Prediction of preeclampsia

There are currently no tests that can be used in the first or second trimester of pregnancy to predict pregnancy-associated hypertension^5,7.

Despite this, there are currently two conditions or strategies that are used in clinical practice as criteria for determining the risk of developing preeclampsia. One focuses on detecting clinical risk factors (pre-pregnancy or pregnancy-specific) obtained with a good interrogation at the first prenatal control, and the other strategy consists of an algorithm based on several factors: clinical risk findings, mean arterial pressure, uterine artery pulsatility index determined by Doppler in the first trimester, and placental growth factor (PGF) determined in blood serum at the end of the first trimester.

The risk factors found with the clinical history are divided into high and moderate risk^5,8,9. High risk includes chronic arterial hypertension, diabetes mellitus, renal disease, autoimmune diseases, uterine artery Doppler abnormality, previous history of preeclampsia, history of fetal or neonatal death associated with preeclampsia. Moderate risk includes first pregnancy, family history of preeclampsia, multiple pregnancy, age over 40 years (Table 1).

Table 1 Risk factors for preeclampsia 

Using the risk factors recommended by the World Health Organization (WHO)⁸ which are similar to those of ACOG^5,9, O'Gorman et al.¹⁰ showed that 94% of cases of preeclampsia were detected in gestations of less than 32 weeks, 90% of cases in gestations of less than 37 weeks and 89% of preeclampsia ≥ 37 weeks, but with 64% of false positives. We observed that in more than 50% of the cases with these factors, preeclampsia did not develop, and this means that it is not an adequate method to detect it.

On the other hand, using the multiple screening (algorithm) with a prevalence of 2.9% of preeclampsia, 75% of cases of preeclampsia far from term and 43-47% of cases of preeclampsia at term are detected, with a false positive of 10%^11,12. These findings are similar to those found with the multicenter study in which such an algorithm was used to recommend aspirin for the prevention of preeclampsia¹³. The International Federation of Gynecology and Obstetrics (FIGO) recommends such screening in the first trimester (11-14 weeks)¹². We can mention that there are some disadvantages of screening based on this algorithm: a computerized program is required to calculate the risk and it is not possible to do it in all clinics and hospitals in the world. Economic investment is required to perform PGF, with sonographers who are experts in studying the Doppler phenomenon of the uterine artery and ultrasound equipment of adequate quality. In addition, it is necessary to perform it between 11-14 weeks; after that gestational age its usefulness has not been proven. On the other hand, at this gestational age many of the patients in low- and middle-income countries per capita have not started prenatal control or are starting it and it is impossible to perform this algorithm.

The ACOG⁹ and WHO⁸ recommend as screening for preeclampsia risk only the presence of risk factors obtained from the clinical history and consider that there is a lack of evidence or proof to recommend the algorithm based on clinical, biochemical and biophysical factors.

Evidence using aspirin in the prevention of preeclampsia

Low-dose aspirin has been used for nearly 40 years to prevent preeclampsia based on the fact that acetylsalicylic acid is a platelet antiaggregant and cyclooxygenase inhibitor and thus has anti-inflammatory and antiangiogenic properties. Several obstetrics and gynecology and public health policy organizations initiated this recommendation nearly a decade ago^14-16. In spite of its use for so many years, there are doubts about its benefit, the patients or population that benefits, the moment to initiate it and to omit it, the adequate dose, side effects, other advantages beyond the possible prevention of preeclampsia.

The previous section noted the two criteria for considering the risk of preeclampsia and the organizations that support them. Low-dose aspirin ranges from 50 to 150 mg per day^12,14-17. Many studies initiate prevention after 12 weeks and mostly before 20 weeks; some initiate it between 11 and 32 weeks^9,17. Most studies continue aspirin until term or very close to term of pregnancy.

In 1998¹⁸ a large randomized controlled study was published in the USA that included patients with risk factors such as diabetes, chronic hypertension, history of preeclampsia and multiple pregnancy. The treatment group received 60 mg of aspirin. The study ended with 1,254 patients in the aspirin group and 1,249 in the placebo group and there was no significant difference in the incidence of preeclampsia. These results discouraged the use of aspirin to prevent preeclampsia. In 2007, the Cochrane organization¹⁹ did a systematic review including 59 studies (37,560 patients) and found 17% reduction in preeclampsia (RR = 0.83 [95% CI, 0.77-0.89]). In 2017²⁰, another randomized study selected patients based on risk detected by an algorithm (multiple factors) and administered 150 mg at bedtime. This study showed a decrease

in preterm preeclampsia from 4.3% (placebo) to 1.6% (aspirin). It was the first large study to find benefit with twice the dose of aspirin as in previous research. Subsequently, new reviews and recommendations on the use of aspirin in the prevention of preeclampsia have emerged.

The U.S. Preventive Services Task Force¹⁷ analyzed the results of 16 studies in which aspirin was used to prevent preeclampsia. The population was high-risk and they found a 15% reduction in preeclampsia (0% heterogeneity) with a 95% confidence interval of 5%-25% (RR = 0.85 [95% CI, 0.75-0.95]). In those analyses, that group¹⁷ showed that low-dose aspirin, in addition to preeclampsia, reduced preterm delivery, small-for-gestational age/intrauterine growth restriction, and perinatal mortality. It was shown that the effect was not related to an onset before or after 16 weeks of gestation. In addition, they found no side effects such as fetal intracranial hemorrhage, postpartum hemorrhage, or placental abruption. This group suggested using aspirin at a dose of 81 mg each day in the highrisk factor population, starting at 12 weeks of pregnancy.

The preventive effect decreases as the risk of developing preeclampsia diminishes. It is estimated that, in a low-risk population, the possibility of developing preeclampsia is about 2% and in this case the number of patients to treat (NPT) to avoid preeclampsia is 500. On the other hand, in a group at high risk of developing preeclampsia, the risk is 20% and in this case the NPT will be about 50.

The ASPRE study²⁰ used 150 mg of aspirin per day and found a decrease in preeclampsia far from term, but not in term preeclampsia or in aggregated preeclampsia.

Giving aspirin until 36-37 weeks of gestation seems to be the most reasonable, first, because there is no evidence of prevention of preeclampsia at term²¹ and because of the possible effects on bleeding at delivery or cesarean section. In fact, some anesthesiologists avoid regional anesthesia because of the current or very recent use of aspirin²².

Recommendations from obstetrics and gynecology organizations

Recommendations on the use of aspirin for the prevention of preeclampsia from 6 prestigious organizations or expert groups with worldwide impact are noted in Table 2.

Table 2 Recommendations from associations or expert groups for the use of aspirin in the prevention of preeclampsia. 

WHO: World Health Organization; USPSTF: US Preventive Services Task Force; FIGO: International Federation of Gynecology and Obstetrics; ACOG: American College of Obstetricians and Gynecologists; ISSHP: International Society for the Study of Hypertension in Pregnancy; NICE: The National Institute for Health and Clinical Excellence in the UK

The UK National Institute for Health and Clinical Excellence (NICE) in a 2019 guideline suggests using aspirin at doses of 75-150 mg depending on risk factors, from 12 weeks of pregnancy to term²³.

For the American College of Obstetricians and Gynecologists - ACOG, as published in 2018, aspirin should be initiated at a dose of 81 mg per day according to risk factors - with one high-risk or two moderate-risk clinical factors (similar to NICE guidelines) - from 12 to 28 weeks of gestation and maintained until delivery.

The International Federation of Obstetricians and Gynecologists in their 2019 guidelines recommend starting aspirin at a dose of 150 mg at night between 11-14 weeks, based on the risk result obtained by the first trimester screening that evaluates preterm preeclampsia, and should be administered until the pregnancy is terminated or preeclampsia appears, or 36 weeks of gestation is reached.

For the World Health Organization, according to 2021 recommendations, aspirin should be given at a dose of 75 mg (or doses close to this) per day, starting at 12 weeks of pregnancy, based on clinical risk factors (similar to NICE and ACOG) and maintained until the time suggested by each country's guidelines for discontinuation of anticoagulants in pregnant women.

The United States Preventive Services Task Force (USPSTF) updated its recommendations in 2021 and suggested using for the prevention of preeclampsia 81 mg of aspirin every day after 12 weeks of pregnancy, in patients at high risk according to clinical criteria. This group does not indicate a specific time until when to use aspirin.

For the International Society for the Study of Hypertension in Pregnancy (ISSHP), the recommendation to give aspirin to prevent preeclampsia has two different connotations. If the multivariable algorithm is used and high risk is shown, 150 mg is recommended. If clinical risk criterio plus blood pressure are used, aspirin should be given at doses ranging from 100-162 mg per day. In both situations, it should be started before 16 weeks of gestation, taken at bedtime and discontinued at 36 weeks of pregnancy.

The first conclusion is that all these organizations recommend aspirin to prevent preeclampsia and preferably at the beginning of the second trimester of gestation^24,25. Most organizations suggest using low doses or less than 100 mg and using clinical risk criteria to suggest the use of aspirin. There is no consensus on the precise moment to stop using aspirin.