[Abstract]HELLP syndrome, characterized by hemolysis,elevated liver enzymes, and low platelets,is one of the diseases related to hypertension in pregnancy. If the pregnancy is not terminated soon after HELLP is diagnosed, liver failure or disseminated intravascular coagulopathy (DIC)may occur. HELLP syndrome occurs in 0.2%–0.9% of all pregnancies; Onset before 24 weeks of gestation is extremely rare but is more likely to result in stillbirth. Women who have had a stillbirth often hope for another pregnancy soon after,but there is little information about the risks and outcomes for subsequent pregnancy in women who developed HELLP syndrome in early pregnancy.Thus, it is important to accumulate data on these outcomes in this population. Here, we report a case in which severe HELLP syndrome developed at 22 weeks of gestation, resulting in stillbirth, and was followed six months later by a pregnancy that with early intervention, produced a live birth

Kanto Akiko

Matsumura Noriomi

Murakami Kosuke

Shimaoka Masao

Shiro Reona

Yo Yoshie

[Abstract] HELLP syndrome, characterized by hemolysis,elevated liver enzymes, and low platelets,is one of the diseases related to hypertension in pregnancy. If the pregnancy is not terminated soon after HELLP is diagnosed, liver failure or disseminated intravascular coagulopathy (DIC) may occur. HELLP syndrome occurs in 0.2%–0.9% of all pregnancies; Onset before 24 weeks of gestation is extremely rare but is more likely to result in stillbirth. Women who have had a stillbirth often hope for another pregnancy soon after,but there is little information about the risks and outcomes for subsequent pregnancy in women who developed HELLP syndrome in early pregnancy.Thus, it is important to accumulate data on these outcomes in this population. Here, we report a case in which severe HELLP syndrome developed at 22 weeks of gestation, resulting in stillbirth, and was followed six months later by a pregnancy that with early intervention, produced a live birth.application/pdfdepartmental bulletin pape

Kanto, Akiko

カントウ, アキコ

Murakami, Kosuke

ムラカミ, コウスケ

Yo, Yoshie

ヨウ, ヨシエ

Shimaoka, Masao

シマオカ, マサオ

Shiro, Reona

シロ, レオナ

Matsumura, Noriomi

マツムラ, ノリオミ

Kindai University Academic Resource Repository

47Vol.45, No.2  47-51, 2020Acta Med Kindai UnivHELLP syndrome at 22 weeks of gestation with resulting stillbirth and a favorable outcome in a subsequent pregnancy: A case reportAkiko Kanto, Kosuke Murakami, Yoshie Yo, Masao Shimaoka,Reona Shiro, Noriomi MatsumuraDepartment of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, JapanAbstract HELLP syndrome, characterized by he-molysis, elevated liver enzymes, and low platelets, is one of the diseases related to hypertension in pregnancy. If the pregnancy is not terminated soon after HELLP is diagnosed, liver failure or disseminated intravascular coagulopathy (DIC) may occur. HELLP syndrome occurs in 0.2%–0.9% of all pregnancies; Onset before 24 weeks of gestation is extremely rare but is more likely to result in stillbirth. Women who have had a still-birth often hope for another pregnancy soon after, but there is little information about the risks and outcomes for subsequent pregnancy in women who developed HELLP syndrome in early pregnancy. Thus, it is important to accumulate data on these outcomes in this population. Here, we report a case in which severe HELLP syndrome developed at 22 weeks of gestation, resulting in stillbirth, and was followed six months later by a pregnancy that with early intervention, produced a live birth.Key   words : HELLP syndrome, hypertensive disorder of pregnancy,  preeclampsia,  second trimester,  stillbirthIntroduction     HELLP syndrome, diagnosed on the basis of hemolysis, liver dysfunction, and thrombocyto-penia, generally occurs (80%–90% of cases) in the context of hypertension, proteinuria, and edema—the identifying features of maternal hypertensive disorder 1. HELLP syndrome can be fatal as a re-sult of progression to liver failure and disseminated intravascular coagulopathy (DIC), if diagnosis is delayed. Maternal mortality resulting from HELLP has been reported to be in the range of 2%–24% 1. HELLP syndrome occurs in 0.2%–0.9% of all pregnancies. Approximately 10% of cases occur at 24–26 weeks, 70% at 27–37 weeks, and 20% after 38 weeks of gestation 2; onset before 24 weeks is very rare.  A study that followed women with a his-tory of HELLP syndrome reported that in the next pregnancy, HELLP syndrome recurred in 13% and preeclampsia occurred in 16% of cases 3; however, it is unclear whether HELLP syndrome (or other pregnancy complications) are more likely in preg-nancies following HELLP syndrome that occurred very early in pregnancy.  Here, we report a case in which severe HELLP syndrome developed at 22 weeks, resulting in stillbirth, and was followed six months later by a pregnancy that produced a term birth.Case presentation The patient was a 27-year-old primipara with no prior pregnancies. The patient had been treated for asthma in childhood but had not re-quired treatment as an adult; her family history was unremarkable. The patient was naturally preg-nant and had routine medical examinations prior Received April 3, 2020; Accepted May 29, 2020DOI:10.15100/00021270A. Kanto et al.48to the event. At 18 weeks of gestation, leg edema appeared, but her blood pressure was within nor-mal limits, and there was no proteinuria. At 22 weeks and 1 day of gestation, the patient presented to clinic complaining of epigastric pain for 3 days. An abdominal ultrasonography showed no major abnormality, and the patient was decided that there was no need for hospitalization. On the following day, at 22 weeks and 2 days of gestation, the patient returned with increased epigastric pain and was promptly admitted to hospital for severe general-ized edema, headache and epigastric pain, elevat-ed blood pressure (now 144/99 mmHg), and gross hematuria. At this time, blood tests from the pre-vious day were found to be abnormal, with aspar-tate transaminase (AST) 107 U/L, alanine amino-transferase (ALT) 126 U/L, lactate dehydrogenase (LDH) 339 IU/L, and platelets 60,000 /μL (Table 1). On transabdominal ultrasonography: uterine artery Doppler revealed notches in the blood flow waveform (Fig. 1); the fetus showed asymmetri-cal growth restriction, with estimated weight 431 Table 1.    Laboratory results at admission.Result Normal rangeWBC (/μL) 8,400 3,300–8,600Hb (g/dL) 10.7 11.6–14.8PLT (x10,000/μL) 6.0 15.8–34.8AST (U/L) 107 13–30ALT (U/L) 126 7–23LDH (IU/L) 339 124–222T Bil (mg/dL) 0.9 0.4–1.5Cr (mg/dL) 0.57 0.46–0.79BUN (mg/dL) 13 8–20CRP (mg/dL) 2.601 0.0–0.9Abbreviations: WBC, white blood cell; Hb, hemoglobin; PLT, platelets; AST, aspartate transaminase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; T Bil, total bilirubin; Cr, creatinine; BUN, blood urea nitrogen; CRP, c-reactive proteinFigure 1.   Blood flow in the uterine artery. Notches were found in the uterine artery blood flow waveform.HELLP syndrome at 22 weeks of gestation49g (−1.5 standard deviation [SD]); fetal movement was poor, and the amniotic fluid index was 10.7 cm. The patient was diagnosed with HELLP syndrome, and treatment was initiated with nicardipine hydrochloride (1 mg/h) to lower blood pressure and magnesium sulfate hydrate (1 g/h) to prevent vasospasm and eclampsia. Twenty units of platelets were transfused but despite this, the pa-tient’s clinical condition rapidly deteriorated (lab-oratory data are shown in Fig. 2). Pregnancy was deemed to be life-threatening, and an emergency cesarean section was performed under general anesthesia. A male infant (360 g) was delivered through a longitudinal midline incision. A large amount of serous ascites was observed in the ab-dominal cavity. Apgar scores were 1 at 1 min and 1 at 5 min (heart rate less than 100) and resuscitation was done, but failed to respond and he was deemed stillborn. The platelet count had increased to 72,000 /µL following transfusion on the day of the cesar-ean section but then decreased to 37,000 /µL on postoperative day (POD) 1, requiring a further transfusion of 15 units of platelets. Blood pressure was controlled with oral nifedipine (20 mg/day). Liver enzymes gradually decreased and normalized on POD 8. Urine protein was 5.68 g/day on POD 3 but decreased to 1.32 g/day by POD 12. On POD 14, the patient was discharged. By POD 20, urinary protein had fallen below 300 mg/day. On POD 36, urine protein was 40 mg/day and blood pressure was 117/78 mmHg. At 197 days after the cesarean section, the patient presented following a positive pregnancy test, reportedly 5 weeks after her last menstrual period. Ultrasound confirmed an intrauterine ges-tational sac consistent with 5 weeks of gestation. Figure 2.    Changes in the laboratory values. (A) AST/ALT/LDH　(B) Hb/PLT　(C) aPTT/AT III/PT-INR　(D) Cr / Urine TP Abbreviations: AST, aspartate transaminase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; Hb, hemo-globin; PLT, platelets; aPTT, activated partial thromboplastin time; AT III, antithrombin III; PT, prothrombin time; INR, international normalized ratio; Cr,creatinine; TP, total protein; C/S, cesarean section; POD, postoperative day.A. Kanto et al.50Blood tests were negative for antiphospholipid antibodies, anti–β2 glycoprotein 1 antibodies, and antinuclear antibodies, and showed no evidence of antiphospholipid antibody syndrome or other au-toimmune disorders or abnormal coagulation. Her blood pressure was within normal range, but home blood pressure measurement was ordered because she had hypertension during her last pregnancy and was considered to be at high risk this time as well. Oral acetylsalicylic acid, 81 mg/day, was com-menced (and continued until 28 weeks) in the hope of suppressing platelet function and preventing hy-pertensive disease. At 10 weeks of gestation, the pa-tient presented with blood pressure 146/87 mmHg. Home blood pressure was within normal limits, but the systolic blood pressure was close to 140 mmHg, therefore, oral hydralazine hydrochloride, 20 mg/day, was started. At 28 weeks, ultrasound estimated the fetal weight to be −1.6 SD, prompt-ing the diagnosis of fetal growth restriction. There were no other fetal abnormalities. At 31 weeks, the estimated weight of the fetus was −1.7 SD, and at 31 weeks and 4 days the patient was hospitalized to observe the condition of the fetus closely. Fol-lowing admission, her blood pressure remained stable on oral hydralazine hydrochloride, 20 mg/day, at roughly 110/70 mmHg, and her urine was free of protein. The estimated fetal weight contin-ued to be low but increased, ranging from −1.3 SD to −1.7SD, and nonstress tests were in the normal range. An elective cesarean section was performed at 37 weeks and 5 days, as indicated by a previous cesarean section. The female infant weighed 2,276 g (small for gestational age) and had Apgar scores of 8 and 9 at 1 min and 5 min, respectively. The mother and child were both well and discharged on POD 8. Ten years later, the patent is normotensive and is not on any medication. The child is also in good health.Discussion We treated a rare condition—HELLP syn-drome at 22 weeks of gestation. HELLP syndrome can be severe, escalating to hepatic failure and DIC and requiring pregnancy termination without delay. In our reported case, LDH was not so high, and nei-ther Tennessee classification 4 nor Mississippi-tri-ple class system 5 was met, but it was predicted that the condition would rapidly worsen from the symp-toms, high AST / ALT, and low platelets, and it was managed as HELLP syndrome. Total Bilirubin was normal, and haptoglobin or peripheral blood pic-ture was not examined. The most important dif-ferential diagnosis for HELLP syndrome is acute fatty liver of pregnancy (AFLP). However, the distinction between HELLP syndrome and AFLP is not easy due to the similarity of symptoms and blood test findings 6. The pathology of AFLP was hepatic insufficiency, and the absence of signifi-cant thrombocytopenia, hyperbilirubinemia, pro-longed prothrombin time, and extreme decrease in antithrombin III activity were not consistent with the present case and was excluded. Gastrointestinal disease was also a differential diagnosis based on symptoms, but this was ruled out due to changes in blood test data and ultrasound findings. Epigastric pain and rapid elevation of liver enzymes were not typical of hemolytic or autoimmune diseases, and these were also excluded. Previously, corticosteroid administration was reported to extend gestational age 7. However, the effect of extending gestational age by cortico-steroid administration has been denied 8,9. The cur-rent recommendation is to terminate the pregnancy as soon as possible after 34 weeks of gestation; prior to 34 weeks, corticosteroid administration is recommended to promote infant maturation, with pregnancy termination 48 hours later 2,10. If the cer-vix is mature and induction of delivery is expected, vaginal delivery may be considered, but cesarean section is often performed for preterm delivery. In our reported case, as shown in Fig. 2, the patient’s condition rapidly deteriorated, so there was no time to administrate corticosteroid and wait for 48 hours. It was not clear whether the cause of still-birth is due to the rapid progression of HELLP syn-drome or the immaturity of the infant. While it has been suggested that HELLP syndrome is likely to occur as a complication of autoimmune diseases, such as antiphospholipid antibody syndrome 11, the factors influencing the development of HELLP and the risk of recurrence in a subsequent pregnancy are unclear—certainly, in the present case, autoimmune disease was not present. Further, it has been reported that just 1.5% of HELLP syndrome cases occur prior to 24 weeks of gestation 12; indeed, a recent PubMed search of HELLP syndrome before 24 weeks of gestation (using the terms “HELLP syndrome” and “second trimester pregnancy”) yielded only 11 case reports. A retrospective cohort study previously reported a stillbirth rate of 9% and perinatal mortality rate of 20% in HELLP syndrome cases 13. The authors could find no reports summarizing perinatal mor-tality in HELLP syndrome occurring prior to 24 HELLP syndrome at 22 weeks of gestation51References 1. D’Anna R (1996) The HELLP syndrome. Notes on its pathogenesis and treatment. Minerva Ginecol 48: 147-154 2. Haram K, Svendsen E, Abildgaard U (2009) The HELLP syndrome: Clinical issues and management. A Review. BMC Pregnancy Childbirth 9: 8 3. Leeners B, et al. (2011) Recurrence risks of hyperten-sive diseases in pregnancy after HELLP syndrome. J Peri-nat Med 39: 673-678 4. Shibai BM, et al. (1993) Maternal morbidity and mor-tality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Ob-stet Gynecol 169: 1000-1006 5. Martin JN Jr, et al. (1999) The spectrum of severe pre-eclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification. Am J Obstet Gynecol 180: 1373-1384 6. Minakami H, et al. (2014) Differentiation of acute fatty liver of pregnancy from syndrome of hemolysis, elevated liver enzymes and low platelet counts. J Obstet Gynaecol Res 40: 641-649 7. TO’Brien JM, Milligan DA, Barton JR (2000) Impact of high-dose corticosteroid therapy for patients with HELLP (he-molysis, elevated liver enzymes, and low platelet count) syn-drome. Am J Obstet Gynecol 183: 921-924 8. Kozyrskyj A, Klassen TP, Moffatt M, Harvey K (2010) Short-course antibiotics for acute otitis media. Cochrane Database Syst Rev 9: CD001095 9. Pourrat O, et al. (2016) High-dose methylprednisolone to prevent platelet decline in preeclampsia: A randomized controlled trial. Obstet Gynecol 128: 153-15810. ACOG practice bulletin (2019) No. 202: Gestational hypertension and preeclampsia. Obstet Gynecol 133: e1-e2511. Aloizos S, et al. (2013) HELLP syndrome: Understand-ing and management of a pregnancy-specific disease. J Obstet Gynaecol 33: 331-33712. Okai T, et al. (2009) Acta Obstet Gynaecol Jpn 61: 1543-156713. Gasem T, et al. (2009) Maternal and fetal outcome of pregnancy complicated by HELLP syndrome. J Matern Fetal Neonatal Med 22: 1140-114314. Alghamdi A, Tabb D, Hagan L (2018) Preterm labor caused by hemolysis, elevated Liver enzymes, low plate-let count (HELLP) syndrome and postpartum infection complicated with actinomyces species: A case report. Am J Case Rep 19: 1350-135315. Regan AK, et al. (2019) Association between interpreg-nancy interval and adverse birth outcomes in women with a previous stillbirth: An international cohort study. Lancet 393: 1527-1535weeks of gestation, but this is likely to be much worse—indeed, among the 11 reported cases of HELLP syndrome before 24 weeks of gestation, there was only one live birth 14.  An international cohort study has reported a good prognosis for pregnancy within 12 months following stillbirth 15; however, there have been no reports of outcomes for pregnancies following stillbirth in the context of HELLP syndrome. In our reported case, hypertension occurred from the ear-ly stage of pregnancy and was managed as chronic hypertension. At birth, the infant weight was low (2,276 g at 37 weeks of gestation); however, at 10-year follow-up, the mother was normotensive with-out medication, and the child was in good health. Unfortunately, HELLP syndrome that develops in early second trimester is more likely to result in worse prognosis. Women who have experienced stillbirth often hope to have another pregnancy very soon after, but there is a great deal of anxi-ety about the course of the next pregnancy. It is important to accumulate reports on the outcome of pregnancies following stillbirth due to HELLP syn-drome in order to provide more accurate prognoses to patients and their families. Moreover, in the case of subsequent pregnancy, the prognosis may be im-proved by taking measures such as increased med-ical examinations and management at specialized hospitals.AcknowledgementNo funding was sought or secured in relation to this case report.DeclarationThe authors report no conflicts of interest in this work.

<Case Reports> HELLP syndrome at 22 weeks of gestation with resulting stillbirth and a favorable outcome in a subsequent pregnancy: A case report

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〈Case Reports〉HELLP syndrome at 22 weeks of gestation with resulting stillbirth and a favorable outcome in a subsequent pregnancy: A case report

〈Case Reports〉HELLP syndrome at 22 weeks of gestation with resulting stillbirth and a favorable outcome in a subsequent pregnancy: A case report

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