Aspirin for preeclampsia prevention in low- and middle-income countries: mind the gaps.

Preeclampsia is a syndrome that continues to be a major contributor to maternal and neonatal mortality, especially in low-income countries. Low-dose aspirin reduces the risk of preeclampsia, but the mechanism is still unknown. Risk factors to identify women at risk of preeclampsia are based on clinical characteristics. Women identified as high-risk would benefit from aspirin treatment initiated, preferably at the end of the first trimester. Current efforts have largely focused on developing screening algorithms that incorporate clinical risk factors, maternal biomarkers, and uterine artery Doppler evaluated in the first trimester. However, most studies on preeclampsia are conducted in high-income settings, raising uncertainties about whether the information gained can be totally applied in low-resource settings. In low- and middle-income countries, lack of adequate antenatal care and late commencement of antenatal care visits pose significant challenges for both screening for preeclampsia and initiating aspirin treatment. Furthermore, the preventive effect of first-trimester screening based on algorithms and subsequent aspirin treatment is primarily seen for preterm preeclampsia, and reviews indicate minimal or no impact on reducing the risk of term preeclampsia. The lack of evidence regarding the effectiveness of aspirin in preventing term preeclampsia is a crucial concern, as 75% of women will develop this subtype of the syndrome. Regarding adverse outcomes, low-dose aspirin has been linked to a possible higher risk of postpartum hemorrhage, a condition as deadly as preeclampsia in many low- and middle-income countries. The increased risk of postpartum hemorrhage among women in low-income settings should be taken into consideration when discussing which pregnant women would benefit from the use of aspirin and the ideal aspirin dosage for preventing preeclampsia. In addition, women's adherence to aspirin during pregnancy is crucial for determining its effectiveness and complications, an aspect often overlooked in trials. In this review, we analyze the knowledge gaps that must be addressed to safely increase low-dose aspirin use in low- and middle-income countries, and we propose directions for future research.

Low-dose aspirin use in pregnancy and the risk of preterm birth: a Swedish register-based cohort study.

BACKGROUND: Preterm birth is the leading cause of neonatal mortality and morbidity. Women who have had a previous preterm birth are at increased risk for preterm birth in their subsequent pregnancies. Low-dose aspirin use reduces the risk for preterm birth among women at risk of developing preeclampsia, however, it is unclear whether low-dose aspirin may reduce the risk of recurrent preterm birth. OBJECTIVE: This study aimed to investigate the association between low-dose aspirin use and preterm birth among women with a previous preterm birth. STUDY DESIGN: We conducted a Swedish register-based cohort study and included women who had a first and second pregnancy between 2006 and 2019, with the first pregnancy ending in preterm birth (medically indicated or with spontaneous onset <37 weeks of gestation). The association between low-dose aspirin use and preterm birth in the second pregnancy was estimated via logistic regression via standardization and expressed as marginal relative risks with the 95% confidence interval. RESULTS: Among the study cohort (N=22,127), 3057 women (14%) were prescribed low-dose aspirin during their second pregnancy and 3703 women (17%) gave birth prematurely. Low-dose aspirin use was associated with a reduced risk for preterm birth, (marginal relative risk, 0.87; 95% confidence interval, 0.77-0.99). There were no statistically significant associations between low-dose aspirin use and an altered risk for moderate preterm birth, defined as birth between 32 and 36 weeks' gestation (marginal relative risk, 0.90; 95% confidence interval, 0.78-1.03), or very preterm birth, defined as birth <32 weeks' gestation (marginal relative risk, 0.75; 95% confidence interval, 0.54-1.04). Regarding the onset of preterm birth, low-dose aspirin use was associated with a reduced risk for spontaneous preterm birth (marginal relative risk, 0.70; 95% confidence interval, 0.57-0.86) but no reduction in the risk for medically indicated preterm birth (marginal relative risk, 1.09; 95% confidence interval, 0.91-1.30) was observed. CONCLUSION: Among women with a previous preterm birth, low-dose aspirin use was associated with a reduced risk for preterm birth. When investigating preterm birth by onset in the second pregnancy, low-dose aspirin use was associated with a reduced risk for spontaneous preterm birth. Our results suggest that low-dose aspirin may be an effective prophylaxis for recurrent preterm birth.

Brain Vascular Dysfunction in Mothers and Their Children Exposed to Preeclampsia.

Preeclampsia is a maternal syndrome characterized by the new onset of hypertension and proteinuria after 20 weeks of gestation associated with multisystemic complications, including brain alterations. Indeed, brain complications associated with preeclampsia are the leading direct causes of fetal and maternal morbidity and mortality, especially in low- and middle-income countries. In addition to the well-recognized long-term adverse cardiovascular effects of preeclampsia, women who have had preeclampsia have higher risk of stroke, dementia, intracerebral white matter lesions, epilepsy, and perhaps also cognitive decline postpartum. Furthermore, increasing evidence has also associated preeclampsia with similar cognitive and cerebral disorders in the offspring. However, the mechanistic links between these associations remain unresolved. This article summarizes the current knowledge about the cerebrovascular complications elicited by preeclampsia and the potential pathophysiological mechanisms involved, emphasizing the impaired brain vascular function in the mother and their offspring.

Dysregulation of vascular endothelial growth factor receptor 2 phosphorylation is associated with disruption of the blood-brain barrier and brain endothelial cell apoptosis induced by plasma from women with preeclampsia.

Disruption of the blood-brain barrier (BBB) is central in the pathophysiology of acute cerebral complications in women who have preeclampsia. Underling mechanisms are unclear. Using female human brain endothelial cells as an in vitro model of BBB, we show that plasma of women with preeclampsia increases cell apoptosis and permeability via activation of the vascular endothelial growth factor receptor 2 (VEGFR2). Since plasma of women with preeclampsia also enhanced VEGFR2 phosphorylation in the tyrosine 951 but decreased phosphorylation at the tyrosine 1175, we propose the former would be the more likely active form of VEGFR2 responsible for BBB alterations.

Low-Dose Aspirin for Preventing Birth of a Small-For-Gestational Age Neonate in a Subsequent Pregnancy.

OBJECTIVE: To estimate whether low-dose aspirin use is associated with an altered risk of delivering a small-for-gestational age (SGA) neonate among women with a history of having an SGA neonate in a prior pregnancy. METHODS: We performed a Swedish register-based cohort study including women in their second pregnancy who had a history of having an SGA neonate (birth weight less than the 10th percentile). The association between use of low-dose aspirin in subsequent pregnancy and birth of an SGA neonate or a severely SGA neonate (birth weight less than the third percentile) were estimated using inverse propensity-weighted estimation, accounting for potential confounders. RESULTS: Among 8,416 women who gave birth to an SGA neonate in their first pregnancy, 801 (9.5%) used low-dose aspirin during their second pregnancy. The incidence of SGA neonates was similar among women using low-dose aspirin (21.7%) and those who did not use aspirin (20.7%). Low-dose aspirin use in pregnancy was not associated with an altered risk of having an SGA neonate (adjusted relative risk [aRR] 0.86, 95% CI 0.67-1.10) or a severely SGA neonate (aRR 0.98, 95% CI 0.71-1.34). Given the strong association between preeclampsia and SGA, we performed subgroup analyses based on preeclampsia status. Among women who had an SGA neonate and co-existing preeclampsia in their first pregnancy, low-dose aspirin was not associated with an altered risk of having an SGA (aRR 0.83, 95% CI 0.63-1.10) or severely SGA (aRR 1.02, 95% CI 0.73-1.44) neonate. Additionally, no association was seen among women who developed preeclampsia in their second pregnancy. CONCLUSION: Among women with a history of having an SGA neonate, low-dose aspirin was not associated with a decreased risk of having an SGA or severely SGA neonate in subsequent pregnancy. These findings suggest that low-dose aspirin should not be used to prevent recurrent SGA.