Amniocentesis and chorionic villus sampling for prenatal diagnosis

RHL Commentary by Oladapo OT

1. EVIDENCE SUMMARY

Various approaches in current obstetric practice for definitive chromosomal diagnosis of the fetus include second trimester amniocentesis (usually performed between 16 and 18 weeks' gestation), early trimester amniocentesis (at 9–14 weeks' gestation) and chorionic villus sampling (CVS) by transabdominal or transcervical route. This review (1) assessed the comparative safety and diagnostic accuracy of all types of amniocentesis (both early and late) and chorionic villus sampling (transabdominal or transcervical) for prenatal diagnosis. It included a total of 14 randomized controlled trials evaluating pregnant women undergoing invasive prenatal testing for fetal chromosomal or genetic disorders.

1.1 Second trimester amniocentesis versus control (no testing)

The review shows that second trimester amniocentesis significantly increases the risk of spontaneous miscarriage in women who undergo the procedure compared with those who do not [2.1% versus 1.3%; relative risk (RR) 1.6, 95% confidence interval (CI) 1.02–2.52). This evidence is essentially based on the findings of a large multicentre trial involving 4606 women in the 1980s.

1.2 Second trimester amniocentesis versus early amniocentesis

Second trimester amniocentesis was found to be comparatively safer than early amniocentesis for invasive prenatal diagnosis. Early amniocentesis is technically more demanding and is associated with increased total pregnancy loss (7.6% versus 5.9%; RR 1.29, 95% CI 1.03–1.61) and congenital abnormalities (4.6% vs 2.7%) compared with second trimester amniocentesis. It is also associated with increased risk of laboratory failures and multiple needle insertions.

1.3 Second trimester amniocentesis versus transcervical CVS

Four trials show that the risks of total pregnancy loss (14.5% versus 11.0%, RR 1.40, 95% CI 1.09–1.81) and spontaneous miscarriage (12.9% versus 9.4%) are higher with transcervical CVS compared with second trimester amniocentesis. Although this finding appears plausible considering the technicality involved in the two procedures, the result needs to be interpreted cautiously as these trials demonstrated a large clinical heterogeneity and the finding was not consistent between the largest two of the four trials. In addition, the trial that reported the highest rate of total pregnancy loss in the transcervical CVS group (19.5%) also recorded a significant loss to follow up (33.5%) (2).

1.4 Second trimester amniocentesis versus transabdominal CVS

Evidence on the comparative safety of transabdominal CVS and second trimester amniocentesis is provided by the subgroup analysis of one trial, which showed no significant difference in the total pregnancy loss between the two procedures (6.3% versus 7%). However, the risk of spontaneous miscarriage, which may be different between the two techniques, was not separately reported in this comparison. With respect to external validity of this finding, it is important to note that majority (71%) of the procedures in this trial were performed by a single experienced operator. The possibility of the risks of both procedures disappearing in the hands of a skilled operator has to be borne in mind and the result may need to be validated by a similar outcome from trials involving many operators with different levels of experience and expertise.

1.5 Transcervical versus transabdominal CVS

The comparison of transcervical and transabdominal CVS does not show statistically significant differences in the rates of total pregnancy loss and spontaneous miscarriage. However, transcervical CVS appears to be technically more demanding as indicated by the increased risks of multiple insertions (11.2% versus 4.1%) and vaginal bleeding (10% versus 1.6%).

1.6 Diagnostic accuracy of procedures

Most of the trials were not well designed to assess adequately the diagnostic accuracy of invasive prenatal testing and therefore could not provide a satisfactory answer to the second question of the review. Although, available data suggests that second trimester amniocentesis is likely to be more accurate, the reality is that women presently can not weigh the benefits of undergoing any of the existing procedures against their risks of diagnostic imprecision.

The authors concluded that on safety grounds, second trimester amniocentesis is better than transcervical CVS and early amniocentesis and in situations where prenatal diagnosis in the first trimester becomes essential, options to be considered should be transabdominal CVS and transcervical CVS, in that order of preference.

The criteria employed in the review for selection of eligible studies allowed relevant trials to be identified. However, the outcome measures included a wide range of variables and were not designated as primary and secondary outcomes. Fewer outcome variables that portray safety and diagnostic accuracy of the techniques would allow users of the review to weigh and appreciate their clinical significance. Nevertheless, infectious morbidity as an outcome measure that depicts safety should be considered for the benefits of review users in under-resourced settings.

The basis for the use of total pregnancy loss (which included all terminations of pregnancy) to illustrate safety in the comparison of invasive prenatal tests is not clear since the aim of these interventions is to identify genetically abnormal fetuses for subsequent pregnancy termination. Though it can be argued that pregnancy terminations would balance out in a properly randomized trial of two interventions, it is unlikely that such balance would be achieved when an invasive technique is compared with no intervention (e.g. second trimester amniocentesis versus control). Trials that reported only total pregnancy losses without specifying the number of spontaneous miscarriages may not have conclusively provided evidence on the comparative safety of the interventions.

Most of the included studies in the review are of high methodological quality as indicated by the proportion of the trials with adequate allocation concealment (12/14). Appropriate statistical methods were used to summarize the findings and the data were clearly presented under different subheadings for easy understanding. As part of the conclusion, the authors noted the significance of users’ satisfaction in translating research evidence into clinical practice by recommending assessment of women’s views about alternative procedures in future research.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

The burden of genetic disorders is heavy in all parts of the world but the impact is most felt in under-resourced settings owing to lack of preventive measures and specialized health and social services to care for affected individuals. As a result of the high birth rate, consanguinity and procreation till later reproductive years, a large number of infants with genetic disorders are born every year to families in underserved populations. In India for instance, approximately half a million children are born annually with congenital malformations, most of which are related to genetic or chromosomal aberration (3). It is estimated that about 9000 babies with thalassaemia major, 5200 babies with sickle cell disease and 21 000 babies with Down syndrome are born in India each year (3). Since there is no cure or effective treatment, such high frequencies have significant implications on national resources amidst competing health and social needs of the population.

Of increasing pubic health importance in many developing countries are single-gene disorders, which have characteristic geographic and racial preponderance. Common examples are sickle cell anaemia in individuals of African descent, β-thalassaemia in those from the Mediterranean, α-thalassaemia in South-east Asians and Tay Sachs disease in Ashkenazi Jews. Of all these disorders, only sickle cell anaemia has an incidence greater than 1 per 1000 in any ethnic group. The high frequency of the carrier status of the disease among the African populations, particularly those from West African countries, has ensured the persistence of the sickle cell gene. For instance in Nigeria, where the prevalence of carriers of the gene is approximately 25% (4), about 1–2% of children are born with sickle cell anaemia. The economic implications of providing care for affected children coupled with the generally unfavourable outcome have resulted in a rising demand for prenatal diagnosis of sickle cell anaemia in Nigeria in recent time.

2.2. Applicability of the results

The findings from the review have significant implications on the practice of obstetric specialists involved in prenatal testing in the developing countries. This is corroborated by several observational studies that attempt to provide local information on the safety of chorionic villus sampling in some developing settings like Nigeria (5, 6). It should be noted, however, that all the included trials that generated the evidence of this review were conducted in developed countries. Since the indication and scope for prenatal genetic testing, as well as infrastructural and technical capabilities may considerably differ between the developed and developing settings, the results need to be treated with caution. The operators in all the trials included in the review were generally experienced and must have done at least 20 procedures before participating in the trial. The level of experience and expertise of operators in under-resourced settings (most of whom are still on their `learning curve`) may not produce similar results in such settings. Likewise, the interventions in the included trials were conducted in conditions and circumstances that may not be readily available in many under-resourced populations. A study in Nigeria highlights the difficulty associated with inadequate provision of basic infrastructural facilities such as power supply in the provision of high-quality prenatal diagnostic services (5).

Another important aspect to consider is the baseline risks of the participants in the reviewed studies and that of the potential clients in under-resourced populations. Some of the large trials that influenced the results of the review randomized women with low risk of genetic disorders. As most women presenting for invasive prenatal testing in developing-country settings are more likely to be those at high risk of genetic disorders (as a result of prohibitive costs and other factors), it is uncertain whether similar or worse outcomes would be expected in these populations.

2.3. Implementation of the intervention

The effectiveness of this intervention depends on the availability of appropriate diagnostic tools and technical proficiency for invasive prenatal diagnosis. Besides the expertise required for the collection of sample, the procedure requires a highly technical laboratory support that may not be readily available in under-resourced settings. Presently, prenatal diagnosis in many developing countries is still in its infancy and services, where they exist, are still rudimentary (5). This may be connected with the poor awareness of the existence of such services within the population and the financial implications for individuals who need them. In Nigeria for instance, chorionic villus sampling costs between approximately US$ 620 and 775, which is beyond the reach of most couples at risk of having genetically abnormal offspring. Besides costs, religious, social, infrastructural, political and cultural barriers may also restrict the feasibility of incorporating invasive prenatal screening of all at-risk pregnant women into the existing healthcare services. As a result of these factors, routine screening of pregnant women aged 35 years and above as practiced in developed countries is unlikely to be a common practice in Nigeria and other similarly under-resourced countries for some time to come.

Nevertheless, as second trimester amniocentesis and transabdominal CVS are technically less demanding compared to early amniocentesis and transcervical CVS, translating the evidence from this Cochrane review into clinical practice among operators in developing countries should not be problematic. The generally late presentation of their obstetric population for antenatal care also makes second trimester amniocentesis a more feasible option for women who need them. Availability of non-invasive triple marker testing for detection of Down syndrome, however, is likely to restrict the uptake of invasive methods by women over the age of 35 years where both types of services are available.

Therefore, the implementation of this intervention has to be balanced against the specific needs of the population needing obstetric interventions, its feasibility and cost-effectiveness as well as views of the potential clients. Pregnant women who request invasive prenatal testing should be counselled appropriately on the various available approaches to make an informed choice. Clinicians and operators alike should not take advantage of the weak medico-legal systems in under-resourced settings to coerce women to accept techniques that contravene what is suggested by available evidence, but with which they are more familiar. In the present situation, the financial and emotional savings of detecting a specific genetic disorder must be able to justify the high cost of any invasive prenatal test employed. Mechanisms for quality assurance have to be put in place to maintain standards and deviation from evidence-based approach should be met with some form of sanction. Introduction of invasive prenatal testing services in settings where there are strong cultural, religious and political barriers to prenatal diagnosis needs to be gradual and should be preceded by education of the populace on the benefits and risks. Necessary measures must be taken to prevent the abuse of this technology in settings where they are readily accessible. For instance, the use of amniocentesis or CVS for fetal sex determination and selective abortion of female fetuses as practiced in some developing countries should be discouraged (7).

3. RESEARCH

Subsequent trials should address the issue of diagnostic accuracy of the methods as it has to be balanced with their safety concerns for women to make an informed choice. New trials should include centres from developing settings to improve their external validity and universal applicability. Outcome measures should include infectious morbidity to provide information for settings where postoperative infection is still a major problem. The cost-effectiveness of introducing the intervention in individual populations, amidst other pressing needs, could be researched to prepare grounds for a successful implementation.

Sources of support: UNDP/UNFPA/WHO/World Bank Special Programme for Research, Development and Research Training in Human Reproduction, Geneva, Switzerland, and Liverpool School of Tropical Medicine, International Health Division, Liverpool, United Kingdom.

Acknowledgement: This commentary was prepared during the Fellowship Programme organized by the Cochrane Infectious Diseases Group in collaboration with the UNDP/UNFPA/WHO/World Bank Special Programme for Research, Development and Research Training in Human Reproduction, Geneva, Switzerland, in August 2006. The United Kingdom Department for International Development (DFID) supports this Programme through the Effective Health Care Alliance Programme at the Liverpool School of Tropical Medicine for the benefit of developing countries. The views expressed are not necessarily those of DFID.

References

• Alfirevic Z, Sundberg K, Brigham S. Amniocentesis and chorionic villus sampling for prenatal diagnosis (Cochrane Review). The Cochrane Database of Systematic Reviews;Issue 3, 2003.
• Borrell A, Fortuny A, Lazaro A, Costa D, Seres A, Pappa S. First trimester transcervical chorionic villus sampling by biopsy forceps versus mid-trimester amniocentesis: a randomized controlled trial project. Prenat Diagn 1999;19:1138–1142.
• Verma IC. Burden of genetic disorders in India. Indian J Pediatr 2000;67(12):893-898.
• Akinyanju OO. A profile of sickle cell disease in Nigeria. Ann N Y Acad Sci 1989;565:126-136.
• Akinyanju OO, Disu RF, Akinde JA, Adewole TA, Otaigbe AI, Emuveyan EE. Initiation of prenatal diagnosis of sickle-cell disorders in Africa. Prenat Diagn 1999;19:299-304.
• Oloyede OA, Akinde J. Chorionic villus sampling through transabdominal needle aspiration. A preliminary report. Trop J Obstet Gynaecol 2005;22:38-39.
• Jha P, Kumar R, Vasa P, Dhingra N, Thiruchelvam D, Moineddin R. Low female-to-male sex ratio of children born in India: national survey of 1.1 million households. Lancet 2006;367:211-218.

This document should be cited as: Oladapo OT. Amniocentesis and chorionic villus sampling for prenatal diagnosis: RHL commentary (last revised: 15 December 2006). The WHO Reproductive Health Library; Geneva: World Health Organization.