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A Novel Treatment for Cervical and Cesarean Section Scar Pregnancies by Transvaginal Injection of Absolute Ethanol to Trophoblasts: Efficacy in 19 Cases

Open AccessPublished:April 30, 2018DOI:https://doi.org/10.1016/j.jmig.2018.04.021

      Abstract

      Study Objective

      To evaluate the efficacy of a nonsurgical treatment for cervical pregnancy (CP) and cesarean section scar pregnancy (CSP).

      Design

      Retrospective clinical study (Canadian Task Force classification III).

      Setting

      Private assisted reproductive technology practice.

      Patients

      Nineteen women with CP (n = 16) or CSP (n = 3), including 6 patients with positive fetal heartbeat.

      Intervention

      Transvaginal local injection of absolute ethanol (AE) into the hyperechoic ring (lacunar space) around the gestational sac under ultrasound guidance.

      Measurements and Main Results

      Serum beta-human chorionic gonadotropin (β-hCG) was measured at frequent intervals, and ultrasound and/or magnetic resonance imaging was used to observe the gestational sac. In 9 patients, the serum β-hCG level was effectively reduced with a single AE injection at 2 hours. In the remaining 10 patients, the level decreased but then increased in 4 and slowly decreased in the other 6; all of these 10 patients required 2 to 5 repeat AE injections. In all patients, serum β-hCG level was reduced by 50% within 3 days and decreased to <10% of the initial level within 14 days. In 18 patients (95%), the level was decreased to 1.0 mIU/mL within 40 days. Seven patients were treated on an outpatient basis. Twelve patients received no anesthesia. Five patients subsequently became pregnant, and each had a live birth. There was no recurrent CP or CSP. The procedure was successful in all 19 patients.

      Conclusion

      This procedure is an effective treatment for CP or CSP that could be used in place of conventional surgical interventions and medical treatment using MTX.

      Keywords

      Among ectopic gestations, which constitute approximately 2% of all pregnancies, cervical pregnancy (CP) and cesarean scar pregnancy (CSP) are rare. The reported incidence of CP and CSP is 1 in 1000 to 95,000 pregnancies [
      • Celik C.
      • Bala A.
      • Acar A.
      • Gezginç K.
      • Akyürek C.
      Methotrexate for cervical pregnancy: a case report.
      ] and 1 in approximately 2000 in patients with previous CSP [
      • Seow K.M.
      • Huang L.W.
      • Lin Y.H.
      • Lin M.Y.
      • Tsai Y.L.
      • Hwang J.L.
      Cesarean scar pregnancy: issues in management.
      ], respectively. CP and CSP are among the most difficult conditions to treat, and hysterectomy or uterine artery embolization is often necessary.
      For the last 25 years, methotrexate (MTX) has been used as a nonsurgical medical treatment in various protocols, including both in situ injection and systemic administration [
      • Ash A.
      • Smith A.
      • Maxwell D.
      Caesarean scar pregnancy.
      ,
      • Yamaguchi M.
      • Honda R.
      • Uchino K.
      • Tashiro H.
      • Ohba T.
      • Katabuchi H.
      Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy: efficacy and subsequent fecundity.
      ], although a consensus regarding the optimal method has not yet been reached. Local injection of MTX is an effective technique for preserving fertility in women with lower uterine ectopic pregnancy; Yamaguchi et al. [
      • Yamaguchi M.
      • Honda R.
      • Uchino K.
      • Tashiro H.
      • Ohba T.
      • Katabuchi H.
      Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy: efficacy and subsequent fecundity.
      ] reported a success rate of 100%. However, local injection of absolute ethanol (AE) has advantages over conventional MTX-based local injection therapy in several respects. First, whereas the response to MTX occurs over 5 to 7 days, because MTX works metabolically by causing death of the villi, ultimately leading to an initial increase in serum beta-human chorionic gonadotropin (β-hCG) level, AE causes a decrease in serum β-hCG level within just 2 hours after the initial injection, which may reflect trophoblastic necrosis through dehydration and coagulation, immediately terminating the cellular function of chorionic villi. This more immediate mode of action may have value, although ultimately, many patients require multiple treatments. Moreover, even when a sufficient effect cannot be obtained with the first injection, AE can be administered repeatedly because, unlike MTX, it has no effects on hematopoietic function.
      Based on previous experience in using AE for tubal gestations [
      • Kaijima H.
      • Osada H.
      • Kato K.
      • et al.
      The efficacy and safety of managing ectopic pregnancies with transvaginal ultrasound-guided local injections of absolute ethanol.
      ], we developed a new method, “trophoblast-target therapy” (TTT), involving injection of AE into the lacunar space rather than into the gestational sac (GS), to treat CP and CSP pregnancies and evaluated its efficacy.

      Materials and Methods

      In this study, we retrospectively evaluated a consecutive series of 19 women with CP (n = 16) or CSP (n = 3), 6 of whom were fetal heartbeat (FHB)-positive, treated at the Kato Ladies Clinic between January 2002 and April 2017. Sixteen women had conceived by in vitro fertilization and embryo transfer (IVF-ET), and 3 had conceived spontaneously.
      All patients who presented with CP or CSP during this time frame were treated with this method of AE injection. All patients consented to undergo this procedure with the understanding that it was not standard care. The study protocol was approved by the Institutional Review Board of Kato Ladies Clinic (no. 17-11; October 1, 2017). Informed consent was obtained from all patients.
      In all patients, the procedure was performed by Dr. Osata, assisted by other doctors and clinic personnel. The diagnosis was made based on each patient's medical history, clinical examination, serum β-hCG level, findings of transvaginal ultrasonography (TVU) and, as necessary, by magnetic resonance imaging (MRI). Serum β-hCG level was measured by the enzyme immunoassay method (AIA-1800; Tosoh, Tokyo, Japan). Monitoring of the β-hCG level after embryo transfer began at 3 weeks 5 days of gestational age (GA). The GS and FHB were monitored from 5 weeks 0 days and 6 weeks 0 days of GA, respectively.
      The following diagnostic criteria for CP [
      • Hofmann H.M.
      • Urdl W.
      • Höfler H.
      • Hönigl W.
      • Tamussino K.
      Cervical pregnancy: case reports and current concepts in diagnosis and treatment.
      ,
      • Kung F.T.
      • Lin H.
      • Hsu T.Y.
      • et al.
      Differential diagnosis of suspected cervical pregnancy and conservative treatment with the combination of laparoscopy-assisted uterine artery ligation and hysteroscopic endocervical resection.
      ] and CSP [
      • Jurkovic D.
      • Hillaby K.
      • Woelfer B.
      • Lawrence A.
      • Salim R.
      • Elson C.J.
      First-trimester diagnosis and management of pregnancies implanted into the lower uterine segment cesarean section scar.
      ,
      • Maymon R.
      • Halperin R.
      • Mendlovic S.
      • Schneider D.
      • Herman A.
      Ectopic pregnancies in a caesarean scar: review of the medical approach to an iatrogenic complication.
      ] were applied: (1) no identifiable intrauterine pregnancy was present despite a normal increase in maternal serum β-hCG detected after 3 weeks 5 days of GA; (2) the GS containing the viable embryo was located below the level of the internal os, within the cervical tissue, and the cervix became hourglass- or barrel-shaped as the GS expanded (for CP); (3) the sliding sign of a miscarriage was absent (in a miscarriage, the GS will slide in the cervical canal when pressure is applied to the cervix using a probe) [
      • Winder S.
      • Reid S.
      • Condous G.
      Ultrasound diagnosis of ectopic pregnancy.
      ]; and (4) the uterine cavity and cervical canal were empty, GS was present in the anterior part of the uterine isthmus, and the myometrial tissue between the bladder and the GS was absent or defective with CSP. To assess embryonic activity, the presence of FHB was also monitored using color-flow Doppler.
      All 19 patients, including those cared for in the outpatient setting, received injections in the operating room. In exceptional circumstances, such as when the crown-to-rump length was greater than 7 weeks and in the presence of bleeding, the patient remained in the hospital. Other patients who came from far away preferred to be hospitalized.
      Of the 16 patients with CP, 7 (36.8%) required a paracervical block (xylocaine 1%), and the other 9 received no anesthesia. No other anesthesia/analgesia, including intravenous, inhalant, or oral medications, was used. Cephem antibiotics (Cefamezinα 2 g for injection; Astellas Pharma, Tokyo, Japan) were administered intravenously once daily at 30 minutes before the procedure.

       Identification of the Lacunar Space by TVU and Local Injection of AE

      The lacunar space occupies the hyperechoic ring (decidua capsularis) created around the GS by the chorionic response [
      • Doubilet P.M.
      Ultrasound evaluation of the first trimester.
      ,
      • Doubilet P.M.
      • Benson C.B.
      First, do no harm…to early pregnancies.
      ]. In TTT, 100% pure AE (Anhydrous Ethanol Injection; Pfizer, Tokyo, Japan) was injected into this lacunar space, not into the GS, under high-intensity imaging TVU guidance, using a 23G Cathelin needle (Kitazato Medical, Tokyo, Japan). In all patients but 1 (patient 17), the injected dose of AE was between 1.0 and 10.0 mL (average, 4.82 mL), depending on the thickness of the hyperechoic ring and dispersion of the liquid. In patient 17, who had a large hematoma, the dose was 17.0 mL. When the GS was small and AE could be smoothly injected, only a minimum amount was required, starting at 1 mL (Table). However, when the GS was large, or when AE injection was difficult, a higher dose was required. Because 1 mL of AE was injected into the tissues over 30 to 40 pushes (Σ0.03–0.25 mL per push), the AE did not enter directly into the vein and thus did not circulate in the systemic blood flow. Occasionally, the white ring was not demonstrated clearly. In such cases, color-flow Doppler was used to detect the presence of blood flow where the white ring should have been, and AE was injected into the site. Patients in whom the white ring was not clearly demonstrated tended to require multiple treatments owing to uncertainty about the exact location of the injection.
      TableCharacteristics of patients with cervical pregnancy or cesarean section scar pregnancy treated by trophoblast-targeted therapy with local absolute ethanol injection
      PatientAge, yrGPGAGS, mmFHBInitial β-hCG, mIU/mLInitial volume of AE injection, mLβ-hCG at 2 h after AE injection, mIU/mLPercent decrease in β-hCGNo. of AE injectionsTotal volume of AE injection, mLMedical historyRisk factors for ectopy
      132G2P05w6d1383,832175,8699.535-IVF-ET
      237G1P05w6d920,795513,46435.315-IVF-ET
      336G0P05w6d9.518,938217,4567.8410.2LAMSpontaneous pregnancy
      439G0P05w1d764802539616.724LAMIVF-ET
      535G1P05w2d6.561163.259602.613.2D&CIVF-ET
      639G1P15w5d13.536,919334,2307.3210D&CIVF-ET
      741G1P15w3d7.578072622920.212D&CIVF-ET
      833G1P17w6d11+26,930522,14117.815C/SSpontaneous pregnancy
      937G1P15w3d7.519,356314,88323.124D&CIVF-ET
      1038G0P15w6d982317.5713413.317.5D&CIVF-ET
      1138G0P06w0d10.5+12,934510,94415.4210-IVF-ET
      1236G1P16w3d6.587716605631213-IVF-ET
      1340G0P07w2d7+22,2246.516,37126.316.5-IVF-ET
      1438G0P17w1d10.5+29,930625,23015.7211D&CIVF-ET
      1533G0P06w2d63577527172415-IVF-ET
      1642G0P15w3d8.537975308318.815C/S, D&CIVF-ET
      1745G0P07w6d19135,0401778,89041.6553-IVF-ET
      1830G2P26w4d11.5+43,596532,16126.2235C/Sx2Spontaneous pregnancy
      1937G0P06w1d11+72872.5596418.112.5LAMIVF-ET
      AE = absolute ethanol; β-hCG = beta-human chorionic gonadotropin; C/S = cesarean section; D&C = dilatation and curettage; FHB = fetal heartbeat; GA = gestational age; GP = gravida para; GS = gestational sac; IVF-ET = in vitro fertilization and embryo transfer; LAM = laparoscopic myomectomy.
      The median (range) values for the 19 patients were as follows: 5w6d (range: 5w1d-7w6d) for GA at the time of first injection; 18938 mIU/mL (range: 3577-135040 mIU/mL) for initial serum β-hCG level; 13464 mIU/mL (range: 2717-78890 mIU/mL) for β-hCG level at 2 hours after the injection; 2 times (range: 1-5 times) for the number of injections; and 5.0 ml (range: 2.0-53.0 ml) for the total dose of AE injection. The mean ± SD β-hCG percentage decrease was 19.5 ± 9.9% (95% CI: 14.8-24.3%) at 2 hours after the injection.

       Evaluation of the Effect of TTT with AE

      All patients were given injections in the operating room and were then moved to the recovery room to rest. The effect of TTT was evaluated based on the percentage decrease in serum β-hCG level, calculated against the initial level obtained immediately before the first AE injection. If the decrease was <20% at 2 hours postinjection, a second AE dose was administered, and the patient was reevaluated 2 hours later. Depending on the circumstances, the patient either remained in the hospital or went home. For patients whose decline in β-hCG level was still <20% the next day, additional doses were administered until the required decline in β-hCG was achieved. From the second day onward, serum β-hCG level was rechecked every day for 3 days, then every other day twice, followed by every 5 days twice, and finally once a week until the level reached <0.1 mIU/mL. Patients who demonstrated a slow decline in β-hCG level were monitored for a longer period. In addition, the GS was monitored by TVU and, as necessary, by MRI until it completely disappeared.

       Hospitalization

      The procedure was performed on an outpatient basis except in patients with complications necessitating hospital admission. In addition, some of the patients who traveled from afar preferred to be hospitalized, in which case they remained in the hospital until the progress was deemed satisfactory.

       Statistical Analysis

      Descriptive statistics are reported as mean ± SD or number and percentage. Figure 1 was plotted with Excel (Microsoft, Redmond, WA).
      Fig. 1
      Fig. 1(A) Percentage change in serum beta human chorionic gonadotropin (β-hCG) level after trophoblast-target therapy (TTT) in 19 patients with cervical pregnancy or cesarean section scar pregnancy. The x-axis shows days after treatment; the y-axis, percentage of baseline serum β-hCG level. In all patients, the serum β-hCG level decreased to 50% of the initial level within 3 days and to ≤10% within 14 days. (B) Change in serum β-hCG level on a logarithmic scale. The x-axis shows days after treatment; the y-axis, β-hCG level (mIU/mL). In all but 1 patient (patient 17), the β-hCG level decreased to <10 mIU/mL within 27 days after TTT treatment and to <1.0 mIU/mL within 40 days.

      Results

      Table summarizes the patient characteristics. Of the 19 patients, 16 had a CP and 3 had a CSP. The mean patient age was 37.2 ± 3.6 years. Sixteen of the pregnancies resulted from IVF treatment and 3 were spontaneous, of which 2 were CSP and 1 CP. MRI was performed in the 3 patients with CSP. Among the entire group, a positive FHB was present in 6 patients and vaginal bleeding was seen in 7 patients. The success rate of TTT, including repeated applications, was 100% (19 of 19 cases).
      The serum β-hCG level was effectively reduced with a single AE injection at 2 hours in 9 patients. Among the remaining 10 patients, the level decreased but then increased in 4 and decreased slowly in 6; all 10 patients required 2 to 5 repeat AE injections. In all patients, serum β-hCG level was reduced by 50% within 3 days and decreased to <10% of the initial level within 14 days. In all but 1 patient (patient 17), the level decreased to <10.0 mIU/mL at 36 days and to <1.0 mIU/mL at 40 days. Figure 1 shows the percentage change in patients' serum β-hCG levels after the injection and the change on a logarithmic scale after the injection. Figure 2 shows TVU and pelvic MRI images for patient 18 (CP with positive FHB).
      Fig. 2
      Fig. 2Transvaginal ultrasound Doppler and pelvic magnetic resonance imaging (MRI) of patient 18 (cervical pregnancy with positive fetal heartbeat). (A) Transvaginal ultrasound Doppler image demonstrating fetal heartbeat-positive cervical pregnancy. (B–E) Axial (left) and sagittal (right) sections from pelvic MRI. (B) Three days before the injection: serum β-hCG, 43,596 mIU/mL. (C) Day 11 after the injection: serum β-HCG, 302 mIU/mL. (D) Day 18: serum β-HCG, 38.9 mIU/mL. (E) Day 25: serum β-HCG, 6.8 mIU/mL. By day 38, the level decreased to 1.0 mIU/mL. (F) Transvaginal ultrasound of water flow inspection of the endometrium (left) and cervical canal (right) on day 71 (serum β-HCG, undetectable).
      Eleven patients with CP or CSP underwent short-term hospitalization for a mean of 2.3 days (range, 1–4 days). Patient 18 underwent the longest hospitalization, for 25 days. The remaining 7 patients (42.1%) were treated as outpatients.
      There were no adverse effects of the method of treatment and administration of AE. None of the patients had an infection or required a blood transfusion. Only 1 patient (patient 6) required treatment for persistent bleeding and a moderate hematoma around the GS. Transvaginal ligation of cervical arteries was performed to stop the bleeding. Because of this hematoma, the white ring was difficult to identify, and a total of 10 mL of AE was administered over several injections.
      Patients were advised to start IVF treatment or attempt spontaneous pregnancy when the β-hCG level had dropped to <0.2 mIU/mL. Sometimes this took only a month. Of the 16 patients with CP, 8 desired subsequent pregnancies and underwent IVF and ET. Four women became pregnant, of whom 3 delivered vaginally and 1 delivered via cesarean section. Of the 3 patients with CSP, 1 (patient 8) delivered via cesarean section after a spontaneous pregnancy and the other 2 are currently undergoing fertility treatment.

      Discussion

      In CP and CSP, trophoblast cells may invade the cervical wall and cervical blood vessels, and interventions such as dilatation and curettage carry a high risk of rupture, severe bleeding, and hemodynamic collapse [
      • Maymon R.
      • Halperin R.
      • Mendlovic S.
      • Schneider D.
      • Herman A.
      Ectopic pregnancies in a caesarean scar: review of the medical approach to an iatrogenic complication.
      ]. CSP is one of the most difficult conditions to treat if fertility is to be preserved. The risk of bleeding associated with CSP intervention is much higher than that for CP, because CSP occurs in the cervical muscle layer of the cesarean section scar. Therefore, the recommended primary treatment of these conditions has historically been hysterectomy or uterine artery embolization [
      • Maymon R.
      • Halperin R.
      • Mendlovic S.
      • Schneider D.
      • Herman A.
      Ectopic pregnancies in a caesarean scar: review of the medical approach to an iatrogenic complication.
      ,
      • Ravhon A.
      • Ben-Chetrit A.
      • Rabinowitz R.
      • Neuman M.
      • Beller U.
      Successful methotrexate treatment of a viable pregnancy within a thin uterine scar.
      ,
      • Sijanovic S.
      • Vidosavljevic D.
      • Sijanovic I.
      Methotrexate in local treatment of cervical heterotopic pregnancy with successful perinatal outcome: case report.
      ,
      • Timor-Tritsch I.E.
      • Monteagudo A.
      • Mandeville E.O.
      • Peisner D.B.
      • Anaya G.P.
      • Pirrone E.C.
      Successful management of viable cervical pregnancy by local injection of methotrexate guided by transvaginal ultrasonography.
      ].
      Protocols of nonsurgical treatment for CP and CSP are based on the combination of local transabdominal or transvaginal injection of embryocides, including MTX [
      • Tanaka T.
      • Hayashi H.
      • Kutsuzawa T.
      • Fujimoto S.
      • Ichinoe K.
      Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case.
      ], potassium chloride, and hyperosmolar glucose, into the GS, frequently with systemic administration of MTX and/or other embryocides [
      • Ash A.
      • Smith A.
      • Maxwell D.
      Caesarean scar pregnancy.
      ,
      • Sijanovic S.
      • Vidosavljevic D.
      • Sijanovic I.
      Methotrexate in local treatment of cervical heterotopic pregnancy with successful perinatal outcome: case report.
      ,
      • Timor-Tritsch I.E.
      • Monteagudo A.
      • Mandeville E.O.
      • Peisner D.B.
      • Anaya G.P.
      • Pirrone E.C.
      Successful management of viable cervical pregnancy by local injection of methotrexate guided by transvaginal ultrasonography.
      ,
      • Godin P.A.
      • Bassil S.
      • Donnez J.
      An ectopic pregnancy developing in a previous caesarean section scar.
      ,
      • Monteagudo A.
      • Minior V.K.
      • Stephenson C.
      • Monda S.
      • Timor-Tritsch I.E.
      Non-surgical management of live ectopic pregnancy with ultrasound-guided local injection: a case series.
      ]. Recently, good results were reported for CSP with the local injection of MTX alone [
      • Yamaguchi M.
      • Honda R.
      • Uchino K.
      • Tashiro H.
      • Ohba T.
      • Katabuchi H.
      Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy: efficacy and subsequent fecundity.
      ].
      AE was used for induction of mid-trimester abortion as early as 1973 [
      • Gomel V.
      • Carpenter C.W.
      Induction of mid-trimester abortion with intrauterine alcohol.
      ]. In 2006, we reported treatment of ectopic pregnancy with local injection of AE into the GS [
      • Kaijima H.
      • Osada H.
      • Kato K.
      • et al.
      The efficacy and safety of managing ectopic pregnancies with transvaginal ultrasound-guided local injections of absolute ethanol.
      ]. This procedure proved to be effective for early ectopic pregnancy up to 5 weeks of GA, but had no effect on cases with positive FHB owing to the disappearance of the chorionic cavity accompanying the expansion of the amniotic cavity and formation of the amniochorionic membrane. This transition process, in which the chorionic cavity is overtaken by the amniotic cavity in the changing membrane structure of the GS, can be observed with ultrasonography. From the end of 5 weeks to 6 weeks of GA, the amniotic cavity begins to expand owing to an increase of amniotic fluid in the GS. At 7 weeks of GA, the amniotic cavity rapidly expands, while the chorionic cavity shrinks and disappears. At this time, the chorionic membrane is compressed against the wall to cover the outer surface of the amniotic cavity. Finally, the amniotic membrane and the chorionic membrane are fused together to form the strong amniochorionic membrane, which acts as a barrier to trophoblasts and blocks the action of AE. Furthermore, the growing and thickening trophoblast cells do not allow AE to penetrate into the entire trophoblastic layer. Thus, we injected the AE directly to trophoblasts. Trophoblasts form chorionic villi that protrude into the lacunar space (intervillous space). The injection of AE into the lacunar space causes trophoblastic necrosis through dehydration and coagulation, resulting in the demise of gestation.
      The lacunar space cannot be observed directly but is present in the decidua capsularis thickened by the chorionic reaction around the GS and appears as a hyperechoic inner ring (white echogenic rim) on TVU [
      • Doubilet P.M.
      Ultrasound evaluation of the first trimester.
      ]. CP and CSP are rare, and given our small sample size, larger series are needed to corroborate our results and determine the efficacy of this approach.
      In conclusion, TTT with AE injection has several advantages. It is a relatively simple procedure. AE is not toxic and allows for repeat administrations as needed. The effect of AE is rapid, producing a Σ20% decline in β-hCG level within 2 hours, which is favorable for treating such high-risk conditions as CP and CSP. Furthermore, because AE is injected locally using a small-diameter needle (23G), it causes little pain and often does not require anesthesia. Outpatient treatment is also frequently possible. Given all these advantages, this method can be highly beneficial to patients and physicians alike. In this study, AE injection successfully treated 19 ectopic pregnancies. However, a call for larger, multicenter trials is appropriate so that safety can be proven and β-hCG curves can be established.

      Supplementary Data

      The following is the supplementary data to this article:
      • Figure S1

        Transvaginal ultrasound Doppler image of a typical patient with cesarean section scar pregnancy with a fetal heart beat (FHB) (patient 8). The patient was age 33 years, FHB-positive, and spontaneously pregnant at gestational age 7 weeks 6 days, and had a history of cesarean section delivery. The gestational sac (GS) was located within the cervical canal. A transvaginal ultrasound image of the anterior wall of the cervix revealed a hyperechoic ring around the GS with a yolk sac and the fetal pole (red arrow). Fetal cardiac activity was detected below the internal os on M-mode sonography. The mean sac diameter was 11 mm on the initial examination. AE (5 mL) was locally injected into the hyperechoic ring around the GS. The initial serum beta human chorionic gonadotropin level was 26,930 mIU/mL. The level decreased to 22,141 mIU/mL (rate of decrease, 17.8%) within the first 2 hours. The level descended smoothly to 8776 mIU/mL (rate of decrease, 32.6%) the next day, to 263 mIU/mL (rate of decrease, 99.0%) on day 8, and to 0.8 mIU/mL on day 30.

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