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Beyond Fetal Aneuploidy: A Call For A Contemporary Canadian Approach To Prenatal Screening

      In Canada, it is standard of care to offer prenatal screening for the most common trisomies (21, 18, 13) to all pregnant women, using various combinations of biochemical and ultrasound markers. The recent introduction of screening based on cell-free DNA (cfDNA), with its high accuracy, has had a major impact on these conventional screening paradigms. In particular, it is forcing a re-evaluation of the role of the ultrasound and biochemical components of conventional screening protocols, including the measurement of nuchal translucency (NT). However, cfDNA screening is currently limited to detection of trisomies, affecting about 1/500 fetuses and less than 1/2000 live births, while first trimester ultrasound with an NT measurement not only contributes to the detection of aneuploidy and structural anomalies, but also provides additional information that may be used to improve prenatal care and pregnancy outcome. Thus, cfDNA should not be seen as a replacement for first trimester ultrasound, but as a complementary screening test whose relative value needs to be considered as we concomitantly improve effective screening for arguably more prevalent and equally serious disorders (structural anomalies, preeclampsia and preterm birth).
      We are calling for a contemporary Canadian approach to prenatal screening that not only includes strategies to improve aneuploidy detection, but also provides an opportunity to improve maternal and child health. We are calling for the consideration of an “inverted pyramid of care” that would integrate the early detection of the most common fetal trisomies with structural anomalies and the early prediction and prevention of major adverse pregnancy outcomes.
      • Nicolaides K.H.
      Turning the pyramid of prenatal care.

      Preeclampsia

      Preeclampsia (PE) affects between 3% and 5% of pregnant women in Canada. It is associated with major morbidity and sometimes mortality for women and babies, and is a major cause of preterm birth. It is commonly associated with fetal growth restriction (FGR), which has adverse implications for childhood development and certain adult-onset diseases. Although the disease resolves with delivery, the occurrence of PE also affects future maternal cardiovascular health, with a four-fold increase in the risk of future heart failure and a two-fold increase in the risk of death from all cardiovascular causes.
      • Giguere Y.
      • Charland M.
      • Theriault S.
      • et al.
      Linking preeclampsia and cardiovascular disease later in life.
      These findings reinforce the importance of identifying high-risk women and implementing preventive measures.
      Important advances have changed the landscape in the screening and prevention of preeclampsia in Canada. The combination of maternal characteristics, ultrasound and biochemical markers, combined with current first-trimester aneuploidy screening, could detect most cases of preeclampsia requiring preterm delivery and up to 90% of the most severe cases (those requiring delivery before 32 weeks).
      • O'Gorman N.
      • Wright D.
      • Syngelaki A.
      • et al.
      Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 11–13 weeks gestation.
      Moreover, we now know that aspirin (≥100 mg daily at bedtime) initiated in the first-trimester can prevent most severe preeclampsia cases. Several national organizations worldwide have adopted the use of aspirin for women at high-risk of preeclampsia, including the SOGC, RCOG, and ACOG. However, in the absence of a population-based preeclampsia screening program, an approach based on clinical risk factors alone has a low predictive value.
      The ASPRE trial, a multicentre randomized clinical trial performed across 12 countries, involved screening for PE in 26 941 women and the randomization of 1776 participants, determined to be at increased risk, to placebo or aspirin (150 mg at bedtime).
      • Rolnik D.L.
      • Wright D.
      • Poon L.C.
      • et al.
      Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia.
      Here are some of the results:
      • a.
        Most cases of preterm preeclampsia could be detected using a first-trimester screening algorithm.
      • b.
        There was a 62% reduction of preterm PE (<37 weeks) and 82% reduction of early-onset PE (<34 weeks) when aspirin was initiated at 11 to 14 weeks' gestation.
      • c.
        A trend toward reduction of stillbirths and neonatal deaths, fetal growth restriction, and respiratory distress syndrome was observed.
      These data support the contention that it is possible to both predict and prevent preterm preeclampsia, thereby improving maternal and child health.

      Preterm birth

      Preterm birth affects about 8% of pregnancies in Canada and remains the most important cause of neonatal morbidity and mortality. The annual health care costs of preterm birth in Canada can be estimated to be greater than 1 billion CAD$.
      We now know that a significant proportion of pregnancies at high risk for preterm birth can be predicted by using mid-trimester measurement of cervical length. We can reduce the incidence of the most preterm cases (<33 weeks) by up to 50% with daily vaginal progesterone started in the mid-trimester in women with a short cervical length.
      • Romero R.
      • Nicolaides K.H.
      • Conde-Agudelo A.
      • et al.
      Vaginal progesterone decreases preterm birth </= 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study.
      Cost-effectiveness studies have shown that introducing universal cervical length assessment at the time of mid-trimester fetal anatomy ultrasound could lead to a 20% decrease of preterm birth for an incremental cost-effectiveness ratio of 43 to 21 144 CAD$ per quality-adjusted life year (QALY). The Society of Maternal-Fetal Medicine is now recommending transvaginal measurement of cervical length for all pregnant women in mid-trimester. It is time to implement a preterm birth screening program as part of prenatal screening in Canada.

      Fetal structural anomalies

      Historically, the first trimester ultrasound has been useful for pregnancy dating, to confirm viability, and to rule out multiple pregnancy, while the detailed anatomical scan at 18 to 20 weeks gestation remains the gold standard for structural malformation detection.
      However, it is now clear that first trimester ultrasound, when performed with appropriate training and following a standardized protocol, has the potential to identify a significant proportion of important structural anomalies. This is a major advantage over second trimester detection of anomalies in terms of enhancing options for pregnancy management, and increasing parental autonomy. It is now time to call the first trimester (11–14 weeks) ultrasound an anatomic scan in Canada.

      Inverting the pyramid of care

      Typical Canadian antenatal care is very similar to the model instituted in the UK more than a century ago. Most women are seen once or twice in the first half of pregnancy, with antenatal visit frequency increasing to weekly during the last month, presumably to detect hypertensive disorders. Yet we now know that the risk of hypertensive disorders, as well as preterm birth, can be effectively screened for during the first half of pregnancy. The Fetal Medicine Foundation (FMF) has proposed we invert the “pyramid of care” and target efforts into effective screening for these adverse outcomes in the first trimester to introduce effective preventive measures.
      • Nicolaides K.H.
      Turning the pyramid of prenatal care.
      Canada has the resources, the expertise and the leadership to initiate these important changes in clinical practice. Many centres in Canada offer first-trimester combined screening for aneuploidy to at least some women. It is time to expand this practice nationally, and to build on these programs to include additional screening and preventive measures that can be completed at the same time. As an important first step, the FMF first trimester preeclampsia screening algorithm is currently undergoing validation in Canada (PREDICTION study: Québec City, Montréal, Toronto, Calgary, funded by the Canadian Institutes for Health Research).

      Conclusion

      Overall, we need to standardize the inversion of the pyramid of care across Canada, further expand what we do in tertiary centres, and provide education and training to our colleagues in community and rural settings. The concept of population screening not only for aneuploidy, but also for preeclampsia, birth defects and preterm birth can and should be implemented.
      We call for the introduction of universal screening programs for preeclampsia and preterm birth to accompany the current first and second trimester visit aimed at detecting aneuploidy and fetal anatomical anomalies. This could be the first step in the inversion of the pyramid of antenatal care that could ultimately lead to improved perinatal outcomes, and more efficient use of health care resources (Figure).
      Figure
      FigureThe Canadian inverted pyramid of care.
      *Adapted from Nicolaides et al.
      • Nicolaides K.H.
      Turning the pyramid of prenatal care.
      The Canadian inverted pyramid of care would include: (1) 11- to 14-week ultrasound that includes crown-rump length for optimal pregnancy dating; diagnosis of multiple gestation and chorionicity; fetal anatomy including nuchal translucency for detection of major defects and aneuploidy screening; uterine artery Doppler to predict early adverse outcomes of pregnancy including preterm preeclampsia, fetal growth restriction and stillbirth; (2) 18- to 22-week ultrasound to complete the fetal anatomy evaluation and to measure the cervical length to predict preterm birth; (3) 34- to 36-week ultrasound for fetal presentation, to estimate fetal weight and amniotic fluid (combined with Doppler when necessary) to predict late adverse outcomes of pregnancy including term preeclampsia, fetal growth restriction, fetal macrosomia, and stillbirth. Maternal characteristics, biophysical and biochemical markers (e.g., PAPP-A, PlGF) along with cell-free DNA testing would be added when appropriate. At each step, a positive screening would lead to an evidence-based intervention that could improve the outcomes of pregnancy.

      References

        • Nicolaides K.H.
        Turning the pyramid of prenatal care.
        Fetal Diagn Ther. 2011; 29: 183-196
        • Giguere Y.
        • Charland M.
        • Theriault S.
        • et al.
        Linking preeclampsia and cardiovascular disease later in life.
        Clin Chem Lab Med. 2012; 50: 985-993
        • O'Gorman N.
        • Wright D.
        • Syngelaki A.
        • et al.
        Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 11–13 weeks gestation.
        Am J Obstet Gynecol. 2016; 214: e1-12
        • Rolnik D.L.
        • Wright D.
        • Poon L.C.
        • et al.
        Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia.
        N Engl J Med. 2017; 377: 613-622
        • Romero R.
        • Nicolaides K.H.
        • Conde-Agudelo A.
        • et al.
        Vaginal progesterone decreases preterm birth </= 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study.
        Ultrasound Obstet Gynecol. 2016; 48: 308-317

      Linked Article

      • Au-delà de l'aneuploïdie : pour une approche canadienne moderne en matière de dépistage prénatal
        Journal of Obstetrics and Gynaecology Canada Vol. 40Issue 3
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          Au Canada, les soins normalement offerts aux femmes enceintes comprennent le dépistage prénatal des trisomies les plus courantes (21, 18, 13) reposant sur diverses combinaisons de marqueurs biochimiques et échographiques. L'arrivée récente du dépistage au moyen de l'ADN acellulaire (ADNa), une technique d'une grande précision, a toutefois eu un effet majeur sur les paradigmes de dépistage traditionnels. Ce test force plus particulièrement la réévaluation du rôle que jouent les éléments biochimiques et l'échographie, dont la mesure de la clarté nucale (CN), dans les protocoles de dépistage traditionnels.
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