HHS Public Access

Author manuscript
Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
Author Manuscript

Published in final edited form as:

Semin Fetal Neonatal Med. 2020 October ; 25(5): 101123. doi:10.1016/j.siny.2020.101123.

Prevention of Preeclampsia
Marwan MA’AYEH, MB BCh, Maged M. COSTANTINE, M.D.
Department of Obstetrics & Gynecology, The Ohio State University College of Medicine, 395 W
12th Ave, 5th Floor, Columbus, Ohio

Abstract
Preeclampsia is an obstetric disorder that affects 3–8% of pregnant women and remains a leading
Author Manuscript

cause of short- and long-term neonatal and maternal morbidity and mortality. Professional
societies recommend the use of low dose aspirin to prevent preeclampsia in high-risk women.
However, interest in prevention of this disease and better understanding of its pathophysiology
have led to growing research on other agents. This review focuses on the main therapeutic agents
evaluated or in use for preeclampsia prevention.

Keywords
Preeclampsia; Aspirin; Statin; Metformin; Esomeprazole; Pregnancy

Introduction, Epidemiology, and Risk Factors

Author Manuscript

Preeclampsia is a multisystem disorder that affects 3–8% of pregnancies in the US and 1.5
and 16.7% worldwide, and results in 60,000 maternal deaths and >500,000 preterm birth
worldwide each year. Geographic, social, economic, and racial differences may explain the
different rates of preeclampsia seen in different populations. Worldwide, preeclampsia is the
second leading cause of maternal death, with estimates of at least 16% among low-middle
income countries up to more than 25% in certain countries in Latin America1–3.

Preeclampsia is characterized by new-onset hypertension which usually occurs after 20

weeks’ gestation, and evidence of end-organ dysfunction3. The end-organ disease resulting
from the preeclampsia is varied, and can include proteinuria, acute kidney injury, hepatic
dysfunction, hemolysis, thrombocytopenia, and – less frequently – liver rupture, seizures
(eclampsia), stroke, and death4. There are a number of risk factors for developing
Author Manuscript

preeclampsia such as history of preeclampsia in a prior pregnancy, diabetes, hypertension,

obesity, and multiple pregnancy3. The reported incidence of preeclampsia for twin gestation
ranges from 8–20% and for triplets’ ranges from 12–34%, however if the index pregnancy
affected by preeclampsia was a multiple gestation, the risk of recurrence in a subsequent
pregnancy is lower than if the index pregnancy was a singleton (6.8% vs. 14.1%, p <
0.001)5,6.

Address and correspondence to: Marwan Ma’ayeh, The Ohio State University College of Medicine, Department of Obstetrics &
Gynecology, Columbus, Ohio 43210, Telephone (work): 614-366-6224, Fax: 614-293-5877, maay01@osumc.edu.
 MA’AYEH and COSTANTINE Page 2

Preeclampsia remains a major cause of maternal mortality and morbidity including seizures,
Author Manuscript

acute kidney injury, pulmonary edema, severe hypertension, cerebrovascular events, and
liver injury3. However, the consequences of preeclampsia are long-arching, and
preeclampsia has been associated with an increased risk of future maternal cardiovascular,
metabolic, and cerebrovascular diseases and premature mortality7. Preeclampsia is also
associated with adverse neonatal outcomes, usually secondary to iatrogenic preterm delivery
and increased risk of fetal growth restriction and placental abruption. These include
respiratory distress syndrome, bronchopulmonary dysplasia, retinopathy of prematurity,
necrotizing enterocolitis, neonatal intensive care units (NICU) admission,
neurodevelopmental delay, and fetal or neonatal death8.

The adverse intrauterine environment associated with preeclampsia is thought to contribute

to the association between maternal preeclampsia and childhood and adult chronic disease in
the offspring, such as obesity, diabetes, hypertension, and neurodevelopmental abnormalities
Author Manuscript

9,10. Due to the above adverse outcomes, preeclampsia adds a substantial financial burden on

the health care system in the United States, estimated more than $1.03 billion in maternal
costs and $1.15 billion in infant costs, in the first year after delivery 11.

The only current cure for preeclampsia is delivery of the placenta and fetus, however this is
commonly associated with iatrogenic preterm delivery. In an effort to prevent that and
improve outcomes for mothers, children and adult offspring, research efforts are currently
focused not only on treatment of preeclampsia, but on ways to prevent preeclampsia from
occurring. Recent advances in understanding the pathogenesis of preeclampsia and need to
reduce its short- and long-term morbidities, led to research in novel agents for either the
prevention or treatment of preeclampsia. These include agents such as anti-digoxin
antibodies, antithrombin, relaxin, proton pump inhibitors, 3-hydroxy-3-methylglutaryl-
Author Manuscript

coenzyme-A reductase inhibitors (statins), use of apheresis and others. Discussion of all
these therapeutics is beyond the scope of this paper, which will review the most promising
therapeutics aimed at prevention of preeclampsia, including aspirin, statins, metformin, and
esomeprazole.

Pathophysiology of Preeclampsia
While not fully understood, the pathophysiology of preeclampsia is likely a multifactorial
combination of genetic and environmental factors, and abnormal placentation3,12. The
genetic and environmental components to the disease are evident by epidemiological studies
suggesting a hereditary component to preeclampsia, and an apparent contribution of risk
factors such as low socioeconomic status, maternal obesity and geographical variations to
the risk of preeclampsia. 1,3,13.
Author Manuscript

Contemporary evidence suggests that preeclampsia is a two-stage disease. The first stage is
an early pregnancy asymptomatic stage, resulting from poor placentation due to abnormal
trophoblast invasion and spiral artery remodeling. This results in the second stage of the
disease, characterized by a placental ischemia/reperfusion injury and a maternal immune-
mediated response. Consequently, there is a release of anti-angiogenic factors and placental
debris into the maternal circulation and an inadequate release of pro-angiogenic factors. This

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 3

leads to an angiogenic imbalance, immune-mediated exaggerated inflammatory response,

Author Manuscript

and endothelial cell dysfunction which result in enhanced platelet aggregation, abnormal
activation of the coagulation system, and increased systemic vascular. The overall
consequence of this cascade is the clinical manifestations such as elevated blood pressure,
proteinuria and other end-organ injury 3,12,14,15. The poor placentation results in abnormal
fetal perfusion, which is evident by abnormal uterine artery blood flow and a 22.2%
incidence of fetal growth restriction in pregnancies affected by preeclampsia, especially
among preterm gestations 16,17. This abnormal perfusion is often seen on uterine artery
Doppler evaluation as notching. However, the utility of this finding to predict preeclampsia
is limited17.

The placental anti-angiogenic factors most commonly studied and thought to contribute to
the disease are soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng)18,19.
These molecules cause maternal vasoconstriction and hypertension, possibly in an effort to
Author Manuscript

improve placental perfusion20. The pro-angiogenic placental factors inhibited in the disease
process include placental growth factor (PlGF) and vascular endothelial growth factor
(VEGF). This inhibition is likely due to a combination of placental ischemia and the anti-
angiogenic inhibitory effects of sFlt-1 and sEng18,21.

The inflammatory response resulting from preeclampsia activates cyclooxygenase (COX)22,

which increases thromboxane A2 (TxA2) levels and reduces endothelial cell prostacyclin
levels (PGI2)22,23. TxA2 increases platelet aggregation and causes vasoconstriction, and
PGI2 counteracts these effects24. The inflammatory response is therefore also a contributor
to the disease phenotype. (Figure)

Aspirin
Author Manuscript

Aspirin is a non-steroidal anti-inflammatory drug, which acts by non-selectively and

irreversibly inhibiting COX, resulting in anti-platelet and anti-inflammatory effects by
preventing the conversion of arachidonic acid to thromboxane and prostaglandins, including
TxA2 and PGI223,25. PGI2, unlike TxA2, is rapidly repleted, and the overall net effect of
aspirin is therefore a preferential inhibition of TxA223,26. Aspirin also inhibits hypoxia-
induced sFlt-1 overexpression by inhibiting COX-1 as an added mechanism of counteracting
preeclampsia 27,28. (Figure)

Aspirin is currently the only medication recommended for the prevention of preeclampsia.
Studies on aspirin use for preeclampsia prevention date back to 1979, and have used doses
ranging from 50 to 150mg daily starting at various gestational ages in low- and high-risk
women29. Although the results are mixed, more recent systematic reviews and meta-analyses
Author Manuscript

suggest that this may be due to variations in aspirin dosing and timing of drug initiation in
the individual studies, with the most beneficial effects seen when aspirin is started before 16
weeks’ gestation29,30. Currently, both the U.S. Preventive Services Task Force (USPSTF)
and the American College of Obstetricians and Gynecologists (ACOG) recommend aspirin
use for preeclampsia prevention for women at high risk for developing the disease (e.g. those
with chronic hypertension, pre-gestational diabetes mellitus, multifetal gestation, renal
disease, and autoimmune disease, etc), and to be started between 12 and 28 weeks’ gestation

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 4

and continued until delivery3,31. In the U.S. aspirin is available as 81-mg formulation; thus,
Author Manuscript

this is the dose most commonly recommended and clinically used. In addition, there are no
studies comparing the effects of different doses of aspirin and none of the studies suggesting
the benefit from a higher dose were conducted in the US. Moreover, fetal and long-term
children safety data of high-dose aspirin use during gestation are limited.

While ACOG and USPSTF utilize risk factors based on history and clinical characteristics to
identify women at risk for developing preeclampsia, more recent studies have investigated
the use of first-trimester screening tests which include assessment of serum PlGF
concentration, uterine artery doppler studies, and other maternal parameters to identify
patients at highest risk for developing preeclampsia who would benefit from prophylactic
aspirin use32. However, in randomized clinical trials, these screening tests underperformed
due to low positive predictive value. In addition, preeclampsia prevention was limited to
small number of preterm preeclampsia, and most screen-positive patients would not benefit
Author Manuscript

from interventions. Due to their under-performance and lack of data form the U.S., first
trimester screening using biomarkers and ultrasonography remains investigational and is not
endorsed by professional societies in the US 33. However, some experts have advocated for
universal aspirin use during pregnancy, due to its low cost of approximately $5 throughout
pregnancy, its well-studied maternal and neonatal safety profile, and the potential for it to
reduce the burden of preeclampsia, improve maternal and fetal outcomes, and reduce
healthcare cost34,35. This approach has not been endorsed by professional societies in the
U.S.

Lastly, aspirin use appears to be safe during pregnancy as there have been multiple studies
that failed to identify an association between low-dose aspirin use during pregnancy and
higher risk of placental abruption, postpartum hemorrhage, spinal hematoma, congenital
Author Manuscript

anomalies, persistent pulmonary hypertension in the neonate, premature closure of the

ductus arteriosus, or neonatal bleeding complications or intracranial hemorrhage36. There
have also been no notable adverse neonatal or childhood outcomes following in-utero aspirin
exposure, with follow-up to 18 years of age31.

Statins
Statins are competitive inhibitors of the enzyme 5-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase, which converts HMG-CoA to mevalonic acid37. Recently, there is
growing interest in the role of statins to prevent preeclampsia due to increasing number of
studies demonstrating strong biological plausibility to reverse or ameliorate several
pathophysiological pathways associated with preeclampsia. Animal models suggest that
statins increase the production of PlGF, and reduce sFlt and TxA238. Additional pleiotropic
Author Manuscript

actions of statins include enhanced trophoblastic invasion and improved placental blood
flow, anti-inflammatory and antioxidant effects, endometrial protection, inhibition of platelet
adhesion, and anticoagulant effects39. These properties are thought to counteract the
pathophysiological pathways of preeclampsia, and may result in a protective effect against it
or amelioration of its manifestations on maternal, fetal and neonatal wellbeing40. (Figure)

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 5

Studies into the use of statins for preeclampsia have evaluated it using a therapeutic
Author Manuscript

approach for patients who develop preeclampsia, and a prophylactic approach for women at
high-risk for developing the disease. In animal models of preeclampsia, statins were shown
to resolve the clinical manifestations of preeclampsia, and prevent associated fetal growth
restriction41,42. Other findings include increased nitric oxide production in the vasculature,
reversing angiogenic imbalance, and anti-inflammatory and oxidative actions43. Initial data
from case reports demonstrated that, when given to women with preterm preeclampsia,
pravastatin use was associated with improvement in blood pressure and reduction in sFlt-1
serum concentrations, and improved pregnancy outcomes44. Other reports demonstrated that
pravastatin prevented fetal demise in patient with massive perivillous fibrin deposition in the
placenta and improved angiogenic profile45. A pilot multicenter, randomized, placebo-
controlled trial enrolled high-risk women with a history of preeclampsia that required
delivery before 34 weeks in a prior pregnancy. These women were randomized between 12-
Author Manuscript

and 16-weeks’ gestation to receive either pravastatin 10 mg daily or placebo. Findings from
the study demonstrated no identifiable maternal or fetal/neonatal safety risk signals
associated with pravastatin therapy. In addition, clinical outcomes including the rates of
preeclampsia and indicated preterm delivery tended to be lower, and the angiogenic
imbalance reversed in subjects receiving pravastatin46.

However, results from other human studies especially those where pravastatin was used after
the development of preeclampsia, are mixed43. In a prospective cohort of women with
antiphospholipid syndrome and poor obstetrical history, addition of pravastatin to standard
of care in women who developed preeclampsia or intrauterine uterine growth restriction, led
to improved pregnancy and neonatal outcomes. On the other hand, a recent randomized
double-blinded placebo-controlled proof of concept trial (Statins to Ameliorate early onset
Preeclampsia (StAmP) trial) did not show a benefit in using pravastatin in patients who
Author Manuscript

develop early preeclampsia, with no evidence of improved angiogenic biomarkers or lower

preeclampsia rates47. Despite the imitations of the study which included small sample size,
slow recruitment, overoptimistic sample size assumptions, and lack of power to identify
differences in clinical outcomes, the StAmP trial supported the safety of pravastatin as there
were no maternal serious adverse events and extremely low drug concentrations in the cord.
The latter finding is similar to the pilot randomized trial in the US, which showed that the
majority of fetuses exposed to pravastatin, had drug concentration in their cord blood below
or close to the detection limit of the assay46.

Statins were initially classified as Category X by the FDA. This was due to poorly designed,
small, retrospective studies that suggested an increase in teratogenic effects with statin use39,
in addition to the absence of any indications to use statins in pregnancy. More contemporary
Author Manuscript

studies and systematic reviews suggest that statins, and in particular pravastatin, do not
demonstrate increased risk in fetal malformations, stillbirth, spontaneous abortions, or
effects on fetal cholesterol levels or fetal weight39,46. These findings could be expected by
the unique pharmacokinetic and properties of pravastatin. Pravastatin is among the most
hepatoselective and hydrophilic statins with limited transplacental transfer, as demonstrated
in placental transfer studies and from the observed cord blood drug concentrations in the two
clinical trials described above46–48.

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 6

Metformin
Author Manuscript

Metformin, or dimethyl-biguanide hydrochloride, is a biguanide used mainly as an anti-

diabetic agent49. Its mechanisms of action include inhibition of hepatic gluconeogenesis,
reducing gastrointestinal glucose absorption, and increasing glucose absorption by
peripheral tissues49. By inhibiting sFlt-1 and sEng, metformin counteracts their
antiangiogenic effects50. This may overall reverse the placental perfusion and imbalance of
angiogenic and antiangiogenic factors in the clinical preeclampsia spectrum. However,
clinical data on the effectiveness of metformin as a prophylactic agent for preeclampsia
prevention are varied51. In a recent randomized, double blind, placebo-controlled trial of
pregnant women with a BMI >35 without diabetes, the use of metformin resulted in a 75%
reduction in the incidence of preeclampsia52. However, a recent meta-analysis of five
randomized trials concluded that metformin use did not result in a significant reduction in
the incidence of preeclampsia51.
Author Manuscript

The safety profile of metformin use in pregnancy is well-established. The most common
maternal side effect is transient gastrointestinal symptoms in up to 25% of women53.
Although metformin freely crosses the placenta, it is poorly metabolized by the fetus, and
multiple studies have shown no evidence of teratogenicity or adverse fetal or neonatal
effects, however long-term data on neurodevelopmental or metabolic outcomes associated
with its use are limited54–57.

Esomeprazole
The use of proton pump inhibitors including esomeprazole is safe in pregnancy, and has not
been found to be associated with fetal teratogenicity, miscarriage or preterm birth58. In
preclinical studies, esomeprazole was associated with an inhibition of sFlt-1 and sEng
Author Manuscript

production, with associated vasodilation and a reduction in endothelial dysfunction59. In an

sFlt-1 overexpression animal model, esomeprazole was able to counteract preeclampsia
symptoms59.

However, human studies using esomeprazole have been less promising. In a randomized,
placebo-controlled study, there was no apparent pregnancy prolongation or reduction in
sFlt-1 with using 40mg of esomeprazole daily60. Further research is needed to evaluate the
use of higher doses of esomeprazole and using the medication as a prophylactic agent for
preeclampsia prevention.

Conclusion
Author Manuscript

Contemporary research into prophylactic and therapeutic interventions for preeclampsia are
providing novel and promising modalities. Research into this topic remains a major
endeavor, and as our understanding of the disease is evolving, studies will continue to pave
the way for new effective therapeutics for preeclampsia.

Conflicts of Interest & Funding Source:

Maged Costantine, MD is supported by a grant from The Eunice Kennedy Shriver National Institute of Child Health
and Human Development (5 UG1 HD027915-29) and the National Heart, Lung, and Blood Institute

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 7

(5UH3HL140131). This paper does not necessarily represent the official views of the NICHD, NHLBI, or the
National Institute of Health.
Author Manuscript

References
1. World Health Organization. Geographic variation in the incidence of hypertension in pregnancy.
World Health Organization International Collaborative Study of Hypertensive Disorders of
Pregnancy. Am J Obstet Gynecol. 1988;158(1):80–3. [PubMed: 2962500]
2. Firoz T, Sanghvi H, Merialdi M, Von Dadelszen P. Pre-eclampsia in low and middle income
countries. Best Pract Res Clin Obstet Gynaecol. 2011;25:537–48. [PubMed: 21592865]
3. Espinoza J, Vidaeff A, Pettker CM, Simhan H. ACOG Practice Bulletin No. 202: Gestational
Hypertension and Preeclampsia. Obstet Gynecol. 2019;133(1):e1–25.
4. Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 202: Gestational
Hypertension and Preeclampsia. Obstet Gynecol. 2017;133(1):e1–25.
5. Barton JR, Sibai BM. Prediction and prevention of recurrent preeclampsia. Obstet Gynecol.
2008;112:359–72. [PubMed: 18669736]
Author Manuscript

6. Trogstad L, Skrondal A, Stoltenberg C, Magnus P, Nesheim B-I, Eskild A. Recurrence risk of

preeclampsia in twin and singleton pregnancies. Am J Med Genet. 2004;126A:41–5. [PubMed:
15039972]
7. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease
and cancer in later life: Systematic review and meta-analysis. BMJ. 2007;335(7627):974. [PubMed:
17975258]
8. Backes CH, Markham K, Moorehead P, Cordero L, Nankervis CA, Giannone PJ. Maternal
preeclampsia and neonatal outcomes. J Pregnancy. 2011;2011:214365. [PubMed: 21547086]
9. Alsnes IV, Vatten LJ, Fraser A, Bjørngaard JH, Rich-Edwards J, Romundstad PR, et al.
Hypertension in Pregnancy and Offspring Cardiovascular Risk in Young Adulthood: Prospective
and Sibling Studies in the HUNT Study (Nord-Trøndelag Health Study) in Norway. Hypertension.
2017;69(4):591–8. [PubMed: 28223467]
10. Wu CS, Nohr EA, Bech BH, Vestergaard M, Catov JM, Olsen J. Health of children born to mothers
who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol.
2009;201(3):269.e1–269.e10. [PubMed: 19733276]
Author Manuscript

11. Stevens W, Shih T, Incerti D, Ton TGN, Lee HC, Peneva D, et al. Short-term costs of preeclampsia
to the United States health care system. Am J Obstet Gynecol. 2017;217(3):237–48. [PubMed:
28708975]
12. Cunningham F, Leveno K, Bloom F, Spong C, Dashe J, Hoffman B. Williams Obstetrics. 24th ed.
New York: McGraw-Hill Education; 2014.
13. Esplin M, Fausett M, Fraser A, Kerber R, Mineau G, Carrillo J, et al. Paternal and maternal
components of the predisposition to preeclampsia. N Engl J Med. 2011;344(12):867–72.
14. Sargent IL, Germain SJ, Sacks GP, Kumar S, Redman CWG. Trophoblast deportation and the
maternal inflammatory response in pre-eclampsia. J Reprod Immunol. 2003;59:153–60. [PubMed:
12896819]
15. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: Current concepts. Am J Obstet
Gynecol. 1998;179:1359–75. [PubMed: 9822529]
16. Villar J, Carroli G, Wojdyla D, Abalos E, Giordano D, Ba’aqeel H, et al. Preeclampsia, gestational
hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet
Author Manuscript

Gynecol. 2006;194:921–31. [PubMed: 16580277]

17. Sciscione AC, Hayes EJ. Uterine artery Doppler flow studies in obstetric practice. Am J Obstet
Gynecol. 2009;201(2):121–6. [PubMed: 19646563]
18. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, et al. Predictive Value of the
sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med. 2016;374(1):13–22.
[PubMed: 26735990]
19. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, et al. Soluble endoglin and other
circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355:992–1005. [PubMed:
16957146]

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 8

20. Roberts JM. Pathophysiology of ischemic placental disease. Semin Perinatol. 2014;38(3):139–45.
[PubMed: 24836825]
Author Manuscript

21. Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee Kim Y, Gonçalves LF, et al. Evidence
supporting a role for blockade of the vascular endothelial growth factor system in the
pathophysiology of preeclampsia: Young Investigator Award. Am J Obstet Gynecol.
2004;190:1541–50. [PubMed: 15284729]
22. Walsh SW. Eicosanoids in preeclampsia. Prostaglandins, Leukot Essent Fat Acids. 2004;70:223–
32.
23. Walsh SW. Preeclampsia: An imbalance in placental prostacyclin and thromboxane Production.
Am J Obstet Gynecol. 1985;152(3):335–40. [PubMed: 3923838]
24. Moncada S, Vane JR. Arachidonic Acid Metabolites and the Interactions between Platelets and
Blood-Vessel Walls. N Engl J Med. 1979;300:1142–7. [PubMed: 219340]
25. Atallah A, Lecarpentier E, Goffinet F, Doret-Dion M, Gaucherand P, Tsatsaris V. Aspirin for
Prevention of Preeclampsia. Drugs. 2017;77:1819–31. [PubMed: 29039130]
26. Majed BH, Khalil RA. Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and
Their Adaptation during Pregnancy and in the Newborn. Pharmacol Rev. 2012;64(3):540–82.
Author Manuscript

[PubMed: 22679221]
27. Lin L, Li G, Zhang W, Wang Y, Yang H. Low-dose aspirin reduces hypoxia-induced sFlt1 release
via the JNK/AP-1 pathway in human trophoblast and endothelial cells. J Cell Physiol.
2019;234(10):18928–41. [PubMed: 31004367]
28. Li C, Raikwar NS, Santillan MK, Santillan DA, Thomas CP. Aspirin inhibits expression of sFLT1
from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1. Placenta.
2015;36(4):446–53. [PubMed: 25638730]
29. Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia:
systematic review and metaanalysis. Am J Obstet Gynecol. 2018;218(3):287–293.e1. [PubMed:
29138036]
30. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the
prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am
J Obstet Gynecol. 2017;216(2):110–120.e6. [PubMed: 27640943]
31. LeFevre ML. Low-dose aspirin use for the prevention of morbidity and mortality from
Author Manuscript

preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med.
2014;161(11):819–26. [PubMed: 25200125]
32. Rolnik DL, O’Gorman N, Roberge S, Bujold E, Hyett J, Uzan S, et al. Early screening and
prevention of preterm pre-eclampsia with aspirin: time for clinical implementation. Ultrasound
Obstet Gynecol. 2017;50:551–6. [PubMed: 28887883]
33. Rolnik DL, Wright D, Poon L, O’Gorman N, Syngelaki A, Matallana C de P, et al. Aspirin versus
placebo in pregnancies at high risk for preterm pre-eclampsia. N Engl J Med. 2017;377(7):613–22.
[PubMed: 28657417]
34. Ayala NK, Rouse DJ. A Nudge Toward Universal Aspirin for Preeclampsia Prevention. Obstet
Gynecol. 2019;133(4):725–8. [PubMed: 30870274]
35. Werner EF, Hauspurg AK, Rouse DJ. A cost-benefit analysis of low-dose aspirin prophylaxis for
the prevention of preeclampsia in the United States. Obstet Gynecol. 2015;126(6):1242–50.
[PubMed: 26551178]
36. Duley L, Meher S, Hunter KE, Seidler AL, Askie LM. Antiplatelet agents for preventing pre-
eclampsia and its complications. Cochrane Database Syst Rev. 2019;2019(10):CD004659.
Author Manuscript

37. Caniggia I, Post M, Ermini L. Statins, Mevalonate Pathway and its Intermediate Products in
Placental Development and Preeclampsia. Curr Mol Pharmacol. 2016;10:152–60.
38. Costantine MM, Tamayo E, Lu F, Bytautiene E, Longo M, Hankins GDV, et al. Using pravastatin
to improve the vascular reactivity in a mouse model of soluble Fms-like tyrosine kinase-1-induced
preeclampsia. Obstet Gynecol. 2010;116(116):114–20. [PubMed: 20567176]
39. Esteve-Valverde E, Ferrer-Oliveras R, Gil-Aliberas N, Baraldès-Farré A, Llurba E, Alijotas-Reig J.
Pravastatin for Preventing and Treating Preeclampsia: A Systematic Review. Obstet Gynecol Surv.
2018;73(1):40–55. [PubMed: 29368790]

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 9

40. Garrett N, Pombo J, Umpierrez M, Clark JE, Simmons M, Girardi G. Pravastatin therapy during
preeclampsia prevents long-term adverse health effects in mice. JCI Insight. 2018;3(8):e120147.
Author Manuscript

41. Kumasawa K, Ikawa M, Kidoya H, Hasuwa H, Saito-Fujita T, Morioka Y, et al. Pravastatin induces
placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad
Sci. 2010;108(4):1451–5. [PubMed: 21187414]
42. Bauer AJ, Banek CT, Needham K, Gillham H, Capoccia S, Regal JF, et al. Pravastatin attenuates
hypertension, oxidative stress, and angiogenic imbalance in rat model of placental ischemia-
induced hypertension. Hypertension. 2013;61:1103–10. [PubMed: 23460290]
43. Ma’ayeh M, Rood KM, Kniss D, Costantine MM. Novel Interventions for the Prevention of
Preeclampsia. Curr Hypertens Rep. 2020;22(2):17. [PubMed: 32052203]
44. Brownfoot FC, Tong S, Hannan NJ, Binder NK, Walker SP, Cannon P, et al. Effects of Pravastatin
on Human Placenta, Endothelium, and Women with Severe Preeclampsia. Hypertension.
2015;66:687–97. [PubMed: 26222708]
45. Chaiworapongsa T, Romero R, Korzeniewski SJ, Chaemsaithong P, Hernandez-Andrade E, Segars
JH, et al. Pravastatin to prevent recurrent fetal death in massive perivillous fibrin deposition of the
placenta (MPFD). J Matern Neonatal Med. 2016;29(6):855–62.
Author Manuscript

46. Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, et al. Safety and
pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant
women: A pilot randomized controlled trial. Am J Obstet Gynecol. 2016;214(720):e1–17.
47. Ahmed A, Williams DJ, Cheed V, Middleton LJ, Ahmad S, Wang K, et al. Pravastatin for early-
onset pre-eclampsia: a randomised, blinded, placebo-controlled trial. BJOG An Int J Obstet
Gynaecol. 2020;127(4):478–88.
48. Nanovskaya TN, Patrikeeva SL, Paul J, Costantine MM, Hankins GDV, Ahmed MS.
Transplacental transfer and distribution of pravastatin. Am J Obstet Gynecol. 2013;209:373.e1–5.
[PubMed: 24070396]
49. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: From mechanisms of action to
therapies. Cell Metab. 2014;20(6):953–66. [PubMed: 25456737]
50. Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, et al. Metformin as a
prevention and treatment for preeclampsia: Effects on soluble fms-like tyrosine kinase 1 and
soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol. 2016;214:356.e1–
15. [PubMed: 26721779]
Author Manuscript

51. Alqudah A, McKinley MC, McNally R, Graham U, Watson CJ, Lyons TJ, et al. Risk of pre-
eclampsia in women taking metformin: a systematic review and meta-analysis. Diabet Med.
2018;35:160–72. [PubMed: 29044702]
52. Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, et al. Metformin Versus
Placebo in Obese Pregnant Women Without Diabetes Mellitus. N Engl J Med. 2016;374:434–43.
[PubMed: 26840133]
53. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia.
2016;59:426–35. [PubMed: 26780750]
54. Nanovskaya TN, Nekhayeva IA, Patrikeeva SL, Hankins GD V, Ahmed MS. Transfer of metformin
across the dually perfused human placental lobule. Am J Obstet Gynecol. 2006;195:1081–5.
[PubMed: 16824464]
55. Cassina M, Donà M, Di Gianantonio E, Litta P, Clementi M. First-trimester exposure to metformin
and risk of birth defects: A systematic review and meta-analysis. Hum Reprod Update.
2014;20:656–9. [PubMed: 24861556]
Author Manuscript

56. Wouldes TA, Battin M, Coat S, Rush EC, Hague WM, Rowan JA. Neurodevelopmental outcome at
2 years in offspring of women randomised to metformin or insulin treatment for gestational
diabetes. Arch Dis Child Fetal Neonatal Ed. 2016;101:F488–93. [PubMed: 26912348]
57. Rowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S, et al. Metformin in Gestational
Diabetes: The Offspring Follow-up (MiG TOFU): Body Composition and Metabolic Outcomes at
7–9 Years of Age. BMJ Open Diabetes Res Care. 2018;6(1):e000456.
58. Gill SK, O’Brien L, Einarson TR, Koren G. The safety of proton pump inhibitors (PPIs) in
pregnancy: A meta-analysis. Am J Gastroenterol. 2009;104(6):1541–5. [PubMed: 19491869]

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 10

59. Onda K, Tong S, Beard S, Binder N, Muto M, Senadheera SN, et al. Proton pump inhibitors
decrease soluble fms-like tyrosine kinase-1 and soluble endoglin secretion, decrease hypertension,
Author Manuscript

and rescue endothelial dysfunction. Hypertension. 2017;69(3):457–68. [PubMed: 28115513]

60. Cluver CA, Hannan NJ, van Papendorp E, Hiscock R, Beard S, Mol BW, et al. Esomeprazole to
treat women with preterm preeclampsia: a randomized placebo controlled trial. Am J Obstet
Gynecol. 2018;219:388.e1–17. [PubMed: 30055127]
Author Manuscript
Author Manuscript
Author Manuscript

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 11
Author Manuscript

Practice points:

• Aspirin is recommended for the prevention of preeclampsia in high-risk

women

• First trimester screening for preeclampsia is not recommended in the US

Research directions:

• The optimal dose of aspirin in preeclampsia prevention, and the cohort of

women who will benefit from higher dose

• The effectiveness of statins in preventing preeclampsia

• The role of statin in managing pregnancies complicated by early onset

preeclampsia
Author Manuscript
Author Manuscript
Author Manuscript

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.
 MA’AYEH and COSTANTINE Page 12
Author Manuscript
Author Manuscript
Author Manuscript

Figure:
Pathophysiology of Preeclampsia and Proposed Mechanisms of Actions of Preventive
Agents
ASA, Aspirin; COX, cyclooxygenase; sEng, soluble endoglin; sFlt1, soluble fms-like
tyrosine kinase 1; PGI2, prostaglandin I2 (prostacyclin); PlGF, placental growth factor;
TXA2, thromboxane A2; VEGF, vascular endothelial growth factor
Author Manuscript

Semin Fetal Neonatal Med. Author manuscript; available in PMC 2021 October 01.