Recurrent spontaneous abortion (RSA) is defined as two or more consecutive pregnancies resulting in a spontaneous abortion prior to 16–20 weeks of gestational age.   The etiology of RSA is unknown, but one theory proposes that a lack of maternal blocking antibodies to prevent immunologic rejection of the fetus may be responsible.  Intravenous immunoglobulin (IVIg) has been explored as a treatment based on its ability to influence both T and B cell function. 

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

• GENE.00012 Preconceptional or Prenatal Testing of a Parent or Prospective Parent

Note: For further information regarding the use of intravenous immunoglobulin (IVIg) for other conditions, please see:

• CG-DRUG-09 Immune Globulin (Ig) Therapy

Investigational and Not Medically Necessary:

The use of intravenous immunoglobulin (IVIg) 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.

IVIg has been explored as a treatment 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 recurrent spontaneous abortion, these trials, either singly or as part of a meta-analysis, have not demonstrated a clinically significant effect on the incidence of recurrent spontaneous abortion (Porter, 2006).  A position statement from the American Society of Reproductive Medicine (ASRM, 2006) concluded that "For the management of recurrent spontaneous pregnancy loss IVIG is an experimental treatment." 

A blinded randomized controlled trial (RCT) of 41 women treated with IVIg or saline placebo found no differences in live birth rates (Jablonowska, 1999).  A multicenter RCT was conducted involving women diagnosed with lupus anticoagulant, anticardiolipin antibody, or both.  In this study the 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).  More recently, an RCT of 58 women with at least 4 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; also, there was no difference in neonatal data.

Intravenous immunoglobulin (IVIg) is a treatment used for many different conditions that involve parenteral administration of antibodies, also referred to as immunoglobulins (Igs).  The body naturally produces antibodies to fight and create immunity against disease-causing agents such as viruses and bacteria when infections occur.  Once the body has been exposed to an infection, antibodies can sometimes protect us from becoming ill if we are exposed to the same infectious agents sometime in the future.  Under many circumstances a person's ability to produce his or her own Igs is impaired and the use of other methods to boost the immune system becomes necessary. 

IVIg is produced with blood from many different donors.  This blood is then processed leaving only the Ig portion.  This pooling method leads to the term "pooled IgIV" which is sometimes used to describe this substance.  Since preparations of IVIg are derived from donor blood, the potential for contracting diseases, such as hepatitis and HIV, is a concern.  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.  Next, all 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 Ig 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 still exists.  Potential recipients of this treatment should take this risk into consideration when contemplating IVIg therapy.

Immunoglobulins (Igs):  Also known as antibodies, Igs 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.

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:

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

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 OB, Pedersen B, Rosgaard A, et al.   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.
3. 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.
4. 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.
5. 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.
6. 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. 2008; 47:646–651.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American College of Obstetricians and Gynecologists (ACOG). Management of recurrent early pregnancy loss. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2001 Feb. 12 p. (ACOG practice bulletin; no. 24).
2. American Society for Reproductive Medicine.  The Practice Committee of the American Society for Reproductive Medicine. Intravenous immunoglobulin (IVIG) and recurrent spontaneous pregnancy loss. Fertil Steril. 2006; 86( Suppl 4):S226-227.
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:S60.
4. Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD000112.

1. National Library of Medicine.  Medline Plus Health Topics: Immune globulin intravenous Injection. Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682815.html.  Accessed on December 10, 2010. 

Antiphospholipid Antibodies
Intravenous Immunoglobulin
IVIG
Recurrent Spontaneous Abortion