Pravastatin and L-Arginine Use in Early-Onset Severely Growth-Restricted Dichorionic Twins: A Case Report

Introduction

Fetal growth restriction is diagnosed when the estimated fetal weight or abdominal circumference is below the 10th percentile, which occurs in 3% to 9% of pregnancies in developed countries [1]. Early-onset fetal growth restriction refers to growth restriction diagnosed before 32 weeks of gestation and has an incidence of 0.3% to 1% in pregnancies [1,2]. While less common than late-onset fetal growth restriction, it is usually more severe, with a higher risk of placental dysfunction indicated by Doppler abnormalities and a stronger link to hypertensive disorders of pregnancy [3]. Fetuses with severe growth restriction (below the 3rd percentile for gestational age) and/or umbilical Doppler abnormalities are at the greatest risk for fetal demise [3]. Nongenetic causes of fetal growth restriction include local factors affecting the placenta, cord, and uterus, as well as maternal homeostasis during pregnancy. Maternal factors that can impede uteroplacental exchange result in uteroplacental insufficiency and include maternal hypertensive disorders, cigarette use, drug use, alcohol consumption, and primiparity [4]. Each of these conditions, as well as multiple gestation, can affect the oxygen and nutrient supply to the fetus, which are essential for normal fetal growth [5].

Fetal growth restriction complicates about 25% to 47% of twin pregnancies and can involve one or both fetuses. Dichorionic twin pregnancies have a lower incidence, ranging from 11% to 24% [6]. Currently, the only management for these pregnancies is expectant, with intensive fetal surveillance, corticosteroids for fetal lung maturation, and early delivery if warranted [1].

Pravastatin is a hydrophilic statin with limited placental transfer that promotes angiogenic balance and vasorelaxation by the upregulation of nitric oxide and reduction of oxidative stress, thereby improving placental vascular function [7]. L-arginine is a nitric oxide precursor that has been shown to result in a significant mild reduction in umbilical arterial systolic/end-diastolic velocity ratio and improved neonatal outcomes presumably by promoting umbilical blood flow through vasorelaxation [8]. A small observational study demonstrated that women with early-onset uteroplacental dysfunction, evidenced by a uterine artery Doppler pulsatility index above the 95th percentile, who were treated with pravastatin and L-arginine had improved uteroplacental hemodynamics, increased fetal growth, and pregnancy prolongation [9]. A small pilot observational study demonstrated that a combination regimen of pravastatin and L-arginine improved umbilical artery blood flow in dichorionic twin gestations. Five pregnant women with early-onset growth restricted dichorionic twin pregnancies and abnormal umbilical artery Doppler studies (absent or reversed end-diastolic flow) received the regimen, which was initiated between 20 and 24 weeks of gestation. Improvement in Doppler flow was noted approximately 2 to 3 weeks after initiation, and all pregnancies resulted in live births, delivered between 31 and 34 weeks of gestation [10]. In the present report, we describe the case of a 35-year-old woman with a dichorionic twin pregnancy with fetal growth restriction diagnosed at 16 weeks of gestation that was managed with pravastatin and L-arginine and resulted in twin delivery at 32 weeks.

Case Report

A 35-year-old woman, gravida 1, presented with early-onset fetal growth restriction in a dichorionic twin pregnancy that was first noted at 16 weeks and 6 days of gestation (twin A lagging 9 days behind and twin B lagging 5 days behind). The pregnancy was conceived after artificial insemination using donor sperm and ovulation induction with clomiphene. The estimated delivery date was assigned by insemination. Her social history was negative for alcohol, tobacco, and substance abuse. The patient had no past history of pelvic surgery. Her past medical history was negative. She denied connective tissue disease and vascular thrombosis. At her visit at 16 weeks and 3 days of gestation, the maternal serum alpha-fetoprotein, a marker for placental insufficiency and possible anatomic anomalies, was evaluated at 6.82 multiples of the median (adjusted for twin gestation). Noninvasive prenatal screening was low-risk (negative) and confirmed dizygotic twins. Echogenic bowel was noted for twin B, with an unremarkable work-up, including negative maternal serum cytomegalovirus results and negative cystic fibrosis screening. Diagnostic testing via amniocentesis was declined after genetic counseling.

At 19 weeks and 3 days of gestation, the patient was admitted to the hospital owing to hypertension detected at an office visit. At that time, both fetuses were measuring less than the 1st percentile (twin A 201 g, twin B 205 g). Blood pressures normalized during admission without medical therapy. There was no evidence of preeclampsia, with normal renal and liver function tests as well as a normal platelet count. A 24-h urine total protein was normal at 233 mg. The patient was counseled regarding the poor prognosis and maternal and fetal risks of ongoing pregnancy, including severe morbidity and mortality. The patient desired expectant management and declined termination of pregnancy.

At 21 weeks and 3 days of gestation, severe fetal growth restriction persisted in both twins, with twin A at 274 g, and twin B at 283 g (Figures 1, 2). At this time, umbilical artery Doppler studies were measured and demonstrated a normal pulsatility index for twin A and absent diastolic flow for twin B. At 21 weeks and 5 days of gestation, the patient inquired about pravastatin and L-arginine use given the concern for placental insufficiency (abnormal blood flow). Risks versus benefits were extensively discussed, acknowledging the limited data, including potential short- and long-term neonatal risks. After patient consent was obtained, pravastatin 40 mg and L-arginine 1.5 g daily were initiated. At 22 weeks and 6 days of gestation – 9 days after starting pravastatin and L-arginine – twin B’s umbilical artery Doppler demonstrated intermittently absent diastolic flow, but diastolic flow was present in most samples taken. The first course of betamethasone was administered at 23 weeks and 6 days of gestation, when the patient was willing to consider intensive neonatal care, and the fetuses had reached 350 g, an institutional threshold for resuscitation.

At 25 weeks and 6 days of gestation, umbilical artery Doppler for twin A demonstrated increased pulsatility, and for twin B continued to demonstrate intermittent absent diastolic flow, suggesting significant vascular resistance. Hypertension was again noted in the office, and she was admitted to the hospital. Magnesium sulfate was administered for fetal neuroprotection. Preeclampsia was not suspected, with a return to normal blood pressure and no laboratory abnormalities, including no increased proteinuria. A second course of betamethasone was administered. The patient remained inpatient for the remainder of her pregnancy. During that time, fetal growth continued but was less than expected, with an average interval growth of only 12.2 g/day for twin A and 10.3 g/day for twin B. Umbilical artery Doppler for twin A remained normal, with an occasional elevated pulsatility index, while for twin B Doppler continued to show variation between elevated, intermittent, or persistently absent diastolic flow (see Table 1 for umbilical artery Doppler progression over time).

Fetal growth progressed until 32 weeks and 1 day of gestation (Table 2), at which time, the patient had refractory severe range blood pressures requiring treatment with intravenous antihypertensives. In addition, a 24-h total urine protein level returned elevated at 2800 mg. Preeclampsia with severe features was diagnosed. Magnesium sulfate was administered for seizure prophylaxis, and delivery was recommended. Twin neonates were delivered via primary classical cesarean delivery through a Pfannenstiel skin incision. Twin A weighed 1180 g, and twin B weighed 1100 g. Both twins had normal umbilical cord gas studies. The twins spent 61 days in the Neonatal Intensive Care Unit (NICU) without any major complications. They were discharged to home without evidence of any neurodevelopmental delay and continue to meet expected milestones at 6 months of age.

Discussion

We present a case of severe, early-onset fetal growth restriction and placental insufficiency in a dichorionic gestation managed with pravastatin and L-arginine that was prolonged until 32 weeks of gestation, at which time preeclampsia was diagnosed, necessitating delivery. We believe the pravastatin and L-arginine regimen played a role in pregnancy prolongation by improving umbilical artery hemodynamics and likely delaying the onset of preeclampsia. After 61 days in the NICU, both twins were discharged in good condition and have had normal neurodevelopment to date. Gestational age at delivery is the most important determinant of survival and intact neurodevelopment [11]. As with all case reports, these data should be interpreted with caution. Larger, well-powered, randomized trials are needed to prove the efficacy, safety, and feasibility of this regimen.

Pravastatin is a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which converts HMG-CoA to mevalonate in cholesterol synthesis and is typically used for this purpose. With regard to preeclampsia, statins restore angiogenic balance by decreasing the production of soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) and increasing vascular endothelial growth factor and placental growth factor. Statins also reduce inflammation and oxidative stress [12,13]. Normal endothelial function is restored through increased nitric oxide production that promotes vessel relaxation [7]. L-arginine functions synergistically with pravastatin as it is a substrate of nitric oxide. In addition, pravastatin may prevent preeclampsia-mediated altered postnatal growth and metabolic dysfunction [14].

Pregnancy safety data for pravastatin are limited. However, existing data suggest no increased risk of congenital malformation [15]. The drug appears to have a favorable adverse effect profile in pregnancy as well [16]. The hydrophilic statins, as compared with lipophilic, have limited placental transfer, making hydrophilic pravastatin an appealing choice for pregnancy [7]. Following the publication of these data, the Food and Drug Administration requested the removal of its strongest warning label (category X) against statins in pregnancy [7]. Aside from short-term effects, the long-term effects of pravastatin on exposed offspring, including growth, development, and metabolic function, are unknown.

Studies of pravastatin for the prevention of preeclampsia show promising results but remain limited by a small sample size. The INOVASIA (Indonesia Pravastatin to Prevent Preeclampsia Study) trial is one of the largest to date. In this open-label, multicenter trial, pregnant women were randomly assigned to pravastatin 20 mg daily (n=87) or a standard regimen of low-dose aspirin 80 mg and calcium 1 g daily (n=86) starting from 14 to 20 weeks of gestation. The pravastatin group had a significantly lower rate of preterm preeclampsia (13.8% vs 26.7%, P=0.034, odds ratio 0.034, 95% CI 0.202–0.905) and preterm birth (16.1% vs 35%, P=0.003, odds ratio 0.340, 95% CI 0.165–0.7). Most preterm births were indicated. In addition, perinatal outcomes were improved, including Apgar scores and low birth weight [12,17]. Another randomized trial demonstrated that late initiation of pravastatin at 35 to 37 weeks of gestation to individuals at high risk for preeclampsia based on clinical factors and laboratory biomarkers did not reduce the incidence of preeclampsia [18]. This would be consistent with the proposed mechanism of action of second trimester placental-mediated changes. Thus, pravastatin may not be as effective in preventing preeclampsia when initiated later in gestation. Similarly, it may not be effective in the treatment of preeclampsia once it has developed, as evidenced by a study showing that it did not appear to reduce sFlt-1 levels over the first 3 days of use compared with placebo in pregnant individuals with preeclampsia [19].

Less is known about the effects of pravastatin with regard to early-onset fetal growth restriction. Several studies evaluating pravastatin and L-arginine in the treatment of pregnancies at high risk for uteroplacental insufficiency have common components with our case. In all cases, the diagnosis of all patients was made using fetal ultrasound and Doppler. Management was expectant, with intense maternal and fetal surveillance using Doppler and traditional markers of maternal and fetal well-being. The outcomes indicate possible fetal improvement [9,10].

One non-randomized and historically controlled pilot study (n=38) compared Doppler progression, sFlt-1, placental growth factor values, and pregnancy outcomes in pregnant individuals with fetal growth restriction prior to 28 weeks of gestation and found results similar to this case. Study patients were matched to historical controls for gestational age, maternal characteristics, and Doppler severity. Pravastatin resulted in significant improvement in the angiogenic profile. Pregnancy duration and birthweight appeared to increase while preeclampsia was reduced, but the results were not significant, likely due to underpowering [20]. Another nonrandomized study of fetal growth restriction with pravastatin and L-arginine in the second trimester of high-risk pregnancies demonstrated results similar to ours. Improved uteroplacental hemodynamics and prolonged pregnancies for 4.1 months, compared with 26 days in the untreated group, was demonstrated [9]. The diagnosis was made using fetal ultrasound and Doppler, the management was expectant with intense maternal and fetal surveillance using Doppler and traditional markers of maternal and fetal well-being.

Between 2013 and 2016, daily doses of L-arginine and pravastatin were given to 5 women at high risk whose umbilical artery parameters confirmed fetal growth restriction with absent or reversed end-diastolic umbilical artery Doppler flow associated with increased perinatal mortality. The treatment diminished umbilical artery resistance significantly, and all neonates were born at a median of 33 weeks. These data are consistent with the present case [10].

Conclusions

Preeclampsia is often the outcome of early-onset fetal growth restriction related to placental insufficiency. Through a nitric oxide-dependent pathway, pravastatin and L-arginine may improve umbilical artery hemodynamics, promoting pregnancy prolongation in early-onset fetal growth restriction. This regimen appears to be safe based on limited existing data. Adequately powered, randomized trials are needed to confirm these findings. In addition, the generalizability of these findings should be determined for applicability to different populations. This report supports the findings from recent studies showing that combined pravastatin and L-arginine may improve fetal development and survival in fetal growth restriction in monochorionic twin pregnancies. Further studies and controlled clinical trials are awaited to confirm these findings.