Medical Policy



Subject: Administration of Immunoglobulin as a Treatment of Recurrent Spontaneous Abortion
Document #: DRUG.00013 Current Effective Date:    03/29/2017
Status: Reviewed Last Review Date:    02/02/2017

Description/Scope

This document addresses the use of immunoglobulins to treat recurrent spontaneous abortion (RSA).  RSA is defined as two or more consecutive pregnancies resulting in a spontaneous abortion prior to 16–20 weeks of gestational age.

Note:   For further information regarding pre-natal genetic testing, please see:

Note:  For further information regarding the use of immune globulin (Ig) therapy for other indications, please see:

Position Statement

Investigational and Not Medically Necessary:

The use of intravenous, intramuscular, or subcutaneous immunoglobulin as a treatment to prevent recurrent spontaneous abortion in pregnant women with a history of recurrent spontaneous abortion is considered investigational and not medically necessary.

Rationale

The use of intravenous immune globulin (IVIg) has been explored as a treatment for RSA based on its ability to influence both T and B cell function.  While there have been several clinical trials focusing on IVIg therapy as a treatment of RSA, these trials, either singly or as part of a meta-analysis, have not demonstrated a clinically significant effect on the incidence of RSA (Porter, 2006).  A Committee Opinion from the American Society of Reproductive Medicine (ASRM, 2012) stated that "Treatment with intravenous immunoglobulin (IVIG) has also been proposed for unexplained pregnancy loss.  However, several trials and meta-analyses concluded that IVIG is ineffective for primary recurrent pregnancy loss; thus, this treatment is not recommended."

A blinded, randomized controlled trial (RCT) of 41 women treated with IVIg or saline placebo found no differences in live birth rates (Jablonowska, 1999).  In a multicenter RCT involving women diagnosed with lupus anticoagulant, anticardiolipin antibody, or both, participants were randomized to one of two possible treatment groups; the first receiving concomitant heparin, low-dose aspirin and IVIg, and the second receiving only concomitant heparin and low-dose aspirin (Branch, 2000).  IVIg did not improve obstetric or neonatal outcomes beyond those achieved with a heparin and low-dose aspirin regimen.  An RCT of 58 women with at least four unexplained miscarriages tested IVIg vs. placebo and analyzed results by intention-to-treat (Christiansen, 2002).  The live birth rate was the same for both groups; there was no difference in neonatal data.  In 2012, a nonrandomized, controlled, observational study by Moraru and colleagues was published involving 64 women with either RSA or recurrent implantation failure (RIF).  A total of 40 of these subjects underwent treatment with IVIg (20 with RSA and 20 with RIF).  The remaining 24 subjects received standard care (4 RSA, 20 RIF).  Subjects in the standard care group were either self-selected or excluded from the experimental group for a variety of reasons not related to the study criteria.  The results demonstrated that 35 of 40 IVIg group subjects (85%) successfully carried to term, and the live birth rate was 82.5%.  The overall pregnancy and live birth rates for the standard care group were 25% and 12.5%, respectively.  The nonrandomized nature of the study, as well as the small groups used in this study does not allow generalization of these findings.

In 2014, Christiansen and others published the results of the largest RCT conducted to date.  This study involved 82 women with unexplained secondary RSA and a minimum of four miscarriages.  Subjects were assigned to treatment with either IVIg or placebo (albumin), beginning from the time of positive pregnancy test to gestational week 15 or pregnancy loss.  The intention-to-treat analyses showed that the live birth rates were 23/42 (54.8%) in the IVIg group and 20/40 (50.0%) in the placebo group (relative risk [RR]=1.11).  The median gestational length at delivery was minimally higher in the IVIg than the placebo group (282 versus 272 days, p=0.02); the mean birth weight was not significantly increased.  The authors concluded that IVIg did not increase the live birth rate in individuals with secondary RSA, and the treatment cannot be recommended in clinical practice.

In 2016, Wang and colleagues published the results of a meta-analysis involving 11 studies evaluating the use of IVIg for RSA that met inclusion criteria.  The data indicated that the difference in the live birth rate between the IVIg treatment and placebo groups was marginally significant (RR=1.25; p=0.05).  In both cumulative and trial sequential meta-analyses, results indicated a potential beneficial effect of IVIg but the authors stated that the evidence was inconclusive.  A subgroup analysis showed that the live birth rate in primary (RR=0.88) and secondary (RR=1.26) RSA subjects was not significantly different between the IVIg and placebo groups.  Of note, the live birth rate was significantly different when IVIg was administered before conception (RR=1.67; p<0.0001) but not after implantation (RR=1.10).  The authors concluded that the evidence is insufficient to support the beneficial effects of IVIg on unexplained RSA and that further high quality studies are needed to establish any effectiveness.

Finally, in 2015 the American College of Obstetricians and Gynecologists (ACOG) released their practice bulletin addressing early pregnancy loss.  This document does not mention any use of IVIg as appropriate treatment for the prevention of RSA.

There are currently no peer-reviewed published studies addressing the intramuscular (IM) or subcutaneous (SQ) administration of immunoglobulins.  No professional societies or organizations have addressed the administration of IM or SQ in guidelines, position statements, or other documents.  The use of these routes of administration has not been demonstrated to be safe or effective.

Background/Overview

IVIg is a treatment used for many different conditions involving immunoglobulins.  For example, the body naturally produces antibodies to fight and create immunity against disease-causing agents such as viruses and bacteria.  Under many circumstances, a person's ability to produce his or her own immunoglobulins is impaired and the use of other methods to boost the immune system becomes necessary. 

IVIg is produced by pooling blood from many different donors.  The process used to prepare IVIg for use in humans is monitored by the manufacturer and the FDA for the presence of infectious agents.  The monitoring process begins with the screening of potential donors for diseases.  Donors found to be infected are excluded from donating.  Manufacturers use a multi-step process that extracts the desired immune globulins and attempts to remove all other substances.  Finally, samples of each batch of immunoglobulin are tested for the presence of infectious particles.  While all attempts are taken to reduce the risk of infection in the use of IVIg, some small risk persists.  

The treatment of RSA using intramuscular or subcutaneous administration of immunoglobulins has not yet been studied.

Definitions

Immunoglobulins: Also known as antibodies, immunoglobulins are proteins produced by the body to fight disease.

Intravenous Immune Globulin (IVIg): A substance obtained from human blood plasma, which contains immunoglobulins (immune antibodies) to protect against infectious agents that cause various diseases.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:

CPT  
90281 Immune globulin (Ig), human, for intramuscular use
90283 Immune globulin (IgIV), human, for intravenous use
90284 Immune globulin, (SCIg), human, for use in subcutaneous infusions, 100 mg each
   
HCPCS  
J1459 Injection, immune globulin (Privigen), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1460 Injection, gamma globulin, intramuscular, 1 cc
J1556 Injection, immune globulin (Bivigam), 500 mg
J1557 Injection, immune globulin, (Gammaplex), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1559 Injection, immune globulin (Hizentra), 100 mg
J1560 Injection, gamma globulin, intramuscular, over 10 cc
J1561 Injection, immune globulin, (Gamunex-C/Gammaked), non-lyophilized (e.g., liquid), 500 mg
J1566 Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg
J1568 Injection, immune globulin, (Octagam), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1569 Injection, immune globulin, (Gammagard liquid), non-lyophilized (e.g., liquid), 500 mg
J1572 Injection, immune globulin, (Flebogamma/Flebogamma Dif), intravenous, non-lyophilized (e.g., liquid); 500 mg
J1599 Injection, immune globulin, intravenous, non-lyophilized (e.g., liquid), not otherwise specified, 500 mg
S9338 Home infusion therapy; immunotherapy, administrative services, professional pharmacy services, care coordination, all necessary supplies and equipment, per diem
   
ICD-10 Diagnosis  
N96 Recurrent pregnancy loss
O26.20-O26.23 Pregnancy care for patient with recurrent pregnancy loss
   
References

Peer Reviewed Publications:

  1. Branch DW, Peaceman AM, Druzin M, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol. 2000; 182(1 Pt 1):122-127. 
  2. Christiansen O, Larsen E, Egerup P, et al. Intravenous immunoglobulin treatment for secondary recurrent miscarriage: a randomised, double-blind, placebo-controlled trial. BJOG. 2014 Nov 21. [Epub ahead of print]
  3. 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; 17(3):809-816.
  4. Jablonowska B, Selbing A, Palfi M, et al. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Hum Reprod. 1999; 14(3):838-841.
  5. Kotlan B, Padanyi A, Batorfi J, et al. Alloimmune and autoimmune background in recurrent pregnancy loss – successful immunotherapy by intravenous immunoglobulin. Am J Reprod Immunol. 2006; 55(5):331-340.
  6. Moraru M, Carbone J, Alecsandru D, et al. Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells. Am J Reprod Immunol. 2012; 68(1):75-84.
  7. Perricone R, Di Muzio G, Perricone C, et al. High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins. Am J Reprod Immunol. 2006; 55(3):232-239.
  8. Perricone R, De Carolis C, Kroegler B, et al. Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion. Rheumatology (Oxford). 2008; 47(5):646-651.
  9. Stephenson SD, 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.
  10. Wang SW, Zhong SY, Lou LJ, et al. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis. Reprod Biomed Online. 2016; 33(6):720-736.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Obstetricians and Gynecologists (ACOG). Early pregnancy loss. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); May 2015. (ACOG practice bulletin; no. 150).  Available at: https://www.acog.org/-/media/Practice-Bulletins/Committee-on-Practice-Bulletins----Gynecology/Public/pb150.pdf?dmc=1&ts=20161117T0728255373 . Accessed on November 17, 2016.
  2. American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012; 98(5):1103-1111.
  3. American Society for Reproductive Medicine. The Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril. 2008; 90(5 Suppl):S60.
  4. Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev. 2006;(2):CD000112.
Index

Antiphospholipid Antibodies
Intravenous Immunoglobulin
IVIG
Recurrent Spontaneous Abortion

Document History

Status

Date

Action

Reviewed 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale and Reference sections.
Reviewed 02/04/2016 MPTAC review. Removed ICD-9 codes from Coding section.
Reviewed 02/05/2015 MPTAC review. Updated Description/Scope, Rationale and Reference sections.
Revised 02/13/2014 MPTAC review. Revised document title to remove "intravenous". Expanded position statement to include intramuscular and subcutaneous administration. Updated Rationale, Background, and Coding sections.
  01/01/2014 Updated Coding section with 01/01/2014 HCPCS changes; removed C9130 deleted 12/31/2013.
Reviewed 02/14/2013 MPTAC review. Updated Rationale and Reference sections. Updated Coding section with 04/01/2013 HCPCS changes.
  01/01/2013 Updated Coding section with 01/01/2013 HCPCS descriptor changes.
Reviewed 02/16/2012 MPTAC review.
  01/01/2012 Updated Coding section with 01/01/2012 HCPCS changes; removed code C9270 deleted 12/31/2011.
Reviewed 02/17/2011 MPTAC review. Updated Coding and Reference sections.
  10/01/2010 Updated Coding section with 10/01/2010 ICD-9 and HCPCS changes.
Reviewed 02/25/2010 MPTAC review. Updated Coding and Reference sections.
Revised 02/26/2009 MPTAC review. Revised title to remove "and Associated Laboratory Tests". Deleted position statement regarding testing. Revised Rationale, Coding and Reference sections.
  01/01/2009 Updated Coding section with 01/01/2009 HCPCS changes; removed Q4097 deleted 12/31/2008.
Revised 05/15/2008 MPTAC review. Added the following tests to the list of investigational and not medically necessary tests: Antibodies to phosphatidylserine, phosphatidylethanolamine or phospholipids other than anticardiolipin or lupus anticoagulant, testing for maternal serum blocker, and molecular genetic testing for highly skewed X-inactivation patterns. Updated Reference and coding sections.
  04/01/2008 Updated Coding section with 04/01/2008 HCPCS changes.
  01/01/2008 Updated Coding section with 01/01/2008 HCPCS changes; removed HCPCS J1567, Q4087, Q4088, Q4091, Q4092 deleted 12/31/2007. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Reviewed 05/17/2007 MPTAC review. Updated reference section. Updated Coding section with 07/01/2007 HCPCS changes; removed CPT 88180 deleted 12/31/2004, HCPCS J1563 and J1564 deleted 12/31/2005.
Reviewed 06/28/2006 MPTAC review. References updated.
Revised 07/14/2005 MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger Organizations

Last Review Date

Document Number

Title

Anthem, Inc.

09/18/2003

DRUG.00013 Intravenous Immune Globulin Therapy
WellPoint Health Networks, Inc.

04/28/2005

2.09.17 Intravenous Immunoglobulin as a Treatment of Recurrent Spontaneous Abortion and Associated Laboratory Tests