Keywords
preeclampsia - first-trimester screening - aspirin
Palavras-chave
pré-eclâmpsia - rastreio primeiro trimestre - aspirina
Introduction
Preeclampsia (PE) affects 2 to 3% of all pregnancies, and, in developed countries,
its incidence has increased in the last decades.[1]
[2]
[3]
[4]
[5] Preeclampsia is considered one of the most important causes of maternal and perinatal
morbidity and mortality.[1]
[2]
[3]
[6]
[7] This condition is characterized by the development of new-onset high blood pressure
after 20 weeks of gestation, with one or more of the following criteria: proteinuria,
renal insufficiency, liver, neurological or hematological involvement, and fetal growth
restriction.[8] Preeclampsia is usually divided in early or late-onset preeclampsia, depending on
whether the diagnosis is made before or after 34 weeks of gestation.[9]
[10]
[11] This classification is directly related to the prognosis, as early-onset PE is associated
with more severe complications and adverse maternal and perinatal outcomes.[6]
[11]
[12]
[13]
[14] Early-onset PE has a lower incidence than late-onset PE, with a frequencies reported
to be 0.5% and 1.4 to 1.7%, respectively.[5]
[6]
[14]
[15] Preeclampsia can also be classified as preterm or term, according to whether delivery
is needed before or after 37 weeks of gestation.[1]
[6]
[16]
An impaired placentation is thought to be the underlying cause of PE, with complete
resolution of the clinical manifestations within 12 weeks postpartum.[3]
[12] Some authors defend that the incomplete and defective trophoblastic invasion of
the uterine spiral arteries, leading to uteroplacental hypoperfusion is the pathophysiologic
mechanism responsible for the onset of PE.[3]
[7]
[13] Furthermore, the presence of placental lesions associated with underperfusion is
greater in early-onset PE, and these lesions are more severe in cases of very preterm
delivery.[17]
[18]
[19] The trophoblastic invasion of uterine arteries starts as early as 8 to 10 weeks
and is completed around 16 to 18 weeks.[7] Although the mechanism of action of aspirin in reducing PE is still unknown, some
studies proposed that there is an improvement in uterine blood flow with a daily aspirin
intake, suggesting it promotes the transformation of spiral uterine arteries into
low resistance vessels.[7]
[19] Consequently, this pharmacologic intervention should reduce the prevalence of PE
and minimize its complications.[6]
[13]
[19]
[20] Several studies proved that starting prophylaxis after 16 weeks of gestation was
not associated with a significant improvement in outcome.[1]
[7]
[13]
[21] Moreover, a recent meta-analysis concluded that the administration of low-dose aspirin
before 11 weeks had no significant effect in reducing PE.[22] Taking this into consideration, the aspirin intake should start ideally between
the 11th and the 16th weeks.[19]
[22] The aspirin for evidence-based preeclampsia prevention (ASPRE) trial validates these
theories, as the aspirin subgroup had a significant reduction in the incidence of
preterm PE when compared with the placebo subgroup.[6] With regard to the optimal dose of aspirin, doses from 80 to 150 mg have proved
to be effective.[19] However, studies have shown a significant rate of aspirin resistance among pregnant
women of ∼ 30%, 10%, and 5%, for doses of 81 mg, 121 mg, and 162 mg, respectively.[6]
[19]
[23]
[24] Considering that a prophylactic measure has shown to improve pregnancy outcomes,
it is essential to have an effective screening method. Screening for PE in the first
trimester allows the identification of high-risk pregnancies that will benefit from
this intervention.[12] The first-trimester combined screening for PE at 11 to 13 weeks of gestation uses
an algorithm that includes maternal and pregnancy characteristics, such as biophysical
markers—mean arterial pressure (MAP) and uterine artery pulsatility index (UtA PI)—and
biochemical markers—serum levels of pregnancy-associated plasma protein A (PAPP-A)
and placental growth factor (PLGF).[1]
[13]
[20] According to a study published in 2013, this screening method is able to identify
95.3% of the early-onset PE cases and 45.5% of the late onset PE, using 1:200 as the
cut-off risk, with a false positive rate of 10%.[20] A different study revealed that screening by a combination of maternal characteristics,
MAP, UtA PI, PAPP-A, and PLGF was able to identify 96.3% of the early-onset PE cases,
using a cut-off of 1:269, with a 10% of false positives.[4] The objective of our study was to assess the implementation of a combined screening
approach for PE with the prophylactic use of low-dose aspirin in high-risk pregnancies.
Methods
This is a prospective study of women attending our hospital for their routine first-trimester
scan, in the first year of implementation of universal screening for preeclampsia,
from the 1st of March 2017 to the 28th of February 2018.
Population and Screening Method
All the women attending a first-trimester routine visit in our hospital were offered
combined screening for PE, in addition to the routine screening for aneuploidies.
At that first visit, between 9 and 11 weeks of gestation, data was collected on maternal
characteristics, obstetric and medical history.[2] Blood pressure was taken by validated automated devices, following a standardized
protocol.[5]
[13]
[25] Mean arterial pressure was measured twice in each arm and registered. In the same
visit, maternal blood was taken to determine plasma levels of human chorionic gonadotrophin
(HCG) and PAPP-A. At the first trimester ultrasound, between 11 weeks and 13 weeks
and 6 days, gestational age was determined according to the fetal crown-rump length.[26] Transabdominal color Doppler was used to measure the left and right UtA PI, and
the average value was recorded.[5]
[13]
[27] Women diagnosed with a multiple pregnancy or a major fetal abnormality were excluded.
Maternal factors, and biophysical and biochemical markers (MAP, UtA PI, and PAPP-A)
were combined by the software algorithm ViewPoint Version 5.6.12.601 (ViewPoint Bildverarbeitung
GmbH, Wessling, Germany) and the risk of preeclampsia was calculated.[1]
[4]
[12]
[13]
[20] In this study, high-risk was defined as a risk of early-onset PE ≥ 1:50. High-risk
women were advised on their individual risk and offered low-dose aspirin, 150 mg every
night, starting immediately after screening until 36 weeks of gestation. Women classified
as high-risk were monitored in our hospital, in addition to their routine prenatal
care, with follow-up scans at 22, 28, 32, and 36 weeks of gestation.
Outcome Measures
The primary outcome was to determine the incidence of early-onset PE, defined as PE
diagnosed before 34 weeks of gestation. The secondary outcome was to establish the
incidence of total PE, defined as PE diagnosed at any gestational age. Preeclampsia
was defined according to the International Society for the Study of Hypertension in
Pregnancy.[8] The compliance to aspirin was assessed by women's report of daily aspirin intake,
during the follow-up prenatal visits.
Statistical Analysis
All collected data were inserted into an Excel (Microsoft Corp., Redmond, WA, USA)
database to perform a statistical analysis of maternal and pregnancy characteristics.
In each pregnant woman, the mean UtA PI, MAP, and PAPP-A serum levels were converted
to multiples of the median (MoM), corrected for maternal and pregnancy characteristics.[4]
[28] The incidence of both early-onset PE and total PE were calculated, also in Excel.
A Fisher exact test was used to compare the incidence of early-onset PE and total
PE before and after the implementation of screening. Statistical significance was
accepted at the level of p < 0.05.
Results
Population Characteristics and Screening
During the study's duration, a total of 1,297 pregnant women had their 1st trimester ultrasound in our hospital. However, 25 of these women were excluded because
they did not fulfill the eligibility criteria—22 had a twin pregnancy and 3 had a
major fetal abnormality. Consequently, the screening for PE in the 1st trimester was performed in 1,272 singleton pregnancies. The average maternal age
of our population sample was 30 years. The majority was Caucasian (1,051; 82.6%),
had a normal body mass index (BMI) (612; 48.1%), and did not smoke (1,091; 85.8%).
Almost half of them were nulliparous (614; 48.3%), and 21 women had PE in a previous
pregnancy (1.7%). The conception was spontaneous in 1,256 (98.7%), and 36 pregnant
women (2.8%) had chronic hypertension. [Table 1] describes the detailed maternal and pregnancy characteristics of this population.
Table 1
Maternal and pregnancy characteristics
|
Maternal and pregnancy characteristics
|
N = 1,272
|
|
Maternal age (years)
|
|
|
Mean (±SD)
|
30.05 ± 5.9
|
|
Median [range]
|
30 [14–46]
|
|
< 25 years - nr. (%)
|
214 (16.8%)
|
|
25–35 years - nr. (%)
|
725 (57.0%)
|
|
≥ 35 years - nr. (%)
|
333 (26.2%)
|
|
Maternal BMI (Kg/m2)
|
|
|
Mean (±SD)
|
25.06 ± 5.31
|
|
Median [range]
|
24 [15–53]
|
|
Normal BMI (18.5–25) - nr. (%)
|
612 (48.1%)
|
|
High BMI (≥25) - nr. (%)
|
596 (46.9%)
|
|
Low BMI (< 18.5) - nr. (%)
|
64 (5.0%)
|
|
Racial origin - nr. (%)
|
|
|
Caucasian
|
1051 (82.6%)
|
|
Afro-Caribbean
|
161 (12.7%)
|
|
South Asian
|
31 (2.4%)
|
|
East Asian
|
4 (0.3%)
|
|
Mixed
|
25 (2.0%)
|
|
Cigarette smoking - nr. (%)
|
181 (14.2%)
|
|
Obstetric history - nr. (%)
|
|
|
Nulliparous
|
614 (48.3%)
|
|
Multiparous without preeclampsia
|
637 (50.0%)
|
|
Multiparous with preeclampsia
|
21 (1.7%)
|
|
Medical history - nr. (%)
|
|
|
Chronic hypertension
|
36 (2.8%)
|
|
Conception - nr. (%)
|
|
|
Spontaneous
|
1,256 (98.7%)
|
|
Ovulation drugs or IVF
|
16 (1.3%)
|
Abbreviations: BMI, body mass index; IVF, in vitro fertilization; SD, standard deviation.
Of the 1,272 pregnant women that underwent PE screening, 50 (3.9%) screened positive
for early-onset PE, and all of them started low-dose aspirin, 150 mg once per day
at night. In the high-risk group, compared with low-risk group, the mean body mass
index was higher and there was a higher prevalence of Afro-Caribbean origin, personal
history of PE and chronic hypertension ([Table 2]).
Table 2
Maternal and pregnancy characteristics according to the preeclampsia screening risk
group
|
Maternal and pregnancy characteristics
|
High-risk group (n = 50)
|
Low-risk group (n = 1,222)
|
|
Maternal age (years)
|
|
|
|
Mean (±SD)
|
30.82 ± 6.7
|
30.03 ± 5.8
|
|
≥ 35 years - nr. (%)
|
17 (34%)
|
316 (25.9%)
|
|
Maternal BMI (Kg/m2)
|
|
|
|
Mean (±SD)
|
27.04 ± 6.6
|
24.98 ± 5.2
|
|
High BMI (≥25) - nr. (%)
|
28 (56%)
|
568 (46.4%)
|
|
Racial origin - nr. (%)
|
|
|
|
Caucasian
|
35 (70%)
|
1016 (83.1%)
|
|
Afro-Caribbean
|
14 (28%)
|
147 (12.1%)
|
|
Others
|
0 (0%)
|
35 (2.8%)
|
|
Mixed
|
1 (2%)
|
24 (2%)
|
|
Cigarette smoking - nr. (%)
|
6 (12%)
|
175 (14.3%)
|
|
Obstetric history - nr. (%)
|
|
|
|
Nulliparous
|
30 (60%)
|
584 (47.8%)
|
|
Multiparous without preeclampsia
|
13 (26%)
|
624 (51.1%)
|
|
Multiparous with preeclampsia
|
7 (14%)
|
14 (1.1%)
|
|
Medical history - nr. (%)
|
|
|
|
Chronic hypertension
|
18 (36%)
|
18 (1.5%)
|
Abbreviations: BMI, body mass index; SD, standard deviation.
Pregnancy Outcomes
Of the total women enrolled in PE first trimester screening, there were 11 terminations
for fetal abnormalities (0.9%) and 5 miscarriages before 24 weeks of gestation (0.4%).
Sixteen pregnant women were lost to follow-up (1.3%). Therefore, 1,240 pregnancies
were included in the outcome assessment ([Fig. 1]).
Fig. 1 Population selection, screening, and follow-up.
Primary Outcome
Early-onset PE occurred in 3 of the 1,240 pregnancies (0.24%) during our study period.
This was compared with the incidence of early-onset PE observed in our hospital between
2014 and 2016, before the implementation of universal screening. During that period,
early-onset PE was diagnosed in 28 of 3,747 women (0.75%), (p = 0.0099) ([Table 3]).
Table 3
Pregnancy outcomes
|
Pregnancy outcomes
|
Study period
(1st March 2017–28th February 2018)
n = 1,240
|
Before implementation of universal screening
(2014–2016)
n = 3,747
|
P-value
|
|
Primary outcome: diagnosis of PE before 34 weeks of gestation - nr. (%)
|
3 (0.24%)
|
28 (0.75%)
|
p = 0.0099
|
|
Secondary outcome: PE at any gestational age - nr. (%)
|
25 (2.02%)
|
98 (2.62%)
|
p = 0.2904
|
Abbreviation: PE, preeclampsia.
Secondary Outcome
Total PE was diagnosed in 25 of 1,240 pregnancies (2.02%) in our study, compared with
98 of 3,747 (2.62%) observed before the implementation of screening (p = 0.2904) ([Table 3]). Of the total number of diagnosed PE, 3 cases were reported in the high-risk group
and the other 22 in the low-risk group. Also, only 10 cases of PE required a preterm
iatrogenic delivery (before 37 weeks of gestation).
Compliance
The compliance to aspirin was good, as 48 (96%) of 50 high-risk women who started
aspirin at the time of the screening maintained treatment until 36 weeks of gestation.
The other 2 women (4%) stopped taking aspirin for intolerance.
Discussion
In this prospective study, universal screening for PE was performed to all women attending
our hospital for the first-trimester screening of aneuploidies. Based on a combined
model, we identified high-risk pregnancies and started prophylactic aspirin at a dose
of 150 mg per day, from 11 to 14 weeks of gestation until 36 weeks. The combined screening
model used in our study, with an algorithm that considered maternal demographic characteristics,
biophysical and biochemical biomarkers, has proved to be the most effective method
of screening, with a high detection rate for early-onset PE.[1]
[4]
[12]
[13]
[20]
[29] The use of an early screening strategy allows the beginning of aspirin before the
process of placentation is complete. This is in line with the results of several studies
that suggest that the greater benefit of this prophylactic measure happens when it
is started before 16 weeks.[7]
[19]
[21] Early-onset PE was chosen as our primary outcome based on its clinical relevance,
on the higher detection rate of the screening algorithm available and on the major
benefit of aspirin in this subgroup, corroborated by several studies.[7]
[17]
[18]
[21]
[30] The cut-off risk of 1:50 was selected considering the results from previous studies,
as a compromise value to adapt the cut-off to our screening method and to our population,
to have a high detection rate and a small number of false positives. Given the low
rate of positive screen results (3.9%) in our study, we are considering revising our
protocol and opt for a lower cut-off, to include more high-risk patients, in an attempt
to reduce the rate of early-onset PE even further. As for the dosage selected in our
study, we opted to use 150 mg of aspirin per day due to a known dose-dependent benefit
and to reduce the aspirin resistance effect shown by recent evidence.[19]
[23] We also recommended that aspirin should be taken at night, as it is associated with
a superior reduction of PE when compared with daytime administration.[19] Our data showed a lower incidence of both early-onset PE and total PE when compared
with the rates before the introduction of universal screening for PE. The reduction
observed in early-onset PE was more substantial than the reduction seen in total PE,
corroborating previous evidence available.[6]
[7]
[21]
[30] The reduction in the incidence of early-onset PE was statistically significant and
probably meaningful to clinical practice. The performance of first-trimester screening
is poorer for late-onset PE and low-dose aspirin has little or no beneficial effect
in this condition.[4]
[6]
[20]
[30] The 3 cases of early-onset PE reported in the study occurred in the low-risk group,
which probably means that no cases happened in the high-risk group because of the
effect of aspirin prophylaxis, as the estimated number of cases in this group would
be between 2 and 3. Moreover, this corroborates the importance of revising the cut-off
to a more inclusive one. The strengths of our study are its prospective design, the
screening model and prophylactic strategy are in line with the more recent evidence
available and, as far as we know, it is the first study of PE screening and prophylaxis
done in our country.[4]
[6] The main limitation is the small number of patients. We aim to continue PE screening
in the future, obviating this limitation and strengthening the results.
Conclusion
In conclusion, our study showed that the first-trimester screening of PE, which combines
maternal factors, obstetric and medical history, biochemical and biophysical markers,
is useful to predict early-onset PE in a routine care setting. Moreover, our results
evidence a statistical reduction in the incidence of early-onset PE and also a small
reduction of total PE, after the introduction of screening and prophylaxis. The prophylactic
use of low-dose aspirin in high-risk pregnancies is most likely responsible for this
reduction. However, further studies, with a larger population, are needed to corroborate
these results.
