National Medical Policy

Subject:

IVIG for Recurrent Pregnancy Loss

Policy Number:

NMP119

Effective Date*:

March 2004

Updated:

April 2006, March 2007, February 2008, April

2011, October 2011

This National Medical Policy is subject to the terms in the

IMPORTANT NOTICE
at the end of this document
The Centers for Medicare & Medicaid Services (CMS)
For Medicare Advantage members please refer to the following for coverage
guidelines first:
Use

Source

National Coverage Determination

(NCD)
National Coverage Manual Citation
Local Coverage Determination (LCD)

Article (Local)

Reference/Website Link

Intravenous Immune Globulin (IVIG)

http://www.cms.gov/medicare-coveragedatabase/search/advanced-search.aspx
Intravenous Immune Globulin (IVIG)
http://www.cms.gov/medicare-coveragedatabase/search/advanced-search.aspx

Other
None

Use Health Net Policy

Instructions
Medicare NCDs and National Coverage Manuals apply to ALL Medicare members
in ALL regions.
Medicare LCDs and Articles apply to members in specific regions. To access your
specific region, select the link provided under Reference/Website and follow the
search instructions. Enter the topic and your specific state to find the coverage
determinations for your region
If more than one source is checked, you need to access all sources as, on
occasion, an LCD or article contains additional coverage information than
contained in the NCD or National Coverage Manual.
If there is no NCD, National Coverage Manual or region specific LCD/Article,
follow the Health Net Hierarchy of Medical Resources for guidance.

IVIG for Recurrent Pregnancy Loss Oct 11

Current Policy Statement (Update October 2011 A Medline search failed to

reveal any studies that would cause Health Net, Inc. to change its current position)
Health Net, Inc. considers intravenous immunoglobulin (IVIG) for recurrent
pregnancy loss*, also referred to as unexplained habitual abortion or miscarriage,
investigational. Experience with IVIG in treating this condition continues to be
limited to small trials, which shows that IVIG provides no significant beneficial effect
over placebo in preventing further miscarriages.
*NOTE: Per ACOG:

The loss of a pregnancy before 20 weeks is called early pregnancy loss. Most
occur in the first 13 weeks of pregnancy. Often, the early pregnancy loss is a
miscarriage (i.e., also called spontaneous abortion). The presence of fetal
chromosomal abnormalities in clinically recognized early pregnancy loss is >
50%. http://www.acog.org/publications/patient_education/bp090.cfm

Other causes of miscarriage could include genetic factors, anatomic factors,

endocrine factors, infectious factors, immunologic factors, and miscellaneous
factors (i.e. environmental, stress, placental abnormalities, medical illness and
male factors).

Recurrent Pregnancy Loss: Two consecutive losses. Caused by chromosomal

aneuploidy (i.e. trisomy 16 and XO most common) or genetic factors (i.e. Robert
translocation, single gene defects, abnormalities of spindle formation)

Codes Related To This Policy

ICD-9 Codes
634

Spontaneous abortion (miscarriage)

CPT Codes
90283 Immune globulin (IgIV), human, for intravenous use
90765 Intravenous infusion for therapy, prophylaxis, or diagnosis (specify
substance or drug); initial, up to 1 hour (CPT Code deleted. To report use
96365)
90766 Intravenous infusion for therapy, prophylaxis, or diagnosis (specify
substance or drug); each additional hour (list separately in addition to code
for primary procedure) (CPT Code deleted. To report use 96366)
90780 Intravenous infusion for therapy/diagnosis, administered by physician or
under direct supervision of physician; up to one hour (deleted 12/31/2005)
90781 each additional hour, up to eight hours (deleted 12/31/2005)
96365 Intravenous infusion, for therapy, prophylaxis or diagnosis (specif
substance or drug); initial, up to 1 hour
96366 Intravenous infusion, for therapy, prophylaxis or diagnosis (specify
substance or drug); each additional hour (List separately in addition to code
for primary procedure)

HCPCS Codes
C9270 Injection, immune globulin, (Gammaplex), intravenous, nonlyophilized (e.g.,
liquid), 500 mg

IVIG for Recurrent Pregnancy Loss Oct 11

J1561
J1561
J1563
J1564
J1566
J1567
J1568
J1569

Injection, immune globulin, intravenous, 500 mg (deleted 12/31/2002)

Injection, immune globulin, (Gamunex), intravenous, nonlyophilized (e.g.,
liquid), 500 mg
Injection, immune globulin, intravenous, 1gm (deleted 12/31/2005)
Injection, immune globulin, 10 mg (deleted 12/31/2005)
Injection, immune globulin, intravenous, lyophilized (e.g., powder) 500 mg
Injection, immune globulin, intravenous, non-lyophilized (e.g., liquid)
500 mg (deleted 12/31/2007)
Injection, immune globulin, (Octagam), intravenous, nonlyophilized
(e.g.,liquid), 500 mg
Injection, immune globulin, (Gammagard liquid), intravenous, nonlyophilized, (e.g.,liquid), 500 mg

Scientific Rationale Update October 2011

Stephenson et al. (2010) completed a multicenter, double-blinded, RCT comparing
IVIG with saline in women with idiopathic secondary recurrent miscarriage, defined
as a history of at least one prior ongoing pregnancy followed by three or more
consecutive unexplained miscarriages. Patients received either IVIG 500 mg/kg or
the equivalent volume of normal saline. Preconception infusions were administered
1421 days from the projected next menstrual period. With documentation of
pregnancy, the subject received the same infusion every 4 weeks until 1820 weeks
of gestation. The primary outcome was an ongoing pregnancy of at least 20 weeks of
gestation. A total of 82 patients enrolled, of whom 47 had an index pregnancy. All
ongoing pregnancies resulted in live births. Therefore, the live birth rates were 70%
(16/23) in the IVIG group and 63% (15/24) in the control group (P = 0.760); odds
ratio (OR) 1.37 [95% confidence interval (CI) 0.414.61]. Including only clinical
pregnancies (embryo with cardiac activity at 6 weeks of gestation), the live birth
rates were equivalent, 94% (16/17) and (15/16), respectively (P > 0.999); OR 1.07
(95% CI 0.0618.62). Meta-analysis of randomized controlled trials (RCTs)
evaluating IVIG for idiopathic secondary recurrent miscarriage revealed live birth
rates of 70% (31/44) in the IVIG group and 62% (28/45) in the control group (P =
0.503); common OR 1.44 (95% CI 0.593.48). This is the largest RCT to date in
which IVIG was evaluated in women with idiopathic secondary recurrent miscarriage;
no treatment benefit was found. The meta-analysis, which combined this study
results with two prior RCTs, also showed no significant effect of treatment with IVIG.
Antiphospholipid antibodies have been associated with a variety of medical problems,
including arterial thrombosis and venous thrombosis, autoimmune
thrombocytopenia, and fetal loss. In addition to fetal loss, several obstetric
complications have been associated with antiphospholipid antibodies, including
preeclampsia, intrauterine growth restriction, placental insufficiency, and preterm
delivery.
A large proportion of pregnancy losses related to antiphospholipid antibodies occur in
the fetal period (greater than 10 weeks of gestation). However, fetal deaths at these
gestational ages normally account for only a small proportion of all pregnancy losses,
in the general population, which occur more frequently before 10 weeks of gestation.
In a cohort of 76 women with antiphospholipid antibodies, 50% of pregnancy losses
occurred during the fetal period compared with 10% in those women without
antiphospholipid antibodies; also, 84% of women with antiphospholipid antibodies
had at least one fetal death compared with 24% of women without antiphospholipid
antibodies.

IVIG for Recurrent Pregnancy Loss Oct 11

Although antiphospholipid antibodies also are not associated with sporadic embryonic
pregnancy loss, they have been associated with recurrent embryonic or fetal loss or
both. Observational studies have consistently documented positive test results for
antiphospholipid antibodies in a higher proportion of women with recurrent
spontaneous pregnancy loss than in controls. Most studies report positive test results
for antiphospholipid antibodies in 520% of women with recurrent pregnancy loss,
although concerns about whether or not cases would meet current international
criteria for the diagnosis of APS remain a subject of debate among experts.
Preeclampsia is associated with APS. Although 1117% of women with preeclampsia
will test positive for antiphospholipid antibodies, the association is strongest in
women with severe preterm preeclampsia (less than 34 weeks of gestation). In
addition, a prospective evaluation of more than 1,000 women found that women with
antiphospholipid antibodies had an increased risk of pregnancy-induced hypertension
(odds ratio 5.5) and severe pregnancy-induced hypertension (odds ratio 8.1).
Intrauterine growth restriction (IUGR) complicates pregnancies in women with APS,
occurring in 1530% in most series. Although APS is associated with IUGR, there is
conflicting evidence of the link between antiphospholipid antibodies alone and IUGR.
Although some studies have not found a correlation between antiphospholipid
antibodies and IUGR, this discrepancy may result from the inclusion of some women
with low-positive test results for antiphospholipid antibodies.

Scientific Rationale Update February 2008

A Medline search failed to reveal any studies that would cause Health Net, Inc. to
change its current position. The Royal College of Obstetricians and Gynecologists
(RCOG) updated their guidelines on the investigation and treatment of couples with
recurrent miscarriage in 2003, however, their recommendation regarding the use of
immunotherapy, including IVIG is unchanged. The conclude Immunotherapy,
including paternal cell immunization, third-party donor leucocytes, trophoblast
membranes, and intravenous immunoglobulin (IVIG), in women with previous
unexplained recurrent miscarriage does not improve the live birth rate.
There has not been a recent update to the American College of Obstetricians and
Gynecologist (ACOG) practice bulletin on the management of recurrent early
pregnancy loss since 2001. ACOGs practice bulletin concludes Mononuclear cell
(leukocyte) immunization and IVIG are not effective in preventing recurrent
pregnancy loss.

Scientific Rationale - Initial

Recurrent abortion is a growing problem in industrialized countries where women are
delaying childbearing into their 30s and 40s. The exact frequency of spontaneous
abortion in the general population is unknown. With the availability of more sensitive
serum assays, early pregnancies are detected that formerly were written off as
simple abnormal prolongations of the menstrual cycle. Reproductive failure is defined
as the inability to conceive or to carry a pregnancy to term. Spontaneous abortion
refers to a clinical condition describing the loss of the intrauterine product prior to
the viability of the fetus, conventionally accepted as 20 weeks of intrauterine life, or
500 grams of fetal body weight. Recurrent pregnancy loss (habitual abortion or
miscarriage) is defined as two or more consecutive spontaneous abortions prior to 20
weeks gestational age with the same partner. A chromosomal abnormality is still
believed to be the most common etiologic factor behind spontaneous abortions.
Indeed, up to 50% of the examined first trimester losses show some kind of
IVIG for Recurrent Pregnancy Loss Oct 11

chromosomal abnormality. It has been speculated that spontaneous, random errors

in meiosis or mitosis occur in sperms or in oocytes or during early embryogenesis
that will lead to chromosomal damage. Antiphospholipid antibodies (lupus
anticoagulant and anticardiolipin antibodies) remain the only scientifically validated
immune cause of recurrent miscarriage.
It has been suggested that some cases of human reproductive failure may be the
consequence of immunological abnormalities. This concept was strengthened with
the recognition that recurrent miscarriage is associated with the presence of
antiphospholipid antibodies, including the lupus anticoagulant, that antinuclear
antibodies were found to be five times more common in women with unexplained
recurrent miscarriage compared to women with successful pregnancies, and that
antithyroid antibodies were reported to be twice as common in women who
miscarried compared to fertile controls
It is believed that women who have repeated spontaneous abortions lack a key
serum-blocking antibody that is supposed to protect the fetus from rejection by the
mother. The blocking factor belongs to the immunoglobulin G class and acts to
protect the fetus from maternal antibodies and subsequent immunological rejection
via the coating of fetal antigens on the placenta. It is further believed that
homozygosity in the HLA antigen system can prevent the mother from producing
blocking antibodies. Two types of immunotherapy have been explored: (1)
desensitization through injection of a suspension of the husbands white blood cells
(paternal white blood cell immunization or paternal cell alloimmunization); and (2)
serial injections of intravenous immunoglobulin (IVIG).
The use of high-dose IVIG has generated interest because of anecdotal reports of
successful pregnancy outcomes with fewer adverse effects than other modalities of
treatment. Despite the continuing controversy in this field, IVIG administration is
proposed as an immunosuppressive therapy for so-called alloimmune-mediated
recurrent miscarriage because of the observation that it contains antibodies that
block antibody-mediated immune damage. However, few data support the use of
IVIG clinically in women who are suspected of having alloimmune-mediated
recurrent miscarriage. Once limited to a few case series, 6 randomized, controlled
trials and 1 meta-analysis involving a relatively small number of patients now have
been published. Only one study has reported any benefit and even more recent
studies from the scientific literature uniformly discredit the benefit of immune
therapy.
Natural killer cells are lymphocytes that contribute to immune responses. These
lymphocytes are located in the placenta and the inner layer of the uterine wall
(decidua) during pregnancy. It is thought that elevated levels of the natural killer cell
have a correlation to habitual spontaneous abortions.
Natural killer (NK) cell activity may influence both implantation and the maintenance
of pregnancy. Increased peripheral blood NK cell cytotoxic activity has been reported
in women with a history of both recurrent miscarriage and failed IVF cycles.
Similarly, increased numbers of uterine NK cell subsets have been reported in
nonconception cycles of women with a history of recurrent miscarriage. However,
there is no evidence of a correlation between peripheral blood and uterine NK cell
populations. This lack of data needs to be appreciated by both clinicians and women
before they embark upon extensive peripheral blood tests and endometrial biopsy
analyses. The measurement of NK cells in women with reproductive failure is an area

IVIG for Recurrent Pregnancy Loss Oct 11

of active research investigation but, at the present time, no peer-reviewed clinical

applications are available.
Antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies)
remain the only scientifically validated immune cause of recurrent miscarriage.
Nonetheless, the idea that many women with otherwise unexplained recurrent
miscarriage have an aberrant maternal alloimmune response to the semiallogeneic
fetus has generated a remarkable amount of interest and controversy. This
hypothesis holds that normal pregnancy requires maternal immunologic recognition
and an immunosuppressive response to paternally derived antigens expressed by
embryo-fetal tissues. In a reversal of traditional alloimmunological thinking, early
pregnancy loss is supposed to result when there is a failure of maternal alloimmune
recognition of the conceptus. Proponents further hypothesize that alloantibodies and
natural killer cells play a role in the immune destruction of pregnancy and the natural
alloimmune recognition of pregnancy. A major problem in the field has been the lack
of agreement as to which tests indicate an abnormal alloimmune response to
pregnancy and therefore would enable the identification of women with alloimmunemediated recurrent miscarriage. Proponents argue that increased peripheral-blood
natural killercell numbers and the absence of flow cytometrically identified
maternal anti-paternal leukocyte antibodies are relevant markers. Many authorities
disagree, and appropriate identification of women with alloimmune-mediated
recurrent miscarriage is controversial.
Therefore, the usefulness of IVIG as a treatment for recurrent miscarriage would
appear to be limited. Nonetheless, some clinicians continue to treat women with IVIG
using varying regimens. This is not justified scientifically. Randomized trials of
sufficient power and with stratification for primary versus secondary recurrent
miscarriage, preconceptional versus postimplantational administration of IVIG,
number of previous miscarriages and female age are necessary before one can
determine if IVIG is of any benefit to couples with unexplained recurrent miscarriage.

Statements from Professional Societies

American College of Obstetricians and Gynecologists (ACOG) guideline on
Management of Recurrent Early Pregnancy states:
Women with recurrent pregnancy loss should be tested for lupus
anticoagulant and anticardiolipin antibodies using standard assays. If
test results are positive for the same antibody on two consecutive
occasions 6-8 weeks apart, the patients should be treated with heparin
and low-dose aspirin during her next pregnancy attempt. Mononuclear
cell (leukocyte) immunization and IVIG are not effective in preventing
recurrent pregnancy loss.
An association between the luteal phase defect and recurrent
pregnancy loss is controversial. If a diagnosis of luteal phase defect is
sought in a woman with recurrent pregnancy loss, it should be
confirmed by endometrial biopsy. Luteal phase support with
progesterone is of unproven efficacy.
Couples with recurrent pregnancy loss should be tested for parenteral
balanced chromosome abnormalities. Women with recurrent
pregnancy loss and a uterine septum should undergo hysteroscopic

IVIG for Recurrent Pregnancy Loss Oct 11

evaluation and resection. Cultures for bacteria and viruses and tests
for glucose tolerance, thyroid abnormalities, antibodies to infectious
agents, antinuclear antibodies, antithyroid antibodies, paternal human
leukocyte antigen status, or maternal antiparental antibodies are not
beneficial and, therefore, are not recommended in the evaluation of
otherwise normal women with recurrent pregnancy loss. Couples with
otherwise unexplained recurrent pregnancy loss should be counseled
regarding the potential for successful pregnancy without treatment.
American Society for Reproductive Medicine. Intravenous immunoglobulin
(IVIG) and recurrent spontaneous pregnancy loss. A Practice Committee Report. A
Committee Opinion. Birmingham, AL: ASRM; 2002.
IVIG as a treatment for recurrent pregnancy loss should be evaluated
in patients who are informed, consenting participants in an
institutional review board approved randomized clinical trial. For the
management of recurrent spontaneous pregnancy loss, IVIG is an
experimental treatment.
The University Health Consortium (1999) guidelines concluded that the use of
IVIG for recurrent pregnancy loss is "not recommended."
Royal College of Obstetricians and Gynecologists, Scientific Advisory
Committee. The management of recurrent miscarriage. Clinical Green Top Guidelines
No. 17. London, UK: RCOG; June 2001.
Immunotherapy, including paternal cell immunisation, third-party
donor
leucocytes,
trophoblast
membranes
and
intravenous
immunoglobulin (IVIG), in women with previous unexplained recurrent
miscarriage does not improve the live birth rate There is no clear
evidence to support the hypothesis that HLA incompatibility between
couples, the absence of maternal leucocytotoxic antibodies or the
absence of maternal blocking antibodies are related to recurrent
miscarriage. A Cochrane systematic review of 18 randomized
controlled trials has shown that the use of various forms of
immunotherapy, including paternal cell immunisation, third-party
donor leucocytes, trophoblast membranes and IVIG, in women with
unexplained recurrent miscarriage provides no significant beneficial
effect over placebo in preventing further miscarriage.

Review History
March 16, 2004
March 2006
April 2006
March 2007
February 2008
April 2011
October 2011

Medical Advisory Council initial approval

Coding update
Update no revisions
Update no revisions
Update no revisions
Update. Added Medicare Table with link to LCD and articles.
Codes updated. No revisions.
Update. No revisions.

This policy is based on the following evidence-based guidelines:

IVIG for Recurrent Pregnancy Loss Oct 11

1.
2.

3.

The American College of Obstetricians and Gynecologist. ACOG Practice Bulletin.

Clinical Management Guidelines for Obstetrician-Gynecologists. Number 24, Feb.
2001. Management of Recurrent Early Pregnancy Loss.
Royal College of Obstetricians and Gynecologists (RCOG). The investigation and
treatment of couples with recurrent miscarriage. London (UK): Royal College of
Obstetricians and Gynecologists (RCOG); 2003 May. Available at:
http://www.guideline.gov/summary/summary.aspx?ss=15&doc_id=7681&nbr=0
04480&string=recurrent+AND+pregnancy+AND+loss
The American College of Obstetricians and Gynecologist. ACOG Practice Bulletin.
Clinical Management Guidelines for Obstetrician-Gynecologists. Number 118.
January 2011. Antiphospholipid Syndrome. (Replaces Practice Bulletin Number
68, November 2005) Available at:
http://www.acog.org/publications/educational_bulletins/pb118.cfm

References Update April 2011

1.

Tulandi T, Al-Fozan HM. Management of couples with recurrent pregnancy loss.

August 18, 2010. Available at:
http://www.uptodate.com/contents/management-of-couples-with-recurrentpregnancy-loss?source=search_result&selectedTitle=2%7E150

References Update October 2011

1.
2.

Petrozza JC, Robertson AD, OBrien B. Early pregnancy loss. eMedicine. Updated
Jan 5, 2011. Available at: http://emedicine.medscape.com/article/260495overview
Stephenson MD, Kutteh WH, Purkiss S, et al. Intravenous immunoglobulin and
idiopathic secondary recurrent miscarriage: A multicentered randomized
placebo-controlled trial. Hum Reprod. 2010;25(9):2203-2209.

References Update February 2008

1.
2.
3.

Barnsfather K, Pietrantoni M. Intravenous immunoglobulin for recurrent

unexplained pregnancy loss: a case report. J Reprod Med. 2007 Aug;52(8):73740.
Carp HJ, Sapir T, Shoenfeld Y. Intravenous immunoglobulin and recurrent
pregnancy loss. Clin Rev Allergy Immunol. 2005 Dec;29(3):327-32.
Sapir T, Carp H, Shoenfeld Y. Intravenous immunoglobulin (IVIG) as treatment
for recurrent pregnancy loss (RPL) Harefuah. 2005 Jun;144(6):415-20, 454, 453

References Initial
1. Sipak-Szmigiel O, Ronin-Walknowska E, Miklaszwicz A. Application of
intravenous immunoglobulin therapy (IVIG) in pregnant patients with recurrent
spontaneous abortions. Ginekol Pol. 2003 May;74(5):350-5.
2. Heilmann L, von Tempelhoff GF, Pollow K. Antiphospholipid syndrome in
obstetrics. Clin Appl Thromb Hemost. 2003 Apr;9(2):143-50.
3. Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst
Rev. 2003;(1):CD000112.
4. Christiansen OB, Pedersen B, Rosgaard A, Husth M. A randomized, double-blind,
placebo-controlled trial of intravenous immunoglobulin in the prevention of
recurrent miscarriage: evidence for a therapeutic effect in women with secondary
recurrent miscarriage. Hum Reprod. 2002 Mar;17(3):809-16.
5. Carp HJ, Toder V, Gazit E, et al. Further experience with intravenous
immunoglobulin in women with recurrent miscarriage and a poor prognosis. Am J
Reprod Immunol. 2001 Oct;46(4):268-73.

IVIG for Recurrent Pregnancy Loss Oct 11

6. Branch DW, Porter TF, Paidas MJ, et al. Obstetric uses of intravenous
immunoglobulin: successes, failures, and promises. J Allergy Clin Immunol. 2001
Oct;108(4 Suppl):S133-8.
7. Clark DA, Coulam CB, Daya S, Chaouat G. Unexplained sporadic and recurrent
miscarrage in the new millennium: a critical analysis of immune mechanisms and
treatments. Hum Reprod Update. 2001 Sep-Oct;7(5):501-11.
8. Cramer DW, Wise LA. The epidemiology of recurrent pregnancy loss. Semin
Reprod Med 2000;18:3319.
9. Mecacci F, Parretti E, Cioni R, et al. Thyroid autoimmunity and its association with
non-organ-specific antibodies and subclinical alterations of thyroid function in
women with a history of pregnancy loss or preeclampsia. J Reprod Immunol
2000;46:3950.
10. Stephenson MD, Fluker MR. Treatment of repeated unexplained in vitro
fertilization failure with intravenous immunoglobulin: a randomized, placebocontrolled Canadian trial. Fertil Steril 2000;74:110813.
11. Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst
Rev. 2000;(2):CD000112.
12. Porter TF, Scott JR. Alloimmune causes of recurrent pregnancy loss. Semin
Reprod Med. 2000;18(4):393-400.

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IVIG for Recurrent Pregnancy Loss Oct 11

Policy Limitation: Members Contract Controls Coverage Determinations.

The determination of coverage for a particular procedure, drug, service or supply is not based upon the
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13. Stricker RB, Steinleitner A, Bookoff CN, Weckstein LN, Winger EE. Successful
treatment of immunologic abortion with low-dose intravenous immunoglobulin.
Fertil Steril 2000;73:53640.
14. Jablonowska B, Selbing A, Palfi M, Ernerudh J, Kjellberg S, Lindton B. Prevention
of recurrent spontaneous abortion by intravenous immunoglobulin: a doubleblind placebo-controlled study. Hum Reprod 1999;14:83841.
15. Ober C, Karrison T, Odem RR, et al. Mononuclear-cell immunisation in prevention
of recurrent miscarriages: a randomised trial. Lancet. 1999 Jul
31;354(9176):365-9.
16. Daya S, Gunby J, Porter F, Scott J, Clark DA. Critical analysis of intravenous
immunoglobulin therapy for recurrent miscarriage. Hum Reprod Update. 1999
Sep-Oct;5(5):475-82.
17. Stephenson MD, Dreher K, Houlihan E, Wu V. Prevention of unexplained recurrent
spontaneous abortion using intravenous immunoglobulin: a prospective,
randomized, double-blinded, placebo-controlled trial. Am J Reprod Immunol
1998;39:828.
18. Daya S, Gunby J, Clark DA. Intravenous immunoglobulin therapy for recurrent
spontaneous abortion: a meta-analysis. Am J Reprod Immunol. 1998
Feb;39(2):69-76.
19. Rand JH, Wu X-X, Andree HAM, et al. Pregnancy loss in the antiphospholipidantibody syndrome - a possible thrombogenic mechanism. N Engl J Med
1997;337:15460.
20. Perino A, Vassiliadis A, Vucetich A, et al. Short-term therapy for recurrent
abortion using intravenous immunoglobulins: results of a double-blind placebocontrolled Italian study. Hum Reprod 1997;12:238892.
21. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss:
treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone.
Am J Obstet Gynecol 1996;174:15849.
22. Kiprov DD, Nachtigall RD, Weaver RC, Jacobson A, Main EK, Garovoy MR. The use
of intravenous immunoglobulin in recurrent pregnancy loss associated with
combined alloimmune and autoimmune abnormalities. Am J Reprod Immunol
1996;36:22834.
23. Coulam CB, Stephenson M, Stern JJ, Clark DA. Immunotherapy for recurrent
pregnancy loss: analysis of results from clinical trials. Am J Reprod Immunol
1996;35:3529.

IVIG for Recurrent Pregnancy Loss Oct 11

10

24. Christiansen OB, Mathieson O, Husth M, et al. Placebo controlled trial of

treatment of unexplained secondary recurrent spontaneous abortions and
recurrent late spontaneous abortions with i.v. immunoglobulin. Hum Reprod
1995;10:26905.
25. Coulam CB, Krysa LW, Stern J, Bustillo M. Intravenous immunoglobulin for
treatment of recurrent pregnancy loss. Am J Reprod Immunol 1995;34:3337.
26. Silver RM, Branch DW. Recurrent miscarriage: autoimmune considerations. Clin
Obstet Gynecol 1994;37:74560.
27. Daya S, Gunby J. The effectiveness of allogeneic leukocyte immunization in
unexplained primary recurrent spontaneous abortion. Recurrent Miscarriage
Immunotherapy Trialists Group. Am J Reprod Immunol 1994;32:294302.
28. German RSA/IVIG Group. Intravenous immunoglobulin in the prevention of
recurrent miscarriage. Br J Obstet Gynecol 1994;101:10727.
29. Xu L, Chang V, Murphy A, et al. Antinuclear antibodies in sera of patients with
recurrent pregnancy wastage. Am J Obstet Gynecol 1990;163:14937.
30. Maier DB, Parke A. Subclinical autoimmunity in recurrent aborters. Fertil Steril
1989;51:2806.
Important Notice
General Purpose.
Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering
plan benefits and determining whether a particular procedure, drug, service or supply is medically
necessary. The Policies are based upon a review of the available clinical information including clinical
outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device,
evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select
national health professional organizations. Coverage determinations are made on a case-by-case basis
and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract,
including medical necessity requirements. Health Net may use the Policies to determine whether under the
facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically
necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not
constitute coverage. The member's contract defines which procedure, drug, service or supply is covered,
excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current
criteria that have been approved by Health Nets National Medical Advisory Council (MAC). The clinical
criteria and medical policies provide guidelines for determining the medical necessity criteria for specific
procedures, equipment, and services. In order to be eligible, all services must be medically necessary and
otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all
cases, final benefit determinations are based on the applicable contract language. To the extent there are
any conflicts between medical policy guidelines and applicable contract language, the contract language
prevails. Medical policy is not intended to override the policy that defines the members benefits, nor is it
intended to dictate to providers how to practice medicine.
Policy Effective Date and Defined Terms.
The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined
by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for
prior notification. If there is a discrepancy between the policy effective date and legal mandates and
regulatory requirements, the requirements of law and regulation shall govern. * In some states, new or
revised policies require prior notice or posting on the website before a policy is deemed effective. For
information regarding the effective dates of Policies, contact your provider representative. The Policies do
not include definitions. All terms are defined by Health Net. For information regarding the definitions of
terms used in the Policies, contact your provider representative.
Policy Amendment without Notice.
Health Net reserves the right to amend the Policies without notice to providers or Members. In some
states, new or revised policies require prior notice or website posting before an amendment is deemed
effective.
No Medical Advice.
The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to
members. Members should consult with their treating physician in connection with diagnosis and
treatment decisions.

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No Authorization or Guarantee of Coverage.

The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service
or supply. Members and providers should refer to the Member contract to determine if exclusions,
limitations, and dollar caps apply to a particular procedure, drug, service or supply.
Policy Limitation: Members Contract Controls Coverage Determinations.
The determination of coverage for a particular procedure, drug, service or supply is not based upon the
Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the
members contract, and requirements of applicable laws and regulations. The contract language contains
specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums,
eligibility, and other relevant terms and conditions of coverage. In the event the Members contract (also
known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies,
the Members contract shall govern. Coverage decisions are the result of the terms and conditions of the
Members benefit contract. The Policies do not replace or amend the Members contract. If there is a
discrepancy between the Policies and the Members contract, the Members contract shall govern.
Policy Limitation: Legal and Regulatory Mandates and Requirements.
The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable
legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal
mandates and regulatory requirements, the requirements of law and regulation shall govern.
Policy Limitations: Medicare and Medicaid.
Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and
determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid
members shall not be construed to apply to any other Health Net plans and members. The Policies shall
not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation.

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