Routine early ultrasound at weeks 11 –13 of gestation may have the same objective as the current practice of ultrasound at weeks 17 – 19. Since nuchal translucency will be observed at weeks 11 - 1 3, it is likely that early ultrasound will reveal more foetuses with a risk of chromosomal anomalies.
- We did not find evidence on health benefits due routine early ultrasound scans
- Offering routine early ultrasound may lead to a reduction in the number of children born with trisomy 21 (Down syndrome)
- We did not find clinical evidence on harmful effects or risks due to ultrasound scans per se for the mother, foetus or child.
- Early ultrasound may increase the rate of women who are satisfied with prenatal care
- The significance of better diagnostic accuracy of monochorionic twins is unclear
The diagnosis of different conditions
- Early ultrasound may detect almost all monochorionic twins, which may be more difficult at later stages of pregnancy.
- There is substantially uncertainty regarding diagnostic accuracy of ultrasound in the detection of serious structural anomalies, such as congenital heart defects.
- Nuchal translucency measurement combined with a serum test has higher accuracy in detecting cases of trisomy 21 than nuchal translucency measurement alone.
Other consequences of early ultrasound
The results of our economic model analyses show that introduction of a public programme of early ultrasound in addition to ultrasound at weeks 17 – 19 of gestation, may lead to a doubling of running costs compared to the programme currently in place. The actual utilization of ultrasound and foetal diagnostic procedures is higher than the levels estimated by the model. Therefore, it is not granted that the running costs associated with ultrasound and foetal diagnostics in Norwegian prenatal care will increase upon introducing routine early ultrasound. Routine early ultrasound and foetal diagnostics is ethically challenging whether one decides to introduce a routine early ultrasound, or to retain current practice.
Whether to expand the Norwegian publicly offered prenatal care involving one routine ultrasound scan at weeks 17 - 19 of gestation, with an additional routine ultrasound scan at weeks 11 – 13 of gestation is under debate. The Norwegian Council for Quality Improvement and Priority Setting in Health Care discussed the matter in its council meeting on April 11th, 2011. Among the documents supporting the discussion was a report from the Norwegian Knowledge Centre for the Health Services (NOKC) from 2008 regarding the use of ultrasound in prenatal care, and a working paper from 2011 on diagnostic accuracy with regard to the detection of congenital heart defects. The Council determined that further information was required and therefore commissioned another report from NOKC intended to answer questions concerning health effects, diagnostic accuracy and economic consequences associated with the introduction of a programme involving a publicly financed ultrasound scan at weeks 11 - 13 of gestation. A key requirement for the project was that agreement between NOKC and professional experts with regard to the description of current practice and conclusions should be sought.
NOKC established a working group comprising an expert panel in addition to researchers and health economists from the NOKC. The working group drafted a project plan in which the following questions were formulated:
1.What is the current practice with regard to obstetric ultrasonography in Norway?
- Which alternative strategies to offering routine early ultrasound might be considered relevant?
- What is the evidence regarding routine early ultrasound and its health effects?
- What is the diagnostic accuracy of routine early ultrasound with respect to the detection of moochorionicity in twin pregnancies
- What is the diagnostic accuracy of routine early ultrasound with respect to detection of serious structural anomalies
- What is the diagnostic accuracy of routine early ultrasound with respect to detection trisomy 21 (Down syndrome), trisomy 18 and trisomy 13?
- Based on a model incorporating data on diagnostic accuracies, what are the fiscal consequences of introducing a programme of publicly financed routine early ultrasound?
In addition to these questions, the working group chose to include a chapter on ethical challenges.
While the expert panel provided answers to questions 1 and 2,the systematic review of the research evidence was conducted by NOKC. Answers to question 5 were given by NOKC health economists by means of a model and cost analysis, mainly based on the systematic reviews and information provided by the expert panel. The scope of the model was restricted to scenarios in which pregnant women were followed from the first ultrasound scan to a confirmed diagnosis. Members of the expert panel carried out the ethical assessment. NOKC summarized the results and the discussion.
Literature search and inclusion criteria systematic reviews
The reports from NOKC from 2008 and 2011 formed the basis of the assessment. Updating searches were performed in the databases Medline, EMBASE and the Cochrane Library in June 2011. For question 3, 5, 6 and 7 the search was limited to literature published in 2007 and later, no such restriction was used for question 4. In addition references in systematic reviews and references submitted by the expert panel were checked. Included studies should either have a relevant control group or report diagnostic accuracy.
With regard to efficacy questions, question 5 and question 6, we included systematic reviews and studies on early ultrasound scanning provided to a non-selected population of pregnant women. With regard to question 4, studies on confirmed twin pregnancies were included. With regard to safety questions, systematic reviews that had considered prenatal ultrasound without any further specifications of the population.
Outcome measures comprised all positive and negative health effects, including outcomes associated with maternal somatic and mental health, maternal welfare, foetal health, child health and the number of children born with different diagnoses. Safety outcomes included injuries and negative long-term effects directly attributed to the ultrasound examination. Diagnostic accuracy outcomes were sensitivity and specificity relative to a reference of follow-up examinations, autopsy or diagnosis at birth.
Current practice regarding ultrasound in pregnancy
The objective of prenatal care is to:
(Research Council of Norway. Use of obstetric ultrasound, conference, 1995)
The scan at weeks 17 - 19 weeks of gestation is not defined as foetal diagnostics. Should an anomaly be discovered at the scan, a referral to a foetal diagnostic examination will most likely be offered. In 2009, the offer of an ultrasound scan was taken up by 97 % of pregnant women. Estimates from local surveys suggest that over 50 % of pregnant women have already attended an ultrasound scan before presenting for the routine scan. It is unclear how many of these pre-routine scans were justified on medical grounds.
The detection of serious structural anomalies prior to birth may be critical with regard to the facilitation of antenatal follow-up, delivery and rapid treatment after birth. This is particularly the case for congenital heart defects. There is at present no treatment available for serious structural anomalies during pregnancy.
Twin to twin transfusion syndrome (TTS) is one of very few conditions for which treatment is available during pregnancy. Of approximately 60000 pregnancies in Norway, 1000 are twin pregnancies. Between 15 % and 20 % of these are monochorionic and require a follow-up examination to detect twin to twin transfusion syndrome. Treatment may be relevant for approximately 30 pregnancies per year.
Based on figures submitted to the Medical Birth Registry of Norway, 1666 serious foetal structural anomalies were detected in 2009, including those found in interrupted pregnancies and stillborns. Of these, there were 124 cases of trisomy 21, 532 cases of heart defects and 82 cases of trisomy 21. The number of late pregnancy terminations granted by the Norwegian Abortion Boards in 2009 due to serious anomalies was 254, of which 40 were cases of trisomy 21. In the period 2001-2010, almost 90% of pregnancies in which trisomy 21 was detected were terminated. The median week of termination was week 19.
Currently, pregnant women perceived to be at high risk of foetal anomaly, including those 38 years of age or older, receive a routine offer of a foetal diagnostic examination It is recommended that the examination should include an ultrasound scan at 11 - 13 weeks of gestation including measurement of nuchal translucency (NT), possibly combined with a serum test. Approximately 10% (6000) of pregnant women undergo a foetal diagnostic examination, which is a higher figure than what the current recommendations should entail. Based on the number of DRG points generated in the four months from May through August 2011, the annual number of foetal diagnostic examinations could be approximately 45000. This figure includes ultrasound examinations at weeks 11 - 13 of gestation, amniocenteses and chorionic villus samples, as well as other specialized antenatal follow-up intended to examine a medical indication or risk factor
Alternatives for ultrasound examination at weeks 11 – 13 of gestation
The objectives of an early routine ultrasound examination are to determine whether the foetus is alive, the length of the pregnancy, the number of foetuses, the number of placentae, the number of amniotic sacs and to identify anomalies. Whatever the objective may be, nuchal translucency will be observed and indicate a risk of trisomies 21, 18 and to a certain extent congenital heart defects and other anomalies. Two relevant strategies for nuchal translucency measurement stand out. The first is to measure risk based on maternal age, foetal crown rump length and nuchal translucency, while the second is to combine this method with the results from a serum test. The result of the examination will have an impact with regard to follow-up in the remainder of the pregnancy and birth to the same extent as those from the examination at weeks 17 - 19. With regard to follow-up of twins, an early identification of the number of placentae will be of significance. Twins with separate placentae do not require the same intensity of follow-up as twins who share a placenta (monochorionic) do.
Efficacy and safety of routine early ultrasound scans
With regard to efficacy and safety questions, we included five systematic reviews and three recent primary studies. This rendered a total of seven studies which had considered a routine ultrasound scan prior to 14 weeks of gestation. Two studies reported the outcome induced labour due to post-term pregnancy. One study reported a significant reduction in the number of inductions, while the other revealed no effect. We concluded that it is uncertain whether early ultrasound to determine the length of pregnancy has a health effect.
With regard to the outcomes stillbirth, Apgar score, birth weight, maternal anxiety and the number of structural anomalies detected, the included studies reported no significant differences. Due to uncertainty associated with the studies they did not provide a basis on which a conclusion could be drawn. Two studies reported a decline in the number of amniocenteses and chorionic villus samples as a consequence of early ultrasound. We found that the results were not likely to be transferable to a Norwegian context. The reason for this is that the number of invasive tests currently performed in Norway is significantly lower than the amount reported in these studies. A randomized controlled trial from Australia reported a significantly higher number of mothers who were satisfied with prenatal care when they were offered routine early ultrasound, there is uncertainty associated with the estimate of effect. Another study reported that maternal attachment to the foetus was significantly higher at the 26th week of gestation in the group that was offered early ultrasound. We are uncertain as to the importance of this finding.
A Danish observational study reported a significant reduction in the number of live born children with trisomy 21 following the introduction of routine early ultrasound with a risk ratio of 0.60. A similar risk ratio, based on non significant results was observed in a Swedish randomized controlled trial. With a prevalence of live born children with trisomy 21 of 80 per 100000 as reported in the study, this corresponds to 33 fewer live born children with trisomy 21 per 100000 following the introduction of the early scan. Both studies reported a significant increase in the number of antenatally detected cases of trisomy 21. The risk ratio was 1.69 and 1.66 respectively. With a prevalence of 72 per 100000 cases detected antenatally as reported in the Danish control group, this corresponds to 74 more antenatally detected cases of trisomy 21. Both these outcomes are considered transferable to a Norwegian context, though there may be some uncertainty attached to the magnitude of the effect.
None of the studies provided grounds to conclude that ultrasound examinations per se are harmful to the mother, foetus or child. The systematic reviews included stressed the lack of clinical research and systematically registered experience with regard to repeated and prolonged ultrasound examinations early in pregnancy and with new equipment.
Estimates of diagnostic accuracy were employed in the model and cost analyses. We found that there was significant uncertainty associated with the results from the research evidence. We have therefore presented both the summarized research evidence results, as well as the expert panel’s assessment of appropriate values for a Norwegian context, founded on research and experience.
We included four primary studies which reported diagnostic accuracy with regard to the detection of monochorionic twins. The studies reported rates of between 90% and 100% detected cases and between 1% and 2% false positive cases following ultrasound at weeks 11 - 13 of gestation. This means that an early ultrasound scan will be able to detect most monochorionic twins. The expert panel found the result to be transferable to a Norwegian context. Detection rates are probably lower later in pregnancy, but there is uncertainty regarding this due to few available studies. The expert panel estimated that ultrasound at weeks 17 - 19 of gestation will be able to detect approximately 67% of the monochorionic twin cases with an approximately 10% false positive rate.
We included eight primary studies which had considered diagnostic accuracy with regard to the detection structural anomalies following ultrasound at 11 -1 3 weeks of gestation compared to a scan at 17-19 weeks of gestation. Three of the studies found that early ultrasound led to the detection of between 27% and 54% of serious structural anomalies. The rate of false positive cases in the studies was below 1%. Six studies of diagnostic accuracy at weeks 17 - 19 of gestation found between 16% and 100% detected cases. A Swedish randomized trial reported that the ultrasound scan led to the detection of 19% of serious structural anomalies at weeks 11 - 13 and 39% at weeks 17 - 19. There is a great deal of uncertainty surrounding the diagnostic accuracy of early ultrasound scans at weeks 11 - 13 with regard to the detection of structural anomalies. The expert panel’s estimate is that an ultrasound scan at weeks 11 – 13 or weeks 17 - 19 may detect respectively 30% and 50% of serious structural anomalies with a 1% and 0.5% false positive rate.
We included a total of 52 studies on the diagnostic accuracy of detecting trisomy 21, with nuchal translucency (NT) measurement or with nuchal translucency measurement combined with a serum test . Ten studies of early ultrasound with NT reported rates between 62% and 91% (median 75%) of detection of foetuses with trisomy 21. The false positive rate varied between 0% and 29% (median 5%). 17 studies of the combined test reported detection rates between 73 % og 93 % (median 89%) of foetuses with trisomy 21. The false positive rates varied between 2% and 9% (median 4%). Based on the results of these studies, the combined test has a higher diagnostic accuracy than NT alone. The expert panel judged the median values from the studies to be the most relevant estimates for a Norwegian context.
We did not find any studies that could provide a basis for the calculation of the diagnostic accuracy for detection of trisomy 21 at weeks 17 - 19 of gestation. Several studies reported detection rates without stating the false positive rete. The detection rates for trisomy 21 in these studies were significantly lower than those at weeks 11 - 13 of gestation. Based on figures from the Birth Registry of Norway and a Norwegian study, the expert panel’s estimate is that approximately 34 % of cases are detected at the scan as it is currently conducted in Norway. The panel also estimated that 5% of cases would require further foetal diagnostic investigation, but would eventually turn out to be false positive.
Model and costs
Our model analyses show that an early ultrasound scan involving the combined test followed by another scan in weeks 17 – 19 of gestation renders the highest number of detected cases. This applies to the outcomes considered collectively (trisomy 21, structural anomalies and monochorionic twins). This strategy also renders the next to lowest number of false positives. The strategy that generates the lowest number of false positives is the combined test alone.
Which strategy that could be considered cost-effective compared to the current recommended strategy (ultrasound at weeks 17 – 19 of gestation) depends on the objective of the examination and the willingness to pay for a detected case of the relevant condition (trisomy 21, structural anomalies and monochorionic twins). If the objective is to detect the maximum number of total cases of the conditions investigated, the combined test at weeks 11 – 13 of gestation followed by ultrasound at weeks 17 – 19 is the most cost-effective strategy. This requires that one would be willing to pay approximately NOK 393 000 for an additional detected case compared to a strategy of ultrasound at weeks 17 – 19 of gestation.
According to our economic analyses, offering a programme of routine early ultrasound in the form of the combined test followed by an ultrasound scan in weeks 17 – 19 of gestation will double the running costs associated with ultrasound and foetal diagnostics compared to a programme of ultrasound at weeks 17 – 19 of gestation alone. (from approx. NOK 43 million to approx. NOK 86 million). Based on our calculations, the actual running costs associated with ultrasound and foetal diagnostics should be in the order of NOK 104 million. It is therefore not evident that an expanded publicly financed programme will increase the running costs associated with ultrasound and foetal diagnostics in Norwegian prenatal care. Our cost analyses only include incremental costs associated with extra examinations and does not include investment costs or costs related to training, personnel and counselling of pregnant women.
Offering ultrasound examinations as part of prenatal care involves ethical challenges because one examines healthy individuals (women) in order to find conditions which may arise in others (potential children). Further, it is ethically demanding because a major consequence of the examination is abortion, whether it be selective termination on the basis of specific characteristics or as a consequence of inadvertent effects of invasive testing. The former challenges the Biotechnology Act’s preamble and the latter terminates the life of unaffected foetuses.
The right to receive early ultrasound as part of foetal diagnostics is currently restricted to certain groups, particularly pregnant women 38 years or older. A challenging question is whether such restrictions are ethically acceptable from a an equity perspective, given that the right is attached to the pregnant women/couple’s desires and not to the rights of the foetus. Another question is whether a routine offer of an early ultrasound examination will be perceived as an obligation, and in which case, whether the perception of people with disabilities - which might be detected in early ultrasound and form grounds for termination - will change.
There are several methodological challenges with regard to the questions posed in this report. One of the main challenges is how to define a programme of routine ultrasound examination and the criteria by which it should be appraised. Is it a programme designed to provide security and appropriate care to the pregnant woman, or should it be viewed as a screening programme for one or more health outcomes? The description of current practice shows it can be both. Which element that should be emphasized is more of an ethical, political and fiscal question than one of health consequences alone.
We did not find any documentation to support a health benefit associated with early ultrasound, though we cannot rule out that there is one. This might for example involve an increased rate of foetal survival and fewer complications, particularly in the case of monochorrionicity and possibly also congenital heart defects. Studies of diagnostic accuracy suggest that early ultrasound brings greater accuracy and may detect more monochoriotic twin pregnancies. This may have a health impact, since twin to twin transfusion syndrome (TTS) may be treated during pregnancy and untreated TTS often involves a fatal outcome for either or both twins Twin pregnancies are more closely followed up if the twins are monochorionic or if their chorionic status is unclear. Nevertheless, we found no studies which confirm a direct association between a programme of early ultrasound and twin pregnancy outcomes. Neither did we find any studies which confirm a direct association between a programme of early ultrasound and the prognosis of foetuses with congenital heart defects.
We found that an introduction of early ultrasound may lead to fewer live born children with trisomy 21. Whether this is a desired effect or an inadvertent side effect is an ethically challenging question. At the same time, the decision as to who has the right to answer that question is ethically challenging in itself.
Invasive tests are associated with an increased risk of spontaneous abortion of between 0.5 % and 1 %. We found a Danish and a Swedish study which both reported that the number of invasive tests decreased significantly following an introduction of early ultrasound. This means that early ultrasound may lead to a decrease in the number of spontaneous abortions, and therefore have a positive health effect. However, the number of invasive tests currently carried out in Norway is lower than the amounts reported in the studies and we therefore considered the results not to be transferable to a Norwegian context. It is on the contrary reasonable to assume that the number of invasive tests might increase as a result of an introduction of early ultrasound in Norway since more cases with a higher risk of chromosomal anomalies revealed by nuchal translucency will be followed up by invasive testing. Precisely how many is difficult to estimate.
An important question is whether healthy foetuses will be removed at selective pregnancy terminations due to false positive results. A Norwegian study by Kaasen et al. investigated the association between findings at ultrasound and autopsy but found no foetuses that had been aborted as a consequence of false positive results at a foetal diagnostic examination (Kaasen 2006).
The studies of diagnostic accuracy used different definitions, algorithms and threshold/cut-off values for anomaly and different follow-up examinations to confirm findings. Thus, there is a great deal of uncertainty attached to the results and their implications for the Norwegian health service. We have not considered the diagnostic accuracy of ultrasound scans in the follow-up of pregnant women with a known risk of having a foetus with structural anomalies, but we assume on general grounds that it is higher than what would be the case for a non-selected population of pregnant women.
A routine early ultrasound scan at weeks 11 – 13 of gestation may have the same objectives as ultrasound at weeks 17 – 19. However, since nuchal translucency will be observed at weeks 11 – 13, the scan will also reveal the risk for chromosomal anomalies, which is more complicated at later stages of pregnancy. We could not find any documentation to support a health benefit associated with routine early ultrasound. The questions related to obstetric ultrasound and foetal diagnostics are ethically challenging.