Abstract

1. INTRODUCTION

Noninvasive prenatal testing (NIPT) for aneuploidy based on analysis of cell‐free DNA (cfDNA) in the maternal plasma became available in the private sector in 2011 and is now being offered widely throughout the world.1 NIPT is a highly accurate screening test that can be used from 10 weeks in pregnancy to detect Down syndrome (DS) (Trisomy 21) with high sensitivity (99%) and specificity (99.5%).2 However, NIPT is not diagnostic, and confirmation of a positive result by invasive testing (chorionic villus sampling or amniocentesis) is recommended.3 NIPT has been shown to be accurate in both the high‐risk and general pregnancy populations,4 and the use of NIPT as a screening test has been endorsed by professional bodies from several countries who encourage provision of pretest and posttest counseling to support informed choice.3, 5 NIPT has a much greater sensitivity than traditional screening methods such as the combined test that measures nuchal translucency and maternal serum biochemistry and a growing number of studies have confirmed that the introduction of NIPT into the screening pathway has significantly reduced the need for invasive testing.6, 7, 8, 9, 10

Overall, key stakeholders, such as pregnant women and health professionals, are very positive about the introduction of NIPT and highlight benefits such as safety, accuracy, and the detection of pregnancies affected with DS that would have been missed with traditional screening.11, 12, 13, 14 One of the questions raised in the literature about the widespread implementation of NIPT for DS is whether it will lead to an increase in the number of parents seeking prenatal testing and termination of pregnancy with a resultant significant decrease in the number of children born with DS.11, 12, 15, 16, 17 Research with pregnant women11, 12 and parents of children with DS16, 17 identified concerns that fewer children being born with DS could result in a reduction of social supports and resources for children with disabilities and a society that is less tolerant of people who have children with disabilities. Furthermore, these key stakeholder groups felt that a less tolerant society could increase feelings of pressure for pregnant women to have testing and subsequently terminate an affected pregnancy.11, 12, 16

Interest in and uptake of NIPT is high,7 making it likely that the number of parents opting for prenatal testing for DS will grow as many parents who would not have previously opted for prenatal testing because of the risk of miscarriage would be willing to have NIPT.11, 18 It is not yet clear, however, whether the increase in the numbers of women having prenatal testing will directly result in more terminations of pregnancy. There will be wide variation in the number of children born with DS between and even within countries depending on attitudes to prenatal testing, disability, and termination that are influenced by religious, social, and cultural settings, costs of prenatal testing and access to termination of pregnancy. Ultimately, we will see the impact of NIPT on the number of children born with DS from long‐term population‐based studies comparing live birth rates before and after the introduction of NIPT. These population‐based studies are crucial as they reflect the number of children born to parents who have chosen to continue the pregnancy after a prenatal diagnosis of DS as well as the number of children born to parents who decided not to have prenatal diagnosis and then had a baby with DS.

Several studies conducted prior to the introduction of NIPT have reported the number of children born with DS compared to expected numbers based on the prevalence of DS in the general population. These figures vary between countries: in the United States there were 30% fewer individuals with DS (2007),19 50% fewer in the Netherlands (2015),20 48% fewer in England and Wales (2008),21 55% fewer in Australia (2004),22 94% fewer in Taiwan (2010),23 and 55% fewer in China (2011).24 As the numbers of older women giving birth have grown, the numbers of pregnancies affected with DS have also increased. However, in England and Wales21 and in Europe25 the live birth rate remained relatively unchanged between 1990 and 2009 even though prenatal screening and diagnosis became more common over the same period. In contrast, in the United States, the live birth rate has increased since the early 1990s through to 2007.19 One small regional study conducted in the Hampton Roads area of Virginia reported that NIPT has not affected the number of children born with DS in this area.7 More time is needed to see the impact of NIPT on the live birth rate more widely and conclusively.

While we await definitive population‐based studies, there are several lines of evidence available to us now that can help assess the impact the introduction of NIPT might ultimately have on the numbers of parents choosing to continue their pregnancy following a prenatal diagnosis of DS. Here we examine the literature to look at reports of pregnancy outcomes following NIPT. We also describe 2 new audits of NIPT services in clinical practice that were conducted in England and in Singapore.

2. METHODS

3. RESULTS

3.2. Audit of pregnancy outcomes following NIPT as a clinical service in Singapore

Between April 1, 2014, and January 31, 2017, there were 20 701 new bookings at National University Hospital Singapore; 700 women had NIPT (3.4%). For 6 women NIPT indicated that the baby had a high risk of being affected with DS. Five chose to confirm their results by amniocentesis, and the sixth declined further testing. There were no false positives. Of the 5 women with a confirmed pregnancy affected with DS, 4 opted for a termination (80%), and 1 continued the pregnancy. The woman who declined further testing following NIPT also continued the pregnancy. The termination rate for these women with high‐risk NIPT results for DS was 67%. Nine women were lost to follow‐up, and it was not possible to issue a result in 4 cases, because of high variance or low fetal fraction. Over the same period, 706 women (3.4%) opted for an invasive test without prior NIPT, and 39 had a positive result for DS. Twelve cases were lost for follow‐up; of the remaining, 27 women, 25 women chose to terminate their affected pregnancy (92.6%), including 1 woman who had a selective feticide for a single affected twin. There was 1 intrauterine death, and 1 continued pregnancy. Overall, from the 33 cases with confirmed DS following invasive testing or high risk NIPT where outcomes were known, 29 terminated (87.9%) and 4 (12.1%) continued with 1 being stillborn. A summary of the audit findings is presented in Figure 1.

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Figure 1

Flowchart showing numbers of women and outcomes for the Singapore audit

3.3. Audit of pregnancy outcomes following NIPT offered as a clinical service in the United Kingdom

Nine hundred and sixty seven women with a high‐risk DS screening result in the North Thames Region had NIPT and 46 were found to be highly likely to have DS. There were no false positive DS results; however, 3 women in this group were lost to follow‐up. Of the 46 women found to be highly likely to have DS by NIPT, outcomes were available for 43. There were 27 (62.7%) women who chose to terminate the pregnancy, 1 had a still birth (2.3%), and 15 (34.9%) continued the pregnancy. Out of 15 parents who chose to continue the pregnancy, 12 did not have their NIPT result confirmed by invasive testing, 2 had invasive testing, and 1 decision was unknown. Twenty one of the 27 parents who chose to have a termination of pregnancy had invasive testing to confirm the NIPT result, 1 declined and the decision was not reported for 5. A summary of the audit findings is presented in Figure 2.

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Figure 2

Flowchart showing numbers of women and outcomes for the UK audit

4. DISCUSSION

Our literature review and audits show that many women opting for NIPT who had a result indicating they were highly likely to have a baby with DS chose to continue their pregnancy. Although numbers are relatively small, when we look at the data as a whole our findings suggest that the high uptake of NIPT worldwide includes many women who would like additional information about their baby that will not necessarily be used for decision making about termination of pregnancy. In addition, several studies in the review reported that some women declined an invasive test to confirm the NIPT result and continued their pregnancy, further emphasising that many women choosing to have NIPT want information about the health of their baby, but would not risk miscarriage with an invasive test. Differences in the number of live births were seen between countries as women chose to continue pregnancies highly likely to be affected with DS in the United States, the United Kingdom, the Netherlands, and Singapore, but there were no confirmed live births reported in the studies from China, Hong Kong, Taiwan, France, and Spain.

Termination rates for DS prior to the introduction of NIPT vary quite markedly throughout the world. In the United States, a systematic review of termination rates in studies published between 1995 and 2011 found that 67% of women opted for termination of pregnancy following prenatal diagnosis of DS.41 Termination rates of over 90% have been reported in the United Kingdom,21 Australia,42, 43 China,24 and the Netherlands.44 In Taiwan, a termination rate of 67.5% was reported for 200145; however, prenatal screening and diagnosis has since been more widely introduced and the live birth rate for children with DS decreased from 48.7% in 2001 to 6% in 2010.23 Comparison between termination rates reported prior to the introduction of NIPT with termination rates seen in the reviewed studies and audits suggests a general trend towards a decrease in termination rates compared with pre‐NIPT rates (Table 2). Data from the UK audit and research studies35, 36, 37 indicate that termination rates for women having NIPT are considerably lower than the pre‐NIPT termination rate of 92%.21 For the US8, 28, 29, 31, 33 and Dutch34 studies, decreases in the termination rate compared to pre‐NIPT rates were also seen. Notably in the United States, termination rates following a prenatal diagnosis of DS are already low (67%) compared to other countries (>90%). In some countries termination rates were unchanged, for example, in Hong Kong, in the studies reported by Lau et al,26, 27 a termination rate of 100% is in line with reported termination rates above 90% for mainland China.24

It is important to be cautious when interpreting comparisons between the studies discussed here and historical controls, as numbers are small in the included studies and there may be differences between the populations used for determining the historical termination rates and those of the included studies, for example, in the systematic review of termination rates from the United States, Natoli et al41 noted that the summary termination rate that the authors calculated may not be applicable to the entire US population. In addition, the termination rates from the historical controls only include women with a confirmed prenatal diagnosis of DS. To get a complete picture of the impact of NIPT we have calculated termination rates for all women with a high‐risk NIPT result, not all of whom chose to have confirmatory invasive testing. For some studies included in the review there are no differences in how termination rates were calculated compared to historical controls, as all women in the study had their high‐risk NIPT result confirmed.26, 27, 30, 34, 38, 39 To look at termination rates across subgroups in the remaining studies, we could calculate the termination rates for women with and without a confirmed prenatal diagnosis of DS separately. However, this is not possible for all studies as the required information was either not reported or participant numbers were too low to allow a meaningful breakdown. In Chitty et al35 the termination rates for women with and without a confirmed diagnosis after a high‐risk NIPT result were 83% (29/35) and 12.5% (1/8), respectively, and in the UK audit 88% (21/24) and 8% (1/13), respectively. In the US study reported by Dobson et al,33 the termination rates for women with and without a confirmed diagnosis were 80% (28/35) and 27% (4/15), respectively. Notably, Dobson et al33 concluded, as we did, that the overall termination rate was not higher than historical controls and stated that their findings argue against the concern that cfDNA screening would increase rates of pregnancy termination.

As one of the common reasons women have declined screening in the past is the miscarriage risk associated with invasive testing,47, 48 it is not surprising that NIPT is being adopted widely around the world.1 However, our findings suggest that this increase may not impact greatly on the number of babies born with DS as many parents will use NIPT for information and not for decisions about termination of pregnancy. The decrease in termination rates compared with pre‐NIPT rates observed in the reviewed studies, presumably reflects, at least in part, the uptake of NIPT by women seeking information who would not have had prenatal testing in the past as they would not put their pregnancies at risk with invasive testing. We also found evidence that the termination rate for women opting for NIPT was lower when compared to women who chose to go directly to invasive testing following a high‐risk screening result. In the Singapore audit the number of women opting for termination following NIPT (4/6—66.7%) was lower than those who chose invasive testing (25/27—92.6%). Similarly, in the United Kingdom, in 2 prospective studies where NIPT was offered to both high and intermediate risk women the number of live births of children with DS were significantly higher amongst women opting for NIPT compared to women who chose to go straight to invasive testing.35, 36, 37 This difference is most likely due to the variances in motivation for women choosing NIPT versus invasive testing, with the latter group perhaps being more likely to want diagnostic information to make decisions about termination.49

We know from the literature that the uptake of NIPT is high,34, 35 making it likely that detection of DS will increase, but the lower termination rates following NIPT in some countries suggest that live birth rates may remain largely unchanged compared to termination rates prior to the introduction of NIPT. Termination rates did not, however, fall in all studies reviewed here and in settings where NIPT uptake is high and termination rates remain unchanged there will be an overall increase in numbers of terminations of pregnancy and a corresponding decrease in the live birth rate.

Ultimately, however, the research included here describes relatively small numbers of women and can only give insights into pregnancy outcomes following prenatal testing and we do not know how many children with DS were born to parents who chose not to have prenatal testing. Population‐based studies of live birth rates are therefore essential to allow us to see the overall impact of NIPT. The importance of the population‐based studies is highlighted by reports from countries such as the Netherlands where the termination rate following a prenatal diagnosis of DS is high, but the overall live birth rate has increased over time as many women opt not to have DS screening.20 Uptake of DS screening is low in the Netherlands compared to other European countries. This may reflect the fact that parents must make a financial contribution to screening, also that the offer of DS screening is not presented as a routine test and is discussed in a way that emphasises the right not to know.50 Moreover, several studies looking at hypothetical choices have shown that even with NIPT as an option many women will still choose not to have any prenatal testing. In a survey of 2666 women from 9 countries, there was a sizable proportion of women who said they would not have any prenatal testing for DS, including more than one third of women in the Netherlands and Israel.51 Similarly, studies from the United States and the Netherlands found that around one third of people surveyed reported not wanting any tests for DS.52, 53

Research looking at women's hypothetical choices regarding how they would respond to an NIPT result that suggests DS is highly likely support our findings that many women will choose to continue their pregnancies.18, 49, 52, 54 While the data on hypothetical choices needs to be interpreted with caution, as parents may make different choices when faced with real‐life situations, these studies indicate that a significant number of parents would use NIPT for information only, so that they could plan and prepare for the birth of an affected child rather than using the information to make decisions about termination of pregnancy.18, 52, 55, 56 The anticipated high uptake of NIPT suggested in these studies indicates that parents value having screening tests available, regardless of their intention to either terminate or continue an affected pregnancy. Recent research in the United States that surveyed 217 individuals, representative the US population by gender, income, and education, found that the majority (65%) saw the value of having reliable information when making health care decisions and therefore supported having NIPT and other prenatal tests available.57

Decision making about next steps following a diagnosis of DS is complex. Every woman must have access to the support they need to make informed decisions that take into consideration their own circumstances, experiences, the needs of their family and are in keeping with their personal beliefs and values.58, 59 Recent research has highlighted best care practices following a prenatal diagnosis of aneuploidy that include the provision of clear, accurate, and respectful communication about the testing process and results; empathic, nonjudgemental professional support; timely access to services; health professional acknowledgement of the enormity of the decision; and opportunities to discuss the diverse range of feelings that accompany prenatal diagnosis.59 As many parents will have prenatal testing with NIPT for information only, there will be more parents continuing pregnancies knowing that the baby has DS. As many of these women receive the diagnosis in early pregnancy it is important that their ongoing needs for emotional and clinical support are met. Furthermore, knowledge of fetal DS status may allow increased surveillance to prevent intrauterine death as highlighted by recent research from the United States, which found elevated rates of growth restriction, early delivery due to nonreassuring fetal status, and placental insufficiency in a cohort of 64 women continuing the pregnancy with a diagnosis of DS.60 Provision of practical and psychosocial support for individuals with DS and their families will also continue to be needed.

5. CONCLUSIONS

Parents value having the option of NIPT so that they can obtain information about DS early in pregnancy without putting their pregnancy at risk of miscarriage. The data presented here suggest that parents choose NIPT for different reasons, and a significant number of parents will use the results for information so that they can prepare for the birth of a child with DS. Comparison of termination rates reported in the studies reviewed here with termination rates reported prior to the introduction of NIPT suggest that in many settings the implementation of NIPT may not alter the overall numbers of children born with DS. Long‐term population‐based studies are needed to accurately determine the impact of NIPT on the number of children born with DS. Future research should also consider the implications for cost‐effectiveness and service provision of NIPT being used for information and planning as well as to direct decisions about termination of pregnancy.

CONFLICTS OF INTEREST

J.F. is used by the charity Antenatal Results and Choices (ARC), which in the past has received small amounts of funding from some commercial companies marketing NIPT. All other authors declare no conflict of interest.

ACKNOWLEDGEMENTS

Notes

Hill M, Barrett A, Choolani M, Lewis C, Fisher J, Chitty LS. Has noninvasive prenatal testing impacted termination of pregnancy and live birth rates of infants with Down syndrome? Prenatal Diagnosis. 2017;37:1281–1290. https://doi.org/10.1002/pd.5182 [Europe PMC free article] [Abstract] [Google Scholar]

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