Clinical Perinatal/Neonatal Case Presentation ⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢ Placenta Accreta and Methotrexate Therapy: Three Case Reports

George M. Mussalli, MD the treatment of placenta accreta. The known effect of methotrexate Jelpa Shah, MD on reducing placental vascularity, resulting in placental necrosis, and David J. Berck, MD the considerable morbidity and mortality of surgical management of Andrew Elimian, MD placenta accreta, provided the justification for attempting medical Nergesh Tejani, MD treatment of the retained placenta. A MEDLINE search from 1966 to Frank A. Manning, MD 1999 (keywords: placenta accreta, methotrexate, retained placenta, medical treatment) yielded only six other reports of methotrexate management of accreta.4–9 Of the two reports representing an Ameri- Placenta accreta is a complication that is rising in incidence. The can experience,6,7 the authors offer contradictory conclusions regard- reported experience of methotrexate treatment in the conservative ing conservative management and methotrexate treatment for re- management of placenta accreta is scant. Three cases of placenta accreta tained placenta accreta. One case of placenta accreta, one case of managed with methotrexate are presented. placenta percreta, and one case of placenta percreta with bladder Case 1: A woman had an antenatal diagnosis of placenta percreta. A involvement, all managed with methotrexate, are presented here. All successful manual placental removal occurred on post-cesarean day 16. patients were offered and agreed to methotrexate courses as adjunctive Case 2: A woman had retention of a placenta accreta after a term vaginal treatment to conservative management on a case by case basis by the delivery. Successful dilation and curettage were performed on postpar- admitting attending perinatologist. All patients signed an informed tum day 37. Case 3: A woman had an antenatal diagnosis of placenta consent after clearly understanding the toxicity risks and the uncer- previa-percreta with bladder invasion. A simple hysterectomy was per- tain efficacy of methotrexate treatment for the management of re- formed on post-cesarean day 46. tained placenta accreta. The particular methotrexate regimens were Conservative management and methotrexate treatment resulted in uter- selected at the discretion of the individual attending perinatologists. ine preservation in two of our three patients; however, this treatment did Postpartum management for all patients included a plan for hospital- not prevent significant delayed hemorrhage. In view of the rapid resolu- ized observation followed by outpatient follow-up if stable. Patients tion of vascular invasion of the bladder, methotrexate may have an im- were followed with weekly sonography and ␤-human chorionic gona- portant role in the management of placenta percreta with bladder inva- dotrophin (BhCG) serum tests to assess placental volume and declin- sion. The utility of methotrexate treatment with the conservative ing placental function. A weekly physical examination, once the pa- management of placenta accreta requires further evaluation. tient had been discharged from the hospital, was also performed to Journal of Perinatology 2000; 5:331–334. assess for development of endometritis or hemorrhage.

Placenta accreta is an abnormal adherence of placental villi to CASE PRESENTATIONS uterine myometrium. Placenta accreta is now the most common Case 1 cause of emergency postpartum hysterectomy.1 Leaphart et al.2 A 36-year-old gravida 5, para 4004 was admitted at 32 and 5/7 weeks’ reported a catastrophic hemorrhage during a scheduled cesarean gestation; she had been transferred from an outlying institution after hysterectomy for placenta percreta with bladder invasion requiring an episode of painless vaginal bleeding. Her obstetric history included 56 U of packed red blood cells despite ideal multidisciplinary peri- an uncomplicated term vaginal delivery followed by three low trans- operative management in a regional trauma center. Such reports, verse cesarean sections. The prenatal course was significant for a low together with the advances in transfusion services and the develop- maternal serum ␣-fetoprotein and a normal 46XY fetal karyotype by ment of potent antibiotics, have renewed interest in delayed and amniocentesis. Sonography at 24 weeks’ gestation revealed a central nonsurgical management of placenta accreta. placenta previa. Arulkumaran et al.3 reported the first use of methotrexate for On admission, sonography revealed a placenta previa with turbu- lent placental blood flow extending into the surrounding uterine Department of Obstetrics and Gynecology (G. M. M., D. J. B.), Columbia University College of myometrium with preservation of the uterine-bladder interface con- Physicians and Surgeons, New York, NY; and Department of Obstetrics and Gynecology (J. S., A. E., N. T., F. A. M.), New York Medical College, Valhalla, NY. sistent with placenta percreta without bladder involvement. Admission

Address correspondence and reprint requests to George M. Mussalli, Department of Obstet- hematocrit was 35.5%. The patient was given a course of betametha- rics and Gynecology, Jacobi Medical Center, 1400 Pelham Parkway, Bronx, NY 10461. sone and remained under hospital observation in stable condition. In

view of the likelihood of substantial hemorrhage from immediate for a total of three doses was decided on. On postpartum day 6, the operative management of placenta previa-percreta and the possibility patient was discharged with a normal WBC count and a hematocrit of of bladder invasion, a preoperative plan for nonremoval of the pla- 30%. Serial sonography demonstrated no placental blood flow by centa was agreed on by the patient and perinatal team. An amniocen- postpartum day 12, and progressive reduction in placental volume tesis to determine fetal lung maturity at 34 and 2/7 weeks’ gestation thereafter. A serum BhCG on postpartum day 27 was 330 mIU/ml. On was deemed immature, and the patient was given a second course of postpartum day 37, the patient was readmitted with complaints of betamethasone. At 35 and 4/7 weeks’ gestation, the patient underwent nightly fevers and an episode heavy vaginal bleeding accompanied a scheduled cesarean section with a preoperative plan for medical with syncope. Vital signs included a blood pressure of 110/60 mm Hg, therapy without placental removal. A classical uterine incision, to heart rate of 90 beats per minute, and oral temperature of 104.9 ° F. avoid the placenta, was performed with delivery of an infant boy with The abdominal examination was nontender. A pelvic examination Apgar scores of 9 at both 1 and 5 minutes. No cleavage of the placen- revealed no active bleeding with a nontender uterus 8 to 10 weeks in tal plane was identified intraoperatively, which is consistent with the size. She had a WBC count of 18.4 k/mm3 and a hematocrit of 18.8%. diagnosis of accreta, and no attempt was made to deliver the placenta. Despite an absence of typical signs of infection, ampicillin, gentami- Methotrexate (50 mg) was injected into the umbilical vein in an cin, and flagyl were started for presumptive endometritis. The patient attempt to maximize local delivery of the drug and minimize systemic was transfused3Uofpacked red blood cells preoperatively. Dilation toxicity. The uterus was closed and the remainder of the operation and curettage were performed with complete removal of the placenta was uneventful. The estimated operative blood loss was 600 ml. The and estimated blood loss of 800 ml. Immediately after the dilation postoperative course was marked by daily passage of placental tissue and curettage, an additional2Uofpacked red blood cells were given. and slight vaginal bleeding. A BhCG value of 3902 mIU/ml was ob- The postoperative WBC count was 11.0 k/mm3, and the hematocrit tained on postoperative day 2 and fell to 781 mIU/ml by postoperative stabilized at 29.4%. The patient became afebrile immediately after day 15. An intramuscular dose of 50 mg of methotrexate was given on uterine evacuation and was discharged on the following day in good postoperative day 3. Thereafter, the patient received weekly methotrex- condition. ate (50 mg) injections for two additional doses. The patient remained afebrile without evidence of endometritis. A complete blood cell count Case 3 revealed a hematocrit of 32.0% on postoperative day 8. Weekly ultra- A 33-year-old gravida 2, para 1001 was admitted at 27 and 5/7 weeks’ sonography revealed a cessation of placental blood flow and a pro- gestation; she was transferred from an outlying institution for vaginal gressive reduction in placental volume. On postoperative day 16, the bleeding with placenta previa. Her obstetric history included a prior patient had heavy bleeding vaginally and was taken to the operating low transverse cesarean section for breech presentation at term. The ␣ room for an attempt at manual placental removal under general prenatal course was significant for an elevated maternal serum -fe- anesthesia. Preoperative complete blood cell count revealed a white toprotein of 3.7 multiples of the median and normal fetal sono- blood cell count (WBC) of 11.8 k/mm3 and a hematocrit of 29.6%. graphic anatomy with an anterior placenta previa. The placenta was removed completely with an estimated blood loss of On admission, sonography revealed disruption of the echogenic 2000 ml. A uterine packing was placed for 24 hours, and the patient interface between the maternal uterine serosa and bladder with turbu- was transfused4Uofpacked red blood cells and2Uoffresh frozen lent flow extending into the bladder wall indicative of placenta per- plasma intraoperatively. In the 48 hours after the manual placental creta with invasion of the bladder. The patient remained hospitalized removal, the patient required an additional6Uofpacked red blood in stable condition for observation and weekly betamethasone treat- cells and2Uoffresh frozen plasma. Uterine hemorrhage stopped, ments. At 34 and 4/7 weeks’ gestation, an episode of vaginal bleeding and sonography revealed a normal postpartum uterine cavity. The prompted a cesarean delivery. A cystoscopy was performed immedi- hematocrit was stable at 22% on discharge 4 days after the manual ately before the cesarean section by a urology consultant confirming removal. invasion of placental vessels into the bladder wall. At laparotomy, a blush of vessels was seen occupying the utero-vesical fold. A classic Case 2 uterine incision was made, with delivery of an infant boy with Apgar A 29-year-old gravida 1, para 0 was admitted as a transfer from an scores of 8 and 9 at 1 and 5 minutes, respectively. No attempt at pla- outlying hospital after a term vaginal delivery complicated by retained cental removal was made. Methotrexate (50 mg) was injected into the placenta and failed manual placental removal. The patient denied umbilical vein, and the uterus was closed uneventfully. The postoper- prior pregnancies or uterine surgery. Her prenatal course was un- ative course was normal. An intramuscular dose of 50 mg of metho- eventful, with a normal maternal serum ␣-fetoprotein result. On trexate was given on postoperative days 7, 14, 21, and 28 with inter- admission, sonography was consistent with placenta accreta with vening weekly folinic acid rescue at the discretion of the attending nonvisualization of the hypoechoic zone at the placental interface. perinatologist. A serum BhCG was 11,412 mIU/ml. On postoperative Placental removal was not attempted. Serum BhCG was 6270 mIU/ day 30, the patient was discharged from the hospital in stable condi- ml. At the discretion of the attending perinatologist, a regimen of tion with a hematocrit of 35%. On postoperative day 46, the patient methotrexate (50 mg) administered intramuscularly every other day was readmitted with uterine hemorrhage. She had a WBC count of 9.4

332 Journal of Perinatology 2000; 5:331–334 Treatment of Placenta Accreta With Methotrexate Therapy Mussalli et al.

k/mm3, a hematocrit of 27.6%, and a serum BhCG of 165 mIU/ml on contributions of methotrexate versus conservative management in admission. The patient was taken to the operating room where an these reductions are not discernible from our cases. attempt at manual placental removal was unsuccessful. A total ab- In the third case, placental invasion of the bladder was judged by dominal hysterectomy was performed. The bladder flap was free of both obstetric and urologic consultants to require bladder resection placental vessels and was easily dissected. An estimated blood loss of and ureteric reimplantation were immediate cesarean-hysterectomy 3000 ml required replacement with4Uofpacked red blood cells and to have been performed. It is of interest that complete resolution of the 2 U of fresh frozen plasma intraoperatively. In addition, the patient vascular involvement of the bladder after methotrexate treatment received4Uofpacked red blood cells postoperatively. The patient was allowed a simple hysterectomy to be performed 46 days after the deliv- discharged on the fourth day posthysterectomy with a stable hemato- ery date. crit of 26.5%. Histopathologic examination of the placenta confirmed Due to the individual management of these cases, no uniform placenta percreta. regimen of methotrexate was adhered to. However, despite the differ- ing methotrexate courses, none of the patients manifested drug toxicity. The safety of methotrexate treatment of retained gestational tis- DISCUSSION sues, although not without exception, is generally supported in the Surgical management of placenta accreta with immediate hysterec- literature.15,16 tomy can be associated with life-threatening hemorrhage and pre- Our cases demonstrate that immediate hemorrhage can be cludes future childbirth. Several reports of conservative management avoided by not attempting any manipulation of the placenta. This suggest that nonsurgical treatment of placenta accreta is an appropri- underscores the importance of sonographic diagnosis of placenta ate consideration for selected patients.10–12 Only two case reports accreta, preferably antenatally or at time of vaginal delivery when a describe the American experience of methotrexate administration as placenta is not spontaneously expelled. Diagnosis of placenta accreta an adjunct to conservative management of placenta accreta. Legro et and avoidance of attempts to deliver the placenta allow an opportu- al.6 administered methotrexate for retained placenta percreta after a nity for multidisciplinary consultation as well as transfer to tertiary vaginal delivery at 35 weeks’ gestation. A normal uterine cavity was care centers with comprehensive transfusion services. found 8 weeks after delivery, and the patient had a subsequent normal Although two of three patients in our series had uterine preserva- pregnancy. Jaffe et al.7 reported the first case of methotrexate treat- tion with conservative management and methotrexate treatment, in ment after cesarean section with retained placenta percreta and blad- view of the significant risk of delayed bleeding, immediate hysterec- der invasion. Hemorrhage ensued at suction curettage 7 weeks after tomy should be viewed as the safest management option when pla- delivery, requiring hysterectomy, partial bladder resection, and bilat- cental invasion is contained within the uterus. Methotrexate treat- eral ureteral reimplantation. ment may thus be considered for those patients adamant about future The incidence of accreta is known to rise with increasing num- childbearing or avoiding hysterectomy. However, in view of the resolu- bers of cesarean deliveries and uterine curettages.13 The major risk tion of bladder involvement in case 2 and the catastrophic hemor- factor for accreta is the presence of a placenta previa with a previous rhage typically attendant to cesarean-hysterectomies requiring blad- cesarean scar, a situation requiring hysterectomy in ϳ66% of cases.14 der resection, patients with bladder invasion by a placenta percreta In our series, two of the three patients had placenta previa in associa- may be the best candidates for consideration of methotrexate treat- tion with a history of prior cesarean section. However, case 2 had ment. The utility of methotrexate treatment with the conservative accreta occurring with her first pregnancy, thus supporting the rec- management of placenta accreta requires further evaluation. ommendation of routine evaluation of accreta risk on every sonographic study obtained. References In our series, significant delayed hemorrhage occurred in all 1. Eltabbakh GH, Watson JD. Postpartum hysterectomy. Int J Gynecol Obstet 1995; cases despite conservative management and methotrexate treatment. 50:257–62. However, unlike the catastrophic hemorrhages reported accompany- 2. Leaphart WL, Schapiro H, Broome J, Welander CE, Bernstein IM. Placenta previa ing immediate surgical management of placenta percreta,2 the blood percreta with bladder invasion. Obstet Gynecol 1997;89:834–5. product replacement required in all of our cases was well within the 3. Arulkumaran S, Ng CS, Ingemarsson I, Ratnam SS. Medical treatment of pla- capability of the institutional transfusion services. centa accreta with methotrexate. Acta Obstet Gynecol Scand 1986;65:285–6. Historically, endometritis is a feared complication of retained 4. Raziel A, Golan A, Ariely S, Herman A, Caspi E. Repeated ultrasonography and placenta. One of three patients (case 2) was diagnosed with endome- intramuscular methotrexate in the conservative management of residual adher- tritis, and this patient had atypical physical findings presenting on ent placenta. J Clin Ultrasound 1992;20:288–90. postpartum day 37. An infectious sequela thus is not an obligate at- 5. Bakri YN, Rifai A, Legarth J. Placenta previa-percreta: magnetic resonance imag- tendant of conservative management, and indeed may be temporally ing findings and methotrexate therapy after hysterectomy. Am J Obstet Gynecol remote to delivery when it does occur. 1993;169:213–4. Although progressive reduction of maternal serum BhCG values 6. Legro RS, Price FV, Hill LM, Caritis SN. Nonsurgical management of placenta and residual placental volume occurred in all three cases, the relative percreta: a case report. Obstet Gynecol 1994;83:847–9.

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