Intravenous Immunoglobin and Recurrent Miscarriage
Abstract & Commentary
By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff, Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: Treatment with intravenous immunoglobulin does not reduce the likelihood of another early pregnancy loss in parous women with a history of three or more consecutive unexplained miscarriages.
Source: Stephenson MD, et al. Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: A multicentered randomized placebo-controlled trial. Hum Reprod 2010;25:2203-2209.
Secondary recurrent miscarriage (defined as three or more pregnancy losses at < 20 weeks occurring in a women with a least one pregnancy carried beyond 20 weeks) may be explained by a chromosomal abnormality or be "unexplained" (idiopathic). Prior studies have suggested that idiopathic secondary recurrent miscarriage (ISRM) might be associated with an abnormal maternal immune response to subsequent pregnancies. The authors designed and conducted a multicenter, randomized, double-blinded, placebo-controlled trial comparing intravenous immunoglobulin (IVIG) to saline for the treatment of ISRM. Subjects received either preconception infusions of IVIG (500 mg/kg) or the equivalent volume of normal saline 14-21 days from the projected next menstrual period.
Pregnancy was confirmed with a serum beta hCG of at least 5 mIU/mL drawn 1-2 days after a missed menses, and repeated 1 week later, with transvaginal ultrasound performed at 6 weeks of gestation. If a subject became pregnant (confirmed with a serum beta hCG of at least 5 mIU/mL drawn 1-2 days after a missed menses), she received an infusion of her assigned treatment every 4 weeks until 18-20 weeks of gestation. The primary outcome was an ongoing pregnancy of at least 20 weeks gestation. Of the 82 women enrolled in the study, 47 became pregnant and received both the initial and ongoing infusions. The live birth rates did not significantly differ between treatments when all pregnancies (70% [16/23] in the IVIG group and 63% [15/24] in the control group; odds ratio [OR], 1.37; 95% confidence interval [CI], 0.41-4.61) or only clinical pregnancies (defined as the presence of an embryo with cardiac activity at 6 weeks of gestation; 94% [16/17] and 94% [15/16], respectively; OR, 1.07; 95% CI, 0.06-18.62) were considered. Furthermore, the authors combined their results with those of two prior RCTs evaluating IVIG for idiopathic secondary recurrent miscarriage and showed no differences in the live birth rate (70% [31/44] in the IVIG group and 62% [28/45] in the control group; OR, 1.44; 95% CI, 0.59-3.48) in the meta-analysis. The authors concluded that IVIG is not a treatment for recurrent idiopathic pregnancy loss.
Commentary
Few clinical situations compare to the sadness experienced by couples seeking pregnancy who undergo repeated early pregnancy loss. Most of us have managed the awkward transition from joy to sadness when an eagerly anticipated office ultrasound reveals a missed abortion or early fetal demise. The desire to help motivates us as physicians. Unfortunately, it sometimes motivates us to accept interventions that, while well-meaning, are ineffective, excessively costly, or harmful in another way. An immunologic basis for recurrent pregnancy loss has been hypothesized. This well-designed RCT provides strong evidence to recommend against IVIG as a treatment for recurrent pregnancy loss.
Pregnancy loss can occur in women who have never carried a completed pregnancy (primary) or in those with a prior successful pregnancy (secondary). A history of a prior successful and normal pregnancy rules out a lethal chromosomal combination in the couple (such as a balanced translocation in one parent) incompatible with any healthy offspring. Therefore, individuals with secondary miscarriage represent a distinctly different group of women than those who miscarry but have never carried a normal pregnancy (primary).
A study of women carefully monitored with a highly sensitive urine pregnancy test demonstrated that about 30% of pregnancies end in miscarriage.1 About 22% of these losses (7% of all the total number of pregnancies) occur prior to any clinical signs of pregnancy. Since more than half of all losses before 10 weeks are associated with chromosomal abnormalities such as Trisomy 21, Monosomy X (Turner's), and polyploidy, it would be extremely unwise to attempt to influence this natural selection process that begins in the womb.2
That said, I am seeing a significant number of physicians these days ordering chromosome analysis of early abortuses, even in women with secondary miscarriage with no change in partner. I think this is being influenced by the sequential screen and genetic counselors. The argument is that it is comforting to the patient to have an explanation for her loss. True enough, but if we think about this in another way, we already have an answer, since the vast majority of the time we will discover a non-recurring chromosomal abnormality. New estimates suggest that up to 80% of the time we will find a chromosomal abnormality,2 so the likelihood is high that we will find one if we look. However, in a woman with secondary miscarriage we will not gain any useful information that will change the management of a subsequent pregnancy with this expensive genetic analysis. I fail to see the clinical difference between saying: "I am sorry about your loss. Most of these are due to chromosomal problems like Down's syndrome and represent bad luck" and "I am sorry about your loss, the chromosome test tells us that the fetus had [pick one: Down's syndrome, Trisomy 18, Trisomy 13, Monosomy XO, etc.]." In either case, the follow-up conversation must be: "These events occur spontaneously, and there is nothing you did wrong. Fortunately, every pregnancy represents an independent event, like flipping a coin. You are more likely to have a miscarriage as you age, because the process by which the egg cell segregates the chromosomes is more likely to fail as the egg cell waits to complete the process of cell division that begins during fetal life. We can use your age to predict how likely you are to have another chromosomal problem in the next pregnancy. However, the most important piece of information is that since you already have a normal child, there is no lethal chromosomal combination that we would detect by examining the tissue that should prevent you from trying again to become pregnant if you wish."
With runaway health care costs, every test that we order should provide information to change our management. If there were important reasons to understand the genetics of a miscarried gestation, the test would have merit. However, there are no important interventions to prevent miscarriage in women with secondary miscarriage associated with or without a proven chromosomal abnormity. The results of the well-designed RCT by Stephenson et al demonstrate that there is no benefit to the use of intravenous immunoglobulin, even in women with repeated idiopathic miscarriage. Therefore, since there is no clinical difference in the approach to the patient when informed of the genetic combination, I would recommend against chromosomal evaluation of the products of conception in women with a single miscarriage or after repeated secondary miscarriage. Chromosomal tests are of value in evaluating recurrent primary miscarriage, but the best information comes from a karyotype of both parents. There is no difference in the frequency of an abnormal karyotype in couples with infertility without recurrent loss.3
Let us not be seduced by expensive clinical results that offer no benefit to patients. When dealing with couples experiencing recurrent loss, offer your time, recognize and assist with the grief response, and open your heart. I think $1000 invested in an experienced grief counselor will improve outcomes more than the same amount spent on a chromosome analysis. Let's put the caring back in health care.
References
- Wilcox AJ, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189-194.
- Morales C, et al. Cytogenetic study of spontaneous abortions using semi-direct analysis of chorionic villi samples detects the broadest spectrum of chromosome abnormalities. Am J Med Genet A 2008;146A:66-70.
- Papanikolaou EG, et al. Is chromosome analysis mandatory in the initial investigation of normovulatory women seeking infertility treatment? Hum Reprod 2005;20:2899-2903.
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