A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia

Costantine, Maged M.; West, Holly; Wisner, Katherine L.; Caritis, Steve N.; Clark, Shannon; Venkataramanan, Raman; Stika, Catherine S.; Rytting, Erik; Wang, Xiaoming; Ahmed, Mahmoud S.; Welch, Elizabeth; Snodgrass, Wayne R.; Nanovskaya, Tatiana; Patrikeeva, Svetlana; Saade, George R.; Hankins, Gary; Pinheiro, Emily; O’Shea, Kelly; Cattan, Minaz Kolia; Mesches, Gabrielle A.; Ciolino, Jody D.; George, Alfred L.; Fischer, Donald R.; DeAngeles, Donna; Ren, Zhaoxia

doi:10.1016/j.ajog.2021.05.018

Cited by 52 publications

(62 citation statements)

References 52 publications

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“…As a consequence of the lower preterm birth rate, the newborn in the pravastatin groups had fewer low birth weight and very low birthweight babies. In line with our findings, the combined US OPRC study showed a significantly decreased indicated preterm delivery <37 weeks in pravastatin compared to control group (20% vs 55%, p=0.048) 45 . The OPRC study demonstrated a trend toward improved neonatal outcomes in the pravastatin group in terms of increased birthweight, decreased NICU admission, shorter NICU stay, and decreased rate of respiratory distress syndrome 45 .…”

Section: Accepted Manuscriptsupporting

confidence: 91%

“…There were no recognized risks to the mother or fetus associated with pravastatin treatment in this cohort 41 . In addition preeclampsia rate was lower in the pravastatin group compared to placebo in the combined RCT result (10 vs 45%, n =40) 45 .…”

Section: Accepted Manuscriptmentioning

confidence: 80%

“…pravastatin 20 mg or placebo until delivery 41,45 . Additionally, the latest study indicated that there were no significant differences between the two groups in terms of adverse or major adverse events, congenital anomalies, or maternal and umbilical cord blood biochemistry 45 .…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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INOVASIA Study: A Multicenter Randomized Clinical Trial of Pravastatin to Prevent Preeclampsia in High-Risk Patients

et al. 2022

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Objective To determine if treatment with pravastatin prevents preeclampsia in pregnant patients at risk for preeclampsia. Material & Methods The study was performed in four major tertiary hospitals in Surabaya, Bandung, and Makassar between 2017-2021. Pregnant women at high risk of developing preeclampsia were recruited and randomized into an intervention group and control group. The control group received low dose aspirin (80 mg) and calcium (1 g) daily, while the intervention group received additional pravastatin (20 mg twice daily) started from 14-20 weeks’ gestation until delivery. The pregnancy was followed until delivery, and the clinical data was collected. The primary outcome was the occurrence of preeclampsia. Result A total of 173 people participated in this study, including 86 in the control group and 87 in the pravastatin group. The pravastatin group had a significantly lower rate of preterm preeclampsia (13.8% vs 26.7%; p=0.034; (OR=0.034, 95% CI: 0.202-0.905) and preterm birth (16.1 % vs. 36 %; p=0.003; OR= 0.340, 95% CI: 0.165-0.7), mostly indicated preterm birth. Preeclampsia occurs later in the pravastatin group than in the control group (36.39+2.32 vs 34.89+3.38 weeks, p=0.048). Overall the pravastatin group had better perinatal outcomes. Neonates with low Apgar scores (<7) at 1 minute (5.7% vs 25.6%, p=0.000) and 5 minutes (2.3% vs 25.6%, p=0.028) were significantly less common in the pravastatin group. Additionally, the rate of low birthweight babies (< 2500g) was lower in pravastatin group (27.6% vs 40.7%; p= 0.069). Conclusion Pravastatin (20 mg bid) significantly reduces the risk for preterm preeclampsia and preterm birth in women at a high risk of developing preeclampsia.

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Section: Accepted Manuscriptsupporting

confidence: 91%

Section: Accepted Manuscriptmentioning

confidence: 80%

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INOVASIA Study: A Multicenter Randomized Clinical Trial of Pravastatin to Prevent Preeclampsia in High-Risk Patients

et al. 2022

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“…Additionally, the use of T-NPsisFLT1 or PEG-PLA nanoparticles as sFLT1 siRNA placenta specific delivery systems can decrease sFlt-1 in pregnant CD1 mice and silencing sFlt-1 in this way is being studied as a method to ameliorate PreE in similar manners to statins ( Li et al, 2020 ). Furthermore, a 2016 pilot randomized controlled trial assessing the use of pravastatin in PreE found no safety risks ( Costantine et al, 2016 ), while another recent study reported lower rates of PreE and preterm delivery in high-risk individuals treated with pravastatin ( Costantine et al, 2021 ). These results, in conjunction with the known immunomodulatory effects of statins ( Figure 2 ), justify further immune research into pravastatin’s use in PreE prevention and therapy.…”

Section: Pravastatinmentioning

confidence: 99%

Manipulating CD4+ T Cell Pathways to Prevent Preeclampsia

Murray

Gumusoglu

Santillan

et al. 2022

Front. Bioeng. Biotechnol.

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Preeclampsia (PreE) is a placental disorder characterized by hypertension (HTN), proteinuria, and oxidative stress. Individuals with PreE and their children are at an increased risk of serious short- and long-term complications, such as cardiovascular disease, end-organ failure, HTN, neurodevelopmental disorders, and more. Currently, delivery is the only cure for PreE, which remains a leading cause of morbidity and mortality among pregnant individuals and neonates. There is evidence that an imbalance favoring a pro-inflammatory CD4+ T cell milieu is associated with the inadequate spiral artery remodeling and subsequent oxidative stress that prime PreE’s clinical symptoms. Immunomodulatory therapies targeting CD4+ T cell mechanisms have been investigated for other immune-mediated inflammatory diseases, and the application of these prevention tactics to PreE is promising, as we review here. These immunomodulatory therapies may, among other things, decrease tumor necrosis factor alpha (TNF-α), cytolytic natural killer cells, reduce pro-inflammatory cytokine production [e.g. interleukin (IL)-17 and IL-6], stimulate regulatory T cells (Tregs), inhibit type 1 and 17 T helper cells, prevent inappropriate dendritic cell maturation, and induce anti-inflammatory cytokine action [e.g. IL-10, Interferon gamma (IFN-γ)]. We review therapies including neutralizing monoclonal antibodies against TNF-α, IL-17, IL-6, and CD28; statins; 17-hydroxyprogesterone caproate, a synthetic hormone; adoptive exogenous Treg therapy; and endothelin-1 pathway inhibitors. Rebalancing the maternal inflammatory milieu may allow for proper spiral artery invasion, placentation, and maternal tolerance of foreign fetal/paternal antigens, thereby combatting early PreE pathogenesis.

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“…Pravastatin has been used in pregnancy for the prevention of preterm and term PE in high-risk women [75,76]. Animal studies demonstrate that pravastatin treatment improved cardiac remodeling and output postpartum.…”

Section: Future Perspectives In Understanding Pe and The Long-term Risksmentioning

confidence: 99%

Pregnancy Complications Can Foreshadow Future Disease—Long-Term Outcomes of a Complicated Pregnancy

et al. 2021

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During gestation, the maternal body should increase its activity to fulfil the demands of the developing fetus as pregnancy progresses. Each maternal organ adapts in a unique manner and at a different time during pregnancy. In an organ or system that was already vulnerable before pregnancy, the burden of pregnancy can trigger overt clinical manifestations. After delivery, symptoms usually reside; however, in time, because of the age-related metabolic and pro-atherogenic changes, they reappear. Therefore, it is believed that pregnancy acts as a medical stress test for mothers. Pregnancy complications such as gestational hypertension, preeclampsia and gestational diabetes mellitus foreshadow cardiovascular disease and/or diabetes later in life. Affected women are encouraged to modify their lifestyle after birth by adjusting their diet and exercise habits. Blood pressure and plasmatic glucose level checking are recommended so that early therapeutic intervention can reduce long-term morbidity. Currently, the knowledge of the long-term consequences in women who have had pregnancy-related syndromes is still incomplete. A past obstetric history may, however, be useful in determining the risk of diseases later in life and allow timely intervention.

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A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia

Cited by 52 publications

References 52 publications

INOVASIA Study: A Multicenter Randomized Clinical Trial of Pravastatin to Prevent Preeclampsia in High-Risk Patients

INOVASIA Study: A Multicenter Randomized Clinical Trial of Pravastatin to Prevent Preeclampsia in High-Risk Patients

Manipulating CD4+ T Cell Pathways to Prevent Preeclampsia

Pregnancy Complications Can Foreshadow Future Disease—Long-Term Outcomes of a Complicated Pregnancy

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