One year later, in her second pregnancy, she was referred for severe fetal growth restriction and highly abnormal Doppler indices at GA 20+2 (Table 1). Because of first-trimester vaginal bleeding acetylsalicylic acid (ASA) had been withheld. Maternal symptoms were absent, and laboratory results were normal. She was monitored as outpatient until GA 22+2, when blood flow indices in the ductus venosus deteriorated; in addition, she developed symptoms of HELLP syndrome. The diagnosis was confirmed by laboratory results (Fig. 1). Temporizing management was initiated after extensive discussion; however, intrauterine fetal death occurred at GA 22+5 (female, weight: 325 g, <3rd percentile). Apart from a transient rise in blood pressure her postoperative course was uncomplicated.
Thereafter, the patient came for preconception counseling; she was informed about the high chance of another pregnancy failure and the substantial maternal risk, but she opted for another attempt. Her request for immunosuppressive/immunomodulatory treatment during her next pregnancy was denied because of lack of clinical and scientific evidence in HELLP syndrome; peripheral lymphocyte typing had revealed normal results.
Instead, an extensive diagnostic work-up for potential cofactors of recurrent HELLP syndrome was offered. It included parental karyotyping, 3-dimensional ultrasound of the uterine cavity to rule out genital malformations or secondary changes, repeated cervical swabs for chlamydia trachomatis, ureaplasma urealyticum, and mycoplasma hominis, all with negative results. The endocrinological work-up revealed normal early follicular phase hormones; autoimmune thyreoiditis (Hashimoto) was confirmed. Due to rising levels of anti-TPO antibodies, substitution with L-thyroxin (maximum dosage of 50 μg daily) and selen (200 μg daily) was initiated.
The HOMA (homeostasis model assessment) was slightly elevated, a subsequent glucose tolerance test showed a marginally abnormal 2-hour blood glucose concentration. The patient received nutritional advice; she declined treatment with biguanide derivatives.
Screening for thrombophilia did not reveal major inherited or acquired disorders except for homozygosity for the MTHFR (methylentetrahydrofolat-reductase) mutation C677T. Repeated controls for antiphospholipid antibodies remained negative. However, D-dimers were mildly elevated in several analyses.
In 2015, then 39 years old, she miscarried at 8 weeks’ gestation; karyotyping revealed trisomy 22.
In early 2016, now 40 years old, the patient conceived again. She was commenced on prophylactic treatment with low-molecular weight heparin (LMWH) (enoxaparin 40 mg s.c. daily), ASA (100 mg daily), and natural progesterone (400 mg daily intravaginally). The preconception treatment with L-thyroxin (50 μg daily), selen (200 μg daily), myoinositol (1000 mg daily), and folic acid (2.5 mg daily) was continued. Pravastatin (10 mg daily) was started at GA 12. Institutional review board approval is not required for off-label use treatment. After extensive counseling about the medication, written consent was obtained from the patient. Close surveillance (clinical, laboratory, and ultrasound) was initiated. Throughout the entire course of pregnancy she was asymptomatic, and her laboratory results remained within normal range. The obstetric ultrasound revealed adequate growth of a fetus without major malformations, and normal Doppler indices of the fetal, fetomaternal, and uteroplacental vessels (Table 1). Gestational diabetes developed in the third trimester and was controlled with insulin. At GA 37+1, elective cesarean delivery was performed (male; 2920 g, 31st percentile; Apgar scores 9/10/10 at 1, 5, and 10 minutes, respectively; umbilical artery pH 7.35). Both, patient and newborn, made an uncomplicated postoperative/postnatal course and were discharged on day 3.
Pravastatin at a daily dosage of 10 mg, commenced early in the second trimester, in addition to ASA and LMWH, resulted in an uncomplicated pregnancy and term delivery of an AGA healthy neonate in a patient with a history of severe, early-onset, recurrent HELLP syndrome.
Presently, a HMG-Co-A-reductase-mediated decrease in s-Flt-1 synthesis is hypothesized to be the mechanism underlying the positive effect of pravastatin in preeclampsia; in addition, a rise in levels of circulating placental growth factor (PlGF) may contribute to the improvement of the proangiogenic profile and the reversion of sequelae of inflammation and endothelial dysfunction.[5,7,9] The effect of pravastatin on soluble endoglin, another cofactor of vascular homeostasis involved in the pathogenesis of preeclampsia, is less clear, and may include an organ-specific response.
In contrast to preeclampsia, HELLP syndrome is characterized by hepatic and hematologic manifestations. Nevertheless, HELLP syndrome and preeclampsia share the same pathophysiology, and HELLP syndrome is considered a particular manifestation of preeclampsia, respectively.
We assume that the mechanism of action of pravastatin in HELLP syndrome is comparable to its effect in preeclampsia. The hepatic uptake of pravastatin may be of particular advantage in HELLP syndrome because 50% of the absorbed drug is lost by a first-pass effect.
To our knowledge, this is the first report of pravastatin in severe, early-onset, recurrent HELLP syndrome; the positive outcome justifies further clinical trials in women at risk of developing HELLP syndrome.
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Keywords:Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
HELLP syndrome; HMG-CoA-reductase inhibitor; pravastatin