Pravastatin Improves Angiogenic Factors and Feto- Placental Doppler in Pregnancy with Early Severe Fetal Growth Restriction: A Case Report
Summary
Early fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. No therapeutic strategies have proved to be effective in improving fetal and neonatal outcomes either in growth restricted fetuses or any placenta-related disorder such as preeclampsia. Delivery of the fetus and placenta is the only definitive cure. However, recent studies suggest that pravastatin appears to be safe in pregnancy, improves placental perfusion and fetal growth and prevents angiogenic imbalance. Angiogenic (PlGF) and antiangiogenic (sFlt-1) factors and feto-maternal Doppler evaluation are strongly associated with fetal growth restriction prognosis and severity. Thus, pravastatin has been proposed as a promising therapeutic drug for fetal growth restriction. We report the findings of a case of early-onset FGR treated with pravastatin 40mg daily until delivery. During this time, feto-maternal Doppler and angiogenic profile evolution were recorded. Fetal and placental perfusion observed on Doppler and angiogenic imbalance improved after pravastatin was started. sFlt-1 down-regulation was more marked than PlGF up-regulation. The patient developed severe preeclampsia (PE) at 27+6 weeks of gestation, necessitating immediate fetal extraction owing to hypertension refractory to adequate treatment. This report supports further investigation on the use of pravastatin to improve angiogenic profile and feto-maternal circulation in FGR fetuses.
Keywords: Fetal growth restriction; Pravastatin; PlGF, sFlt-1; Feto-placental Doppler
Introduction
Fetal growth restriction (FGR) affects 7-10% of all pregnancies and refers to a fetus that has failed to achieve its biological growth potential [1]. Growth-restricted fetuses have a 5- to 10-fold risk of dying in utero and a higher risk of perinatal morbidity and mortality [2]. Abnormal placentation is a key factor in fetal growth restriction pathophysiology [3]. Several histopathologic features such as villous infarction, maternal vascular changes and villous morphologic alterations are observed more frequently in placentas from pregnancies complicated by FGR [4]. Placental function evaluation by umbilical artery (UA) Doppler velocimetry is the clinical standard for identifying early-onset FGR [1-3] and there is evidence that its use in these pregnancies improves a number of obstetric care outcomes and reduces perinatal deaths [4].
Fetal deterioration latency can vary from case to case; however, it usually lasts weeks and often follows a series of changes reflected in a sequential pattern on Doppler that permits tailoring of fetal monitoring and elective delivery [1].
Uteroplacental insufficiency is associated with a predominantly antiangiogenic environment characterized by up-regulation of soluble fms-like tyrosine kinase-1 (sFlt-1) and down-regulation of placental growth factor (PlGF) [5]. Abnormal angiogenic factor levels in the maternal circulation play a key pathogenic role in the development of endothelial dysfunction with ensuing preeclampsia [5]. The value of angiogenic biomarkers in the prediction, prognosis and characterization of early-onset preeclampsia and FGR has been demonstrated in several studies [5,6]. In uncomplicated pregnancies, PlGF rises until the third trimester of pregnancy and falls thereafter whereas sFlt-1 levels rise as the pregnancy progresses. Thus, the sFlt-1 to PlGF ratio rises with gestational age. These changes are more patent in pregnancies that will eventually develop placental disease [5-7].
No treatment currently exists for placental insufficiency and delivery is the only way to stop disease progression. If preeclampsia or FGR occur early in gestation, the need to deliver the fetus preterm for maternal and/or fetal indications can lead to neonatal death and disability arising from prematurity.
Some studies suggest that statins could be a promising therapeutic or preventive strategy for placental insufficiency [8,9]. Significant clinical benefits and improvement in the angiogenic profile have been reported in patients with early-onset preeclampsia [10] and umbilical artery flow in twin pregnancies with discordant fetal growth seems to improve after pravastatin is started [11]; however, no previous studies reported the effect of pravastatin on the uterine artery Doppler and angiogenic factors of FGR single pregnancies in humans.
Case Report
Case description
A 41-year-old woman with early-onset FGR was referred to our center at 25+4 weeks of gestation (WG). Estimated fetal weight (EFW) at admission (25+4 WG) was 429 grams (g) that corresponded to a zero percentile. After the diagnosis of FGR was confirmed, the patient received a course of antenatal corticosteroids for fetal maturation, amniocentesis was performed and prophylactic low-molecular-weight heparin was initiated owing to the presence of 3 other thrombotic risk factors (obesity, smoking and age >40 years). Negative results were obtained in tests for antiphospholipid antibodies. These tests were repeated on two occasions during pregnancy. Results of the amniocentesis and Doppler findings were suggestive of FGR secondary to severe placental insufficiency (increased pulsatility of the uterine arteries with present bilateral early diastolic notches, normal fetal CGH arrays and negative polymerase chain reaction for cytomegalovirus in amniotic fluid analysis).
The patient was offered treatment with pravastatin and, after being informed of its risks and benefits, consented to its use. Pravastatin was started at 26+2 WG.
This patient was the first to be enrolled in a pilot study where patients presenting FGR before 28+0 WG were offered pravastatin 40mg daily until delivery. The aim of that study was to ascertain whether pravastatin treatment exerted beneficial effects on growthrestricted fetuses. FGR was defined as estimated fetal weight below the third centile or below the 10th centile associated with any fetoplacental Doppler impairment.
The effects of pravastatin were evaluated on feto-maternal Doppler ultrasound (umbilical artery, middle cerebral artery, ductus venosus and uterine arteries) together with serum angiogenic factors (sFlt-1 and PlGF), clinical and biochemical findings related to preeclampsia such as mean systolic and diastolic blood pressures, qualitative proteinuria, 24-hour quantitative proteinuria, prodromal symptoms of eclampsia (headache, visual disturbance, tinnitus, epigastric pain and/or upper right abdominal pain) and other relevant laboratory findings.
Findings
The findings are summarized in Figure 1. No significant effects were observed on any biochemical parameters, blood pressure or middle cerebral artery (MCA) Doppler after pravastatin was started. However, an effect on umbilical artery (UA) pulsatility index (PI), uterine artery (UtA) PI and angiogenic factors was observed after 36 hours. Mean UtA PI dropped significantly (from 3.34 to 2.64, although being both above the 99th percentile for gestational age) and this improvement persisted 7 days later. UA PI had been rising progressively prior to pravastatin and remained around normal values thereafter.
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