxic test. The treatment consisted of
passive immunotherapy by means of intravenous administration of immunoglobulin
(IVIG) at a dose of 0.4 g/kg b.w. Therapy was commenced at week 5-6 of gestation,
infusions were repeated every 3-4 weeks until 28th week of gestation in 5-, 3- and 1-day
protocols. In 2 patients that therapy followed active immunotherapy with paternal
lymphocytes. RESULTS: Eight (80%) patients bore healthy babies (3 preterm); in 2 cases
embryos died at 6-7 week of gestation. CONCLUSIONS: The results confirm the
efficacy of IVIG in pregnant patients with recurrent spontaneous abortions in whom
likelihood of immunological pattern of pregnancy failures is high.
Stricker, R.B., Steinleitner, A., Bookoff, C.N., Weckstein, L.N., & Winger, E.E. (2000).
Successful treatment of immunologic abortion with low-dose intravenous
immunoglobulin. Fertility and Sterility, 73, 536-540.
Summary: OBJECTIVE: To evaluate the efficacy of low-dose intravenous immunoglobulin
(IVIG) treatment in older women with immunologic abnormalities and recurrent
spontaneous abortion (RSA), a condition referred to as immunologic abortion. DESIGN:
Prospective clinical trial. SETTING: Outpatient referral practice. PATIENT(s): Fortyseven women were enrolled in the study. The mean age of the women was 37 years
(range, 28-45 years), and the mean number of prior miscarriages was 3.7. Immunologic
abnormalities included antiphospholipid antibodies (32%), antithyroid antibodies (53%),
antinuclear antibodies (28%), antiovarian antibodies (2%), increased natural killer cells
(40%), increased immunoglobulin (Ig)M level (28%), and increased CD4/CD8 T-cell
ratio (15%). One patient had IgA deficiency, and three women had endometriosis. Thirtyone of the 47 patients (66%) had more than one immunologic abnormality.
INTERVENTION(s): Treatment with IVIG at a dose of 0.2 g/kg within 2 weeks of
attempted conception. Once conception was achieved, IVIG treatment was continued on
a monthly basis at the same dose through 26-30 weeks of gestation. MAIN OUTCOME
MEASURE(s): Successful pregnancy or recurrent abortion.Result(s): Of the 47 women,
36 received initial IVIG treatment, and 24 subsequently became pregnant. Of these
women, 20 continued IVIG treatment through 26-30 weeks of gestation, and 19 (95%)
had a successful term pregnancy. Four women discontinued IVIG therapy after 10-12
weeks of gestation, and 3 (75%) had a successful pregnancy outcome. Of the 11 women
who refused IVIG therapy, 7 became pregnant, and all 7 miscarried. The difference in
pregnancy success rate between the IVIG-treated and untreated groups was significant
(P=.001). Three women had adverse reactions during the low-dose IVIG infusion, and
these reactions resolved when the IVIG brand was changed. Fetal abnormalities were not
observed. CONCLUSION(s): Low-dose IVIG therapy is beneficial for older women with
immunologic abortion.
Stricker, R.B., Steinleitner, A., & Winger, E. E. (2002). Intravenous immunoglobulin (IVIG)
therapy for immunologic abortion. Clinical and Applied Immunology Reviews, 2, 187199.
Summary: Recurrent pregnancy loss associated with immunologic abnormalities has been
termed immunologic abortion. Immunologic abortion occurs primarily in women over the
age of 30 years and may affect either natural or in-vitro fertilization (IVF)-induced
pregnancy. In this article, we review the humoral and cellular immunologic abnormalities
that have been associated with this form of recurrent abortion, and we discuss treatment
options for women with this disorder. In particular, we have focused on intravenous
immunoglobulin (IVIG) treatment for immunologic abortion. We analyzed 14 studies of
IVIG therapy for recurrent loss of natural or IVF-induced pregnancies. Factors associated
with successful use of IVIG were: (a) Older mean patient age; (b) inclusion of women
with immunologic abnormalities; (c) initiation of IVIG therapy prior to conception; and
(d) repeated administration of IVIG at physiologic intervals during pregnancy. When
used according to these parameters, IVIG therapy is safe and effective for women with
immunologic abortion.
Stricker, R. B., & Winger, E. E. (2005). Update on treatment of immunologic abortion with
low‐dose intravenous immunoglobulin. American Journal of Reproductive
Immunology, 54, 390-396.
Summary: PROBLEM: Recurrent spontaneous abortion associated with immunologic
abnormalities has been termed immunologic abortion. Previously we showed that
treatment with low-dose intravenous immunoglobulin (IVIG) appears to be beneficial for
older women with immunologic abortion. We now report the results of IVIG treatment in
a larger group of women with this disorder. METHOD OF STUDY: A total of 99 women
were prospectively evaluated for immunologic abortion, which was defined as three or
more miscarriages and the presence of specific immunologic abnormalities. Prior to the
next conception, patients were treated with IVIG at a dose of 0.2 g/kg. Once conception
was achieved, IVIG treatment was continued on a monthly basis through 26-30 weeks of
pregnancy. RESULTS: The average age of the women was 37 years (range: 28-49), and
the average number of miscarriages was 3.8 (range: 3-12). Of the 99 women, 72 received
initial IVIG treatment, and 50 subsequently became pregnant. Of these women, 42 (84%)
had a successful term pregnancy. Of the 27 women who refused IVIG therapy, 20
became pregnant and 18 (90%) miscarried. The difference in pregnancy success rate
between the IVIG-treated and untreated groups was significant (P = 0.001). Four women
had mild allergic reactions during IVIG infusion, and these reactions resolved when the
IVIG brand was changed. Fetal abnormalities were not observed. CONCLUSION: We
conclude that low-dose IVIG therapy is safe and effective for older women with
immunologic abortion.
van den Heuvel, M. J., Peralta, C. G., Hatta, K., Han, V. K., & Clark, D. A. (2007). Decline in
number of elevated blood CD3+ CD56+ NKT cells in response to intravenous
immunoglobulin treatment correlates with successful pregnancy. American Journal of
Reproductive Immunology, 58, 447-459.
Summary: Problem: Patients with elevated blood natural killer (NK) cells may be offered
intravenous immunoglobulin (IVIG) treatment, but there is controversy about the utility
of blood NK cell testing. Human CD56+ NK cells include several subpopulations that
include the putatively cytotoxic CD56+CD16+ subset. In mouse models of pregnant
failure, NKT cells appear to be important. However, a mouse model may only be
pertinent to a subset of patients, as recurrent pregnancy failure is a heterogenous group.
Method of Study: An ethics-approved observational study was done to observe the effect
of treatment on total blood lymphoid cells, and subsets of CD56+ blood lymphocytes
including CD56+ CD3+ NKT cells determined by flow cytometry, and to correlate with
pregnancy outcome. Fifteen fertile women with a history of successful pregnancy and
thirty-one women suffering from repeated implantation failure or recurrent spontaneous
abortion provided serial blood samples during one menstrual cycle or prior to and during
treatment. IVIG was administered to the latter group with or without heparin/aspirin.
Result: Eight of thirty infertile women presented with high numbers of CD56+ CD3+
NKT cells, which declined after treatment with IVIG. The elevated NKT cell group with
or without concomitant autoimmunity achieved a significantly higher successful
pregnancy rate over the course of the study, as compared to women with average
numbers of NKT cells and no evidence of autoimmunity (P = 0.018). Elevated NKT
levels alone was an independent predictor of success on treatment (P = 0.003).
Conclusion: Elevated NKT cells in recurrent pregnancy loss or implantation failure can
be ameliorated with IVIG treatment, and result in successful pregnancy. Assay of NKT
cell numbers may idengify patients who are more likely to benefit from IVIG therapy and
merits further examination in randomized phase II studies.