During the last several decades, screening methods in pregnancy have shown dramatic improvements in detection rates for fetal aneuploidies, with advances in technology allowing for more comprehensive examinations as early as the first trimester. The results of first trimester screening have demonstrated the potential of predicting other pregnancy complications, such as preeclampsia. Similarly to the evolution of screening methods for aneuploidies, screening methods for preeclampsia have evolved from using maternal characteristics to introducing measurable parameters, and bringing the focus to the first trimester of pregnancy.
Key words first trimester screening • preeclampsia • placental growth factor • uterine artery Doppler
With the advances in scientific research and technology over the last several decades, it is now possible to predict the risk of certain pregnancy complications as early as the first trimester. Our assessment of the risk of pregnancy complications has stemmed from the development of screening methods for fetal aneuploidies. The aim of these screening methods was to identify the high-risk group of women. In the early 1970s, prenatal screening for trisomy 21 was initially based on the association with advanced maternal age. In the next decade, screening was performed by maternal serum biochemistry, combining the results of alpha-fetoprotein (AFP), unconjugated estriol, and human chorionic gonadotropin (hCG) with maternal age. This biochemical screening is then followed by ultrasound examination in the second trimester. As ultrasound technology improved, it was possible to perform detailed ultrasound examinations in the first trimester, between 11 + 0 to 13 + 6 weeks’ gestation, and measurement of the fetal nuchal translucency (NT) thickness became a major determinant in the screening process. Combining maternal age, fetal NT, and the biochemical markers free beta-hCG and pregnancy-associated plasma protein-A (PAPP-A) increased the detection rate of trisomy 21 to about 90%. Including other ultrasound markers such as the nasal bone, flow in the ductus venosus and tricuspid valve, has further increased the detection rate for chromosomal abnormalities.(1, 2) In addition to being an effective method in the screening for aneuploidies, detailed ultrasound examination in the first trimester also allows for early detection of fetal structural abnormalities. There are several abnormalities that can be detected directly (such as anencephaly, exomphalos, gastroschisis, and megacystis) or suspected on the basis of abnormal findings, such as an increased NT, abnormal flow in the ductus venosus or across the tricuspid valve (leading to an increased risk of major cardiac defects).(3, 4, 5) In the case of screening for aneuploidies and structural abnormalities, early detection has provided the possibility of earlier intervention and the option of earlier termination of pregnancy.
After more than 20 years of performing first trimester screening, it has become apparent that the screening results can also be used to predict other pregnancy complications including miscarriage and stillbirth, preterm delivery, preeclampsia, fetal growth restriction, gestational diabetes, and macrosomia.(2) And the inclusion of other factors in addition to those used in first trimester screening (maternal age, nuchal translucency, free beta-hCG and PAPP-A) could potentially allow for improved risk assessment for a variety of conditions. Several studies have developed algorithms using different factors in an attempt to increase the detection rates. These algorithms have used a combination of maternal characteristics and history, ultrasound findings, and biophysical and biochemical tests. At present, risk assessment in predicting pregnancy complications is most effective for preeclampsia and fetal growth restriction.
Preeclampsia (PE) is a major cause of perinatal and maternal morbidity and mortality and affects about 2% of pregnancies.(6, 7, 8) Screening for preeclampsia is aimed at identifying women at high risk for subsequent development of this complication. Initially, maternal factors were used to identify women who were likely to be at high risk. While it is well known that certain factors in the maternal history including increased maternal age, nulliparity, obesity, and a personal or family history of PE increase the likelihood of developing preeclampsia, screening by maternal history alone may only detect about 30% of affected women.(9) Several studies were performed using uterine artery Doppler waveforms between 18–22 weeks of pregnancy to test the predictive value for adverse outcomes, especially preeclampsia and intrauterine growth restriction.(10, 11, 12) An abnormal result was defined as a resistance index (RI) above the 95th centile or the presence of an early diastolic notch (figure 1).(12) It was found that screening for PE by uterine artery Doppler at 22 weeks’ gestation alone or in combination with maternal history increased detection rates to 52% and 57%, respectively. Using uterine artery Doppler to screen for severe preeclampsia, requiring delivery before 34 weeks, has a detection rate of 85%.(9) This allows identification of women at high risk for preeclampsia in the second trimester, and could improve pregnancy outcome through more intensive monitoring. Nevertheless, this could be too late in gestation for effective prophylactic therapy. Earlier identification of risk would allow for earlier intervention, and this has led to the assessment of several parameters measured in the first trimester. Doppler studies of the uterine artery have also moved to the first trimester (figure 2).
In terms of biochemistry results, using PAPP-A provided another measurable option for preeclampsia screening, as it was already a part of the screening performed in the first trimester. The results of first trimester screening have shown an increased risk for the development of preeclampsia (PE) in pregnancies with low levels of maternal serum PAPP-A.(13, 14) Assessment of this biochemical marker in screening for PE has shown that the predictive value of a low PAPP-A is limited, with detection rates of 20.5% for PE and 37.5% for early PE. This is lower than using the maternal history or the uterine artery pulsatility index (PI). However, combining maternal history (table 1), uterine artery PI and PAPP-A led to improved detection rates of 51.4% and 71.9% for all PE and early-PE, respectively.(15) Another study reported that combining uterine artery PI with maternal history was better in predicting preeclampsia than each variable alone. Combining uterine artery Doppler and PAPP-A was also better in predicting small-for-gestational age fetuses (SGA) than using just uterine artery PI alone.(16) Searching for other measurable parameters, several biochemical markers have been studied, of which placental growth factor (PLGF) seems to be the most promising. Preeclampsia is associated with reduced production of the pro-angiogenic protein placental growth factor, and studies have shown reduced maternal serum PLGF concentrations during the clinical phase of PE.(17, 18). Reduced levels of PLGF are apparent before the clinical onset of the disease and are seen from the first trimester of pregnancy.(19) Investigating the screening potential of maternal serum placental growth factor in the first trimester showed the following detection rates for early preeclampsia: 51.7% (using PLGF alone), 62.1% (PLGF in combination with maternal history and characteristics), and up to 89.7% when combining PLGF, maternal history and characteristics, and uterine artery Doppler.(20) Another measurable parameter that has been introduced into several algorithms screening for hypertensive disorders in pregnancy is maternal blood pressure and the mean arterial pressure (MAP). One study demonstrated that the mean arterial pressure was higher in early PE, late PE, gestational hypertension (GH) than in the unaffected group. The detection rate for early PE was 47% when considering only maternal risk factors, and increased to 89.2% using maternal risk factors, uterine artery PI and MAP. Addition of MAP to maternal risk factors and uterine artery PI also increased the detection rates of late PE from 41% to 57% and for GH from 31% to 50%.(21).
Various combinations of the several predictive factors have led to the development of algorithms that use a combination of maternal characteristics, uterine artery PI, MAP, PAPP-A and PLGF. Using this combination of parameters has demonstrated better screening results for early- than late- onset disease. Screening algorithms for early preeclampsia (requiring delivery before 34 weeks) have detection rates of 50% using maternal characteristics, increasing to 90% when adding biophysical markers. When combining maternal characteristics, biophysical and biochemical markers, screening detected 96% of early PE cases and 54% of all cases of preeclampsia.(22) The development of screening algorithms for SGA without preeclampsia and another algorithm for PE, when used in combination, have further improved detection rates. Screen positivity was defined using a risk cut-off of 1 : 200 in the algorithm for early-PE and 1 : 150 in the algorithm for preterm-SGA. The combined use of these algorithms led to detection rates of 95.3% for early-PE, 45.6% for late-PE, 55.5% for preterm-SGA, and 44.3% for term-SGA.(23) The above-mentioned screening methods can identify those women at high risk of developing preeclampsia that would potentially benefit from some type of intervention or prophylaxis. Several studies were performed testing the prophylactic use of vitamins or aspirin in an attempt to decrease the risk of PE, but the results were not as promising as expected. The results for the use of aspirin were not consistent, and it was found that the key to the most effective prophylaxis was in the timing of therapy. A meta-analysis of 34 randomized controlled trials determined that administration of daily low-dose aspirin started at 16 weeks of gestation or earlier was associated with a significant reduction in preeclampsia, severe preeclampsia, intrauterine growth restriction (IUGR) and preterm birth in the women identified to be at risk for preeclampsia.(24) Using abnormal uterine artery Doppler as an inclusion criterion, similar effects of early aspirin prophylaxis were found in women who received ? 80 mg daily and those who received ? 100 mg daily.(25) Early initiation of therapy is more important than the daily dose.
Implementing these results into clinical practice, means expanding the first trimester screening examination from using maternal age, NT measurement, and hCG and PAPP-A levels, to include a more detailed maternal history, measuring the blood pressure to obtain MAP values, the addition of PLGF to the biochemical tests, and measuring the uterine artery pulsatility index. Women determined to be at high risk, with a PE risk cut-off of 1:200 are then recommended prophylaxis with low-dose aspirin started prior to 16 weeks in order to reduce their risk of preeclampsia.
Screening in the first trimester has gone to the next level, from screening for chromosomal and structural abnormalities, to screening for other pregnancy complications such as preeclampsia, which is an important cause of maternal and perinatal morbidity and mortality. (6, 7, 8)With such evolution in screening methods, it is likely that other pregnancy complications will also achieve higher rates of detection in the early stages of pregnancy. This could then possibly lead to a change in prenatal care, creating the “new pyramid” proposed by Professor Kypros Nicolaides, where the emphasis will be on the first trimester of pregnancy, to identify women at high risk for various complications, providing an individualized personal- and disease- specific approach, to improve pregnancy outcome (figure 3).(2) Definitions of terms used in the text: early-PE – if delivery occurred before 34 weeks’ gestation.
SGA – birth weight below the 5th percentile for gestational age. preterm-SGA – if delivery occurred before 37 weeks’ gestation
Disclosures: in relation to this topic, the author has no affiliation with any pharmaceutical company, and has no conflict of interest.
References
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e-mail: l.haak@tiscali.cz
Tab. 1 Maternal history – questionnaire
maternal age
racial origin
cigarette smoking during pregnancy (yes or no)
method of conception (spontaneous or assisted conception
requiring the use of ovulation drugs)
medical history (chronic hypertension, diabetes mellitus,
antiphospholipid syndrome, thrombophilia, sickle cell disease)
medication (antihypertensive, antidepressant, antiepileptic, aspirin,
steroids, betamimetic, insulin, thyroxin)
family history of PE (mother)
parity (parous or nulliparous if no delivery beyond 23 weeks)
obstetric history (including previous pregnancy with PE and SGA)
weight and height measured, BMI calculated
O autorovi| MUDr. Lucia Haaková Ústav pro péči o matku a dítě, Praha
Figure 1 Uterine artery Doppler with early diastolic notch
Figure 2 Uterine artery Doppler in the 1st trimester
Figure 3 Image of used for 1st trimester screening – for measurement of the nuchal translucency (NT) and imaging of the nasal bone
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