The first trimester scan provides a large amount of clinically relevant information. As the resolution of ultrasound improves and as research into the early prediction of a variety of pregnancy complications continues, it is likely to offer ever more information to women and their carers.
The first trimester scan came into being in the early 1990s, with the introduction of nuchal translucency screening for Down syndrome. Since the mid-1990s, the first trimester screening program has incorporated maternal age, nuchal translucency and two biochemical parameters, pregnancy-associated plasma protein A (PAPP-A) and free BHCG, in generating risks for Trisomy 21 (Down syndrome), Trisomy 18 and Trisomy 13. Although many women and clinicians still view the first trimester scan predominantly as a component of Down syndrome screening, it has become apparent that a scan at 11–13+6 weeks has numerous other benefits, including accurate dating, early diagnosis and assessment of multiple pregnancy, diagnosis of a missed miscarriage, assessment of fetal anatomy and identification of uterine anomalies. Likewise, the first trimester screening program, although directed primarily at the commoner chromosomal abnormalities of Trisomy 21, 18 and 13, has been found to identify a wide range of other chromosomal abnormalities (up to 30 per cent of genetic abnormalities found on invasive testing following a high-risk screen result are ‘atypical’1), as well as pointing to an increased risk of a number of structural abnormalities and fetal syndromes, and late pregnancy complications such as pre-eclampsia and fetal growth restriction.
The combined first trimester screen for aneuploidy
Aneuploidy (an abnormal number of chromosomes) is found in 35 per cent of miscarriages, four per cent of stillbirths and 0.3 per cent of live births at term.2 Of those surviving to term, the commonest aneuploidy condition is Down syndrome, with an incidence of approximately 1:700 live births, followed by Trisomy 18, Trisomy 13 and abnormalities of the sex chromosomes. Down syndrome is associated with mild-to-moderate intellectual disability and a range of other potential health problems. Trisomy 13 and 18 are associated with much more severe disability, both mental and physical, and less than five per cent of babies born alive with these conditions will survive to see their first birthday. First trimester screening enables women, while still at an early stage of their pregnancy, to choose whether or not to have invasive testing to diagnose these conditions, based on their calculated level of personal risk.
Nuchal translucency describes the ultrasound appearance of an anechoic space behind the fetal neck, caused by an accumulation of subcutaneous fluid. Although measurable in almost all fetuses between 11 and 13+6 weeks, the median thickness is greater in fetuses affected by aneuploidy. A wide range of fetal conditions may lead to thickening of the nuchal translucency and underlying pathophysiological mechanisms are thought to include cardiac dysfunction, venous congestion of the head and neck, altered composition of the extracellular matrix, abnormal lymphatic drainage, anaemia, hypoproteinaemia and infection.3 For the purposes of first trimester screening for aneuploidy, the nuchal translucency measurement must be performed by an accredited operator using a standardised technique, as described by the Fetal Medicine Foundation.4
PAPP-A is a large glycoprotein produced by the placenta, the main function of which in pregnancy is to enhance the bioavailability of insulin-like growth factors (IGFs) through cleavage of inhibitory binding proteins. Low levels in the first trimester are associated with Down syndrome as well as other outcomes (pre-eclampsia, fetal growth restriction) related to poor early placentation.5
Free BHCG is the beta subunit of human chorionic gonadotrophin, another glycoprotein derived from the placenta, which, in the first trimester of pregnancy, supports the corpus luteum. Levels between 11 and 13+6 weeks tend to be higher than the normal median in fetuses with Down syndrome and lower in those affected by Trisomy 13 and 18.
A background risk for aneuploidy is calculated using maternal age, the gestation of pregnancy and previous history of an affected pregnancy (which increases background risk by 0.6 per cent). Likelihood ratios are then calculated for NT, PAPP-A and free BHCG, based on the difference between the measured values and the normal median at that gestation. The likelihood ratios are used to adjust the background risk. Five per cent of women will have an adjusted risk greater than 1:250 and are described as ‘high risk’, with the option of invasive testing. As the majority of these women will have unaffected pregnancies, the test is said to have a five per cent false positive rate (some programs have a cut-off of 1:300, or an eight per cent false positive rate).
If the five per cent false positive cut off of 1:250 is used, approximately 90 per cent of fetuses with Trisomy 21 are detected. If a cut-off of 1:1000 is used, the false positive rate would be approximately 13 per cent, and about 97 per cent of Trisomy 21 fetuses would be detected.6 Some women will not be reassured by a ‘low risk’ result between 1:250 and 1:1000 and their wishes for further testing should be respected.
Additional markers for Down syndrome, both ultrasound and biochemical, may also be incorporated into the risk assessment, and have the effect of both increasing the sensitivity and decreasing the false positive rate for a given risk cut-off. The most established of these is nasal bone; approximately 68 per cent of Down syndrome fetuses in the first trimester will have an absent nasal bone, while this is seen in only two per cent of euploid fetuses. Hence, the nasal bone is a strong marker for Down syndrome and certification in nasal bone assessment for sonologists has been available through the Fetal Medicine Foundation since 2010. The Doppler waveform of the ductus venosus, as well as maternal serum levels of placental growth factor (PlGF) and alpha feto protein (AFP) may also now be incorporated into the first trimester algorithm and evaluation of numerous other markers continues.
Getting the most out of first trimester screening
- The patient must be appropriately counselled and should understand the nature of the conditions being screened for,the fact that the test is not diagnostic and the nature of the diagnostic options that will be offered following a high-risk result. The options of continuing or terminating an affected pregnancy should also be discussed. Many women will choose not to have screening for aneuploidy, but may still choose to have a first trimester scan for the other advantages it offers.
- All requested demographic information should be entered on the request form, as the interpretation of the biochemical assays is affected by variables such as maternal weight, smoking status, parity, ethnicity, diabetes and IVF conception.
- It has been calculated that detection rates for Down syndrome are highest (96 per cent detection for a five per cent false positive rate) when bloods are taken at ten weeks and the nuchal translucency assessed at 12 weeks.7 Although nuchal translucency can be assessed from 11 weeks to 13+6 weeks, visualisation of fetal anatomy is also improved if the scan is deferred until after 12 weeks.
- It is usually preferable to tell women the exact calculated risk rather than to summarise as low risk or high risk, as risk results will mean different things to different people. Try to make the numbers meaningful: ‘If there were 50 women your age with exactly the same blood and ultrasound results, one would be carrying a baby with Down syndrome and the other 49 would not’.
- Options for women with a high-risk result include invasive procedures such as chorionic villous sampling (CVS) (at 11–14 weeks) and amniocentesis (from 15 weeks), which are diagnostic for aneuploidy. Reassuringly, a recently published meta-analysis assessing procedure-related miscarriage risks for amniocentesis and CVS, using data collected between 2000 and 2014, found miscarriage risks above background of only 0.11 per cent for amniocentesis and 0.22 per cent for CVS.8 Women with a high-risk result who prefer toavoid an invasive procedure, or those with an intermediate risk of 1:250 to 1:1000, may choose to use non-invasive prenatal testing (NIPT) for risk modification. Assessment for soft markers of aneuploidy at the second trimester scan, if negative, will further decrease the risk by at least two, and possibly by up to seven times.9
- A thickened nuchal translucency may have implications other than aneuploidy. The 95th centile for nuchal thickness (NT) is 2.1mm at 11 weeks and 2.7mm at 13+6 weeks and fetuses with a NT between the 95th and 99th centile have been found to have a marginally increased risk of cardiac anomaly, at approximately one per cent. However, for karyotypically normal fetuses, the risk of adverse outcome does not increase significantly until the NT is greater than the 99th centile A thickened nuchal translucency may have implications other than aneuploidy. The 95th centile for nuchal thickness (NT) is 2.1mm at 11 weeks and 2.7mm at 13+6 weeks and fetuses with a NT between the 95th and 99th centile have been found to have a marginally increased risk of cardiac anomaly, at approximately one per cent. However, for karyotypically normal fetuses, the risk of adverse outcome does not increase significantly until the NT is greater than the 99th centile(3.5mm).10 The chance of any adverse outcome (including aneuploidy) then increases exponentially with increasing thickness, from 30 per cent for NT 3.5–4.4mm, to 85 per cent for NT >6.5mm, with complications including fetal death, major structural abnormalities (especially cardiac) and a wide range of syndromes. The finding of a thickened nuchal translucency should prompt as thorough an anatomical review as possible at the time of the first trimester scan, with particular attention to the fetal heart. Women with a NT result ≥3.5mm should be offered detailed structural scans at 16 and 20–22 weeks, and specialised fetal echocardiography should be accessed if available. Parents can be reassured that, for a karyotypically normal fetus, the risk of adverse outcome is no longer statistically increased following completion of a normal, targeted ultrasound at 20–22 weeks.
- Occasionally, a nuchal translucency may be measured at ≥3.5mm, but the aneuploidy risk will still be low; women with these results should consider invasive testing, as there remains a risk of atypical chromosomal abnormalities.11
- Low levels of PAPP-A have also been associated with other adverse outcomes, particularly intrauterine growth restriction. PAPP-A levels less than the first centile (0.29 MoM) have a good predictive value for intrauterine growth restriction later in pregnancy (one in six women will have fetal weight greater than fifth centile, and one in four greater than tenth centile), and serial scans for growth are worthwhile. The positive predictive value for levels between the first and fifth centile(0.29 to 0.45 MoM), on the other hand, is relatively low, with observed rates of fetal growth greater than fifth centile approximately 1.5–2-fold higher than expected.12 Assessment of maternal risk factors, other serum analytes (BHCG greater than first centile, AFP >95 per cent), second trimester fetal growth and uterine artery Dopplers may help improve the predictive value.
Non-invasive prenatal testing
A detailed discussion of the current status and role of NIPT is beyond the scope of this article. Many women are choosing to use NIPT as their primary method of screening, with bloods being taken at about ten weeks gestation. Although this has the advantage of being a highly sensitive and specific screen with the option of CVS for a high-risk result at a relatively early stage of their pregnancy, they should be aware that, at this point in time, screening is limited to numerical abnormalities of chromosomes 13, 18, 21, X and Y. Currently, integrating the NIPT into the screening program as a second-line screen following combined first trimester screening is the more cost-effective option13 and, if a risk cut off of 1:1000 is used, the sensitivity approaches that of NIPT as a primary test. It is also worth noting that, if the high risk result of combined testing is associated with thickened nuchal translucency (≥3.5mm), extremes of biochemical abnormality, structural abnormality or a higher overall risk (for example, >1:50), then up to a third of chromosomal abnormalities will be atypical and not detectable by NIPT and women in these circumstances should be counselled regarding the advantages of invasive testing.14
The first trimester scan and anatomical abnormalities
The ability to diagnose anatomical abnormalities at the time of the first trimester scan is to a large part dependent on the interest and expertise of the clinicians performing the scan. A recent meta-analysis15 found an overall detection rate in the first trimester for major structural abnormalities of 51 per cent (62 per cent when transabdominal and transvaginal approaches were combined). This included a detection rate of 48 per cent for cardiac abnormalities and 51 per cent for brain and spine abnormalities.
Detection rates for cardiac abnormalities of over 90 per cent have been reported for targeted exams in high-risk patients.16
Pregnancy dating in the first trimester
Pregnancy dating is most reliable between eight and 13+6 weeks, as before eight weeks small measurement errors are likely to have a greater effect on gestational age assessment. Crown rump length (CRL) is the most precise parameter at this time, allowing accurate determination of dates to within five days in 95 per cent of cases. From 14 weeks, head circumference (HC) is the most reliable parameter for the purposes of dating the pregnancy.17 By contrast, assessment of gestational age at the time of the routine morphology scan is only accurate to within ten days.
The importance of accurate dating is widely acknowledged, as it affects the reliability of subsequent ultrasound assessment for growth restriction, as well as decision making around both post-term pregnancies and those at the cusp of viability.
Early diagnosis and assessment of multiple pregnancy
Chorionicity is a major determinant of risk in multiple pregnancies and most modern guidelines recommend more intensive monitoring regimes for monochorionic pregnancies than dichorionic pregnancies. The ‘lambda’ or ‘twin peak’ sign describes a triangular projection of chorion extending between the membranes and is highly specific for dichorionic pregnancy. This assessment is best performed at 10–13+6 weeks and becomes less accurate with advancing gestation.
A minor discrepancy in CRL in twins is a not uncommon finding and there is some controversy as to whether the larger or smaller twin should be used for dating. More major size discrepancies in the first trimester (>11 per cent) suggest an increased risk of fetal demise or anomalies in the smaller twin.18
First trimester screening for aneuploidy by nuchal translucency alone or in combination with first trimester biochemistry can be performed. Dichorionic twins are given individual risks based on CRL and NT, while for monochorionic twins, presumed genetically identical, the nuchal measurement should be averaged and the same risk given for both. A discordance in nuchal translucency measurements in monochorionic twins of >20 per cent increases the risk of subsequent development of twin-to-twin transfusion syndrome.19
Uterine abnormalities and adnexal masses
Uterine fibroids are not uncommonly demonstrated at the time of the first trimester scan and are usually of no clinical significance. However, larger fibroids, in particular, may be associated with abdominal pain owing to degeneration, preterm labour or labour dystocia. Adnexal masses are usually benign, but may result in abdominal pain owing to rupture or torsion.
Occasionally, a uterine anomaly, such as a bicornuate or subseptate uterus, may be identified at the time of the first trimester scan. Uterine malformations have been associated with increased risks of miscarriage, preterm birth, malpresentation and fetal growth restriction, although the majority of women will have a normal outcome. 3D imaging, if available, will optimally define a suspected uterine abnormality.
A subchorionic haematoma is seen in approximately three per cent of first trimester scans. Small, asymptomatic haemorrhages do not appear to be associated with an increased risk of adverse outcome. However, a meta-analysis published in 2011 found subchorionic haemarrhages to be associated with overall increased risks of spontaneous miscarriage, preterm birth and preterm rupture of the membranes. There is also an increased risk of stillbirth and abruption, although absolute risks remain low. The greatest risk increase was for abruption, from 0.7 to 3.6 per cent. No significant increase was found in the risk of growth restriction or pre-eclampsia.20
Screening for pre-eclampsia
There has been immense interest in developing early predictive models for pre-eclampsia. None have been shown to have a worthwhile predictive value for identifying women at risk of late onset pre-eclampsia, but many have shown promise in predicting early (<34 weeks) pre-eclampsia. Although early pre-eclampsia is less common than late pre-eclampsia, it is associated with a substantially greater risk of maternal and perinatal morbidity and mortality. Furthermore, low dose aspirin commenced before 16 weeks gestation appears to be effective in reducing the incidence of pre-eclampsia in high-risk women, with the greatest effect being seen on early pre-eclampsia (a relative risk of 0.18 in a 2013 meta-analysis).21 Aspirin also has the advantages of being an inexpensive drug with a good safety profile in pregnancy.
An algorithm incorporating maternal demographic factors, mean arterial blood pressure, uterine artery PI, and PAPP-A and PlGF was evaluated by Poon et al in 2009, and was found to identify 93 per cent of women destined to develop early pre-eclampsia, for a false positive rate of five per cent.22 An Australian centre published a validation of this model (without PlGF) in 2013, which reported a 41.7 per cent detection rate for a false positive rate of five per cent, and 91.7 per cent detection rate for a false positive rate of ten per cent.23 The same group then studied a second cohort of women, where women with an estimated risk of early pre-eclampsia of less than two per cent (ten per cent false positive risk cut off) were advised to take low-dose aspirin, 150mg at night. They were able to demonstrate a ten-fold reduction in the prevalence of early pre-eclampsia.24
Unfortunately, other studies which have evaluated this and similar models have had widely varying results.25 This may be related to difficulty in teaching and maintaining quality standards in uterine artery Doppler assessment.
The Fetal Medicine Foundation Software for calculating aneuploidy risk also offers the option of calculating pre-eclampsia risk using the above algorithm, available to operators who have been credentialed in uterine artery Doppler measurement. Although a few practices in Australia are now offering pre-eclampsia screening at the time of the first trimester scan, it seems that it will be some time before the testing will be feasible on a large scale.
Algorithms for the calculation in the first trimester of risk for growth restriction and preterm birth are also available, but have not yet been widely validated.