Controversies

Do Rh-negative women with first trimester spontaneous abortions need Rh immune globulin?^B

Blaine Hannafin MD*, Frank Lovecchio DO, MPH, Paul Blackburn DO

Department of Emergency Medicine, Maricopa Medical Center, Phoenix, AZ 85006, USA

Received 21 January 2006; accepted 26 January 2006

Abstract

Objective: To examine whether literature supports the use of Rh immune globulin in Rh-negative women with first trimester spontaneous abortions to prevent maternal sensitization to the fetal Rh antigen and subsequent fetal morbidity and mortality.

Methods: We searched MEDLINE (1966-2005), the Cochrane Central Register of Controlled Trials, EMBASE (1990 to 2005), and the reference sections of the articles found. The search is considered updated to December of 2005. Search terms included Vaginal bleeding, Rh negative, Rh immune globulin, RhoGAM, isoimmunization, sensitization, first trimester pregnancy, threatened, and sponta- neous abortion.

Results: The evidence to support the use of Rh immune globulin for a diagnosis of first trimester spontaneous abortion is minimal. There is a paucity of well-designed research that examines maternal sensitization or hemolytic disease of the newborn as an outcome in patients receiving, versus not receiving, Rh immune globulin in first trimester bleeding. There is significant evidence to demonstrate fetomaternal hemorrhage in first trimester spontaneous abortions; yet, no studies demonstrate subsequent maternal sensitization or development hemolytic disease in the fetus as a result of this hemorrhage.

Conclusion: In summary, there is minimal evidence that administering Rh immune globulin for first trimester vaginal bleeding prevents maternal sensitization or development of hemolytic disease of the newborn. The practice of administering Rh immune globulin to Rh-negative women with a first trimester spontaneous abortion is based on expert opinion and extrapolation from experience with fetomaternal hemorrhage in late pregnancy. Its use for first trimester bleeding is not evidence-based.

D 2006

Clinical scenario

A 22-year-old G2P1 woman at 9 weeks gestation presents to the ED with lower abdominal cramping and vaginal bleeding for 2 days. Physical examination is unremarkable except for a closed cervical os. Beta human chorionic

^B Disclosures: The authors received no outside funding, support, or compensation for this project.

* Corresponding author. Tel.: +1 602 445 6196; fax: +1 602 344 1208.

E-mail address: [email protected] (B. Hannafin).

gonadotropin and Transvaginal ultrasound are consistent with a single Intrauterine pregnancy at 9 weeks of gestation. The patient’s blood type is A negative. Should the ED physician administer Rh immune globulin (RhIG)? Has it been shown to decrease maternal sensitization or Fetal complications?

Introduction

First trimester vaginal bleeding is a common complaint in the ED. Although the administration of RhIG to

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488 B. Hannafin et al.

Rh-negative women has become the standard of care, it has been criticized as not being cost-effective and lacking clinical benefit. Although RhIG has been shown efficacious in reducing maternal sensitization and fetal morbidity and mortality peripartum and during the Third trimester [4], its efficacy and use during the first trimester is controversial. In this review, we examined whether literature would support the use of RhIG in Rh-negative women with first trimester spontaneous abortions to prevent maternal sensitization to the fetal Rh antigen, and its subsequent effects on fetal morbidity and mortality.

Methods

We searched MEDLINE (1966-2005), the Cochrane Central Register of Controlled Trials, EMBASE (1990 to 2005), and the reference sections of the articles found. The search is considered updated to December of 2005. Search terms included vaginal bleeding, Rh negative, RhIG, RhoGAM, isoimmunization, sensitization, first trimester pregnancy, threatened, and spontaneous abortion.

published in 1972 to examine the use of RhIG and subsequent sensitization after a first trimester spontaneous abortion [1]. Although methodologically sound, the study population was small (total 57 patients) and may not have been sufficient to demonstrate a difference in the experi- mental and control groups. Nineteen Rh-negative women undergoing first trimester spontaneous abortions were randomized to receive RhIG, and 29 Rh-negative women received either placebo or nothing. No patient in either the experimental or control groups became sensitized.

A more recent (2003) retrospective case control trial undertaken in Mexico examined transvaginal bleeding as a risk factor for sensitization [2]. Cases consisted of consec- utive Rh-negative women who became sensitized during their pregnancies or early postpartum. Transvaginal bleed- ing before week 20 did not significantly increase the risk of isoimmunization, whereas transvaginal bleeding after week 20 was associated with 5 times the risk of isoimmunization. Overall, the authors concluded that transvaginal bleeding at any stage of pregnancy increased the likelihood of

sensitization. Again, the study population was small (24 cases, 24 controls), and no temporal link was made between the time of the transvaginal bleeding and subsequent sensitization. Unfortunately, in the study design, any woman with first trimester bleeding who later became sensitized during her third trimester was considered to have had this sensitization event in the first trimester despite repeated episodes of hemorrhage.

A single case report described maternal sensitization in a woman who had been documented as Rh antibody negative earlier in her pregnancy and had first trimester vaginal bleeding [3]. It should be noted that the patient was documented as seronegative 3 weeks after this episode of vaginal bleeding. However, the patient also had an ultrasound-guided amniocentesis, a well-known cause of sensitization, preformed several months before her docu- mented seroconversion. Although she received RhIG after the amniocentesis, one retrospective analysis has shown that up to 74% of Rh-negative women who become sensitized do so in spite of appropriate RhIG administration or because of an occult sensitizing event [10,18]. This is the only case report of maternal sensitization after first trimester bleeding that we were able to find in the literature, and this case was confounded by a known cause of sensitization, namely amniocentesis.

There is abundant expert opinion over this issue [8 -15]. Most articles we examined favor RhIG administration for first trimester bleeding using the risk-versus-benefit argu- ment. On the contrary, some experts argue the limited supply of RhIG, cost of therapy, and lack of supporting evidence as reasons to forgo RhIG administration for first trimester threatened abortions [5,6]. Most authors agree that if gestational age is in question or if traumatic etio- logy of vaginal bleeding is suspected, RhIG should be administered.

Finally, one can examine studies of fetomaternal hemorrhage and transfusion mismatches and try to extrap- olate this experience to first trimester bleeding [16 -22]. Fetomaternal hemorrhage in the first 20 weeks of gestation can be demonstrated by using the Kleihauer-Betke acid elution assay (KB test) [17]. One study demonstrated that as little as 0.1 mL of Rh-positive blood is required to cause sensitization in healthy Rh-negative male volunteers, and the mean volume of fetal-maternal transfusion at 8 weeks has been calculated to be 0.33 mL [15,16]. Taken together, one could attempt to generalize this data to first trimester threatened abortions. Although women with spontaneous abortion can demonstrate the presence of fetal cells in their circulation after a spontaneous abortion in the first trimester, none of these studies looked at subsequent maternal sensitization or hemolytic disease in the newborn as an outcome. In theory, one could reason that the documented quantity of fetomaternal hemorrhage meets the minimum amount required to cause sensitization; yet, no such study has been undertaken to clinically demon- strate this relationship.

Rh-negative women with first trimester spontaneous abortions need RhIG 489

Applying the evidence

Clinical evidence does not support the use of RhIG for first trimester threatened abortions in Rh-negative women. There is a paucity of well-designed studies that examine maternal sensitization after a first trimester threatened abortion. There is significant evidence to demonstrate fetomaternal hemorrhage in first trimester spontaneous abortions; yet, no studies demonstrate subsequent maternal sensitization as a result of this hemorrhage. At best, one needs to extrapolate the quantity of fetomaternal hemor- rhage required to cause sensitization in the second and third trimesters and transfusion mismatches to estimate the potential for first trimester sensitization. For example, as little as 0.1 mL of Rh-positive blood is required to cause sensitization in Rh-negative male volunteers, and the mean volume of fetal-maternal transfusion at 8 weeks has been calculated to be 0.33 mL [15,16]. Hence, sensitization may occur in theory, but it has never been demonstrated.

Most expert opinion is in favor of RhIG administration during the first trimester. This opinion is based on the extremely low incidence of complications from RhIG administration and the potential grave risks of maternal sensitization that have been extrapolated from experience with late pregnancy bleeding and subsequent sensitization. As one author puts it, bWe prefer to treat a woman unnecessarily rather than withhold Rh immune globulin from a mother who is at risk of Rh immunizationQ [8].

The safety of RhIG has been well documented, and the consequences of maternal sensitization on fetal well-being have likewise been delineated. However, given the lack of supporting evidence, it would seem reasonable to forgo administration of RhIG to Rh-negative women with a first trimester threatened or spontaneous abortions in whom the clinician is certain the gestational age is less than 14 weeks. Likewise, until further data becomes available, the pre- sence of trauma or an uncertain gestational age necessitates RhIG administration.

Ironically, it may be the established tradition of RhIG administration in first trimester bleeding that may be the biggest obstacle to practicing in this manner. Without sound scientific evidence, this has become standard of care.

Conclusions

Current studies do not support the use of RhIG for first trimester bleeding in Rh-negative patients, although the risk of its administration is extremely low. Only a single ran- domized control trial was encountered in examining this question, and it is unlikely that more will be undertaken in the near future. Most experts agree that if the etiology of the bleeding is trauma or if the gestational age is uncertain, then RhIG should be given. Although the tradition of giving

RhIG to all Rh-negative patients with first trimester bleeding is well established among practitioners and in expert opinion, it is not evidence based.

References

1. Visscher RD, Visscher HC. Do Rh-negative women with an early spontaneous abortion need Rh immune prophylaxis? Am J Obstet Gynecol 1972;113:158 - 65.
2. Herna’ndez-Andrade E, Ahued-Ahued JR. Transvaginal bleeding during pregnancy associated with Rhesus-D isoimmunization. Salud Pu’blica de Me’x 2003;45(6):492 - 6.
3. Dayton VD, Anderson DS, Crosson JT, et al. A case of Rh isoimmunization: should threatened first-trimester abortion be an indication for Rh immune globulin prophylaxis? Am J Obstet Gynecol 1990;163(1 Pt 1):63 - 4.
4. Urbaniak SJ. The scientific basis of antenatal prophylaxis. Br J Obstet Gynaecol 1998;105(18):11 - 8.
5. Weinberg L. Use of anti-D immunoglobulin in the treatment of threatened miscarriage in the accident and emergency department. Emerg Med J 2001;18(6):444 - 7.
6. Sotiriadis A, Papatheodorou S, Makrydimas G. Threatened miscar- riage: evaluation and management. BMJ 2004;329(7458):152 - 5.
7. Coppola PT, Coppola M. Vaginal bleeding in the first 20 weeks of pregnancy. Emerg Med Clin North Am 2003;21:667 - 77.
8. Bowman JM. Controversies in Rh prophylaxis. Who needs Rh immune globulin and when should it be given? Am J Obstet Gynecol 1985;151(3):289 - 94.
9. Jabara S, Barnhart T. Is Rh immune globulin needed in early first- trimester abortion? A Review. Am J Obstet Gynecol 2003;188:623 - 7.
10. Robson SC, Lee D, Urbaniak SJ. Anti-D immunoglobulin in RhD prophylaxis. Br J Obstet Gynaecol 1998;105:129 - 34.
11. ACOG practice bulletin. Prevention of Rh D alloimmunization. Number 4, May 1999 Clinical management guidelines for obstetri- cian-gynecologists. American College of Obstetrics and Gynecology. Int J Gynaecol Obstet 1999;66(1):63 - 70.
12. Kavanagh MJ, Dada T. Anti-D immunophrophylaxis within the accident and emergency department. Emerg Med J 2002;19(4):375.
13. Royal College of Physicians of Edinburgh. Statement from the con- sensus conference on anti-D prophylaxis. Vox Sanguinis 1998;74(2): 127 - 128.
14. Everett CB. Anti-D immunoglobulin for bleeding in early pregnancy. BMJ 1990;301(6764):1329.
15. Freda VJ. Recent advances in the Rh problem. Trans N Engl Obstet Gynecol Soc 1964;18:91 - 104.
16. Zpipursky A, Pollock J, Neelands P, Chown B, Israels LG. The transplacental passage of fetal red blood cells and the pathogenesis of Rh immunization during pregnancy. Lancet 1963;ii:489 - 93.
17. Stein AV, Munsick RA, et al. Fetomaternal hemorrhage in threatened abortion. Obstetrics & Gynecology 1992;79(3):383 - 6.
18. Portmann C, Ludlow J, et al. Antecedents to and outcomes of Rh(D) isoimmunization: Mater Mother Hospital, Brisbane 1988-1995. Aust N Z J Obstet Gynaecol 1997;37(1):12.
19. Litwak O, Taswell HF, et al. Fetal erythrocytes in maternal circulation after spontaneous abortion. JAMA 1970;214(3):531 - 4.
20. Leong M, Duby S, Kinch RAH. Fetal-maternal transfusion following early abortion. Obstet Gynecol 1979;54(4):424 - 6.
21. Bergstrom H, Nilson LA, Nisson L, Ruttinger L. Demonstration of Rh antigens in a 38-day-old fetus. Am J Obstet Gynecol 1967;99:130 - 3.
22. Murray S, Barron SL, McNay RA. Transplacental haemorrhage after abortion. Lancet 1970.