In three regions across the country, Santé publique France received reports of "clusters" of transverse agenesis of the upper limbs (TAUL)^¹—a specific type of congenital malformation—suggesting a possible common cause. These clusters were investigated with the support of congenital malformation registries.

On October 4, Santé publique France published the results of its investigations along with a report proposing the creation of a federation of registries to establish a national database. The publication of these studies sparked a debate covered by the media, focusing on the one hand on the factors likely to be responsible for these malformations, and on the other hand on one of the registries, managed by the Hospices Civils de Lyon, for which certain funding agencies had suspended their contributions.

Background

Reports from physicians to the regional health agencies (ARS) and the registry system have identified three clusters of transverse agenesis of the upper limbs (ATMS) in France over the past decade:

• 3 cases in Loire-Atlantique born between 2007 and 2008;

• 7 cases in Ain between 2009 and 2014;

• 4 cases in Morbihan involving children born between 2011 and 2013.

All these reports were forwarded to Santé publique France. Each report was reviewed and investigated according to a standardized protocol:

• first, a verification was conducted to determine whether the cases were identical and whether they met the same clinical criteria;

• then, an investigation was conducted along two lines:

  • an analysis of excess cases relative to the expected number, typically performed by epidemiologists and statisticians at Santé publique France,

  • an investigation into each reported case, conducted by interviewing families about their lifestyle habits, dietary intake, and living environment during pregnancy. This investigation is based primarily on a detailed questionnaire completed in person with the parents concerned.

Families were therefore interviewed and completed a questionnaire. This survey was conducted either in collaboration between the registry and Santé publique France epidemiologists (as in Morbihan), by Santé publique France in collaboration with clinicians in the absence of a registry (as in Loire-Atlantique), or by the partner registry (in Ain). The objective is to determine whether there is one or more common exposures among the different cases. Environmental databases and, where applicable, veterinary services were also consulted. All information derived from the excess-case analyses and investigations was then compiled, and the results discussed in an investigation report for each cluster.

Regarding these three reports, the investigations concluded that there was an excess of cases in Loire-Atlantique and Brittany, but not in Ain. In all three cases, surveys were conducted with the families. Unfortunately, these surveys have not yet identified a common exposure that could be the cause of these severe malformations.

The specific case of Ain

Regarding the cluster in Ain, a debate has arisen over whether or not the number of cases exceeds the expected number.

Regardless of this debate, investigations were conducted with each family to look for possible common causes among the 7 cases, including hypotheses of exposure to chemicals. These investigations did not identify a common exposure.

An 8th suspected case reported on October 29

Furthermore, on October 29, Santé publique France received an email notification from the "Remera" Registry regarding a child born in 2012 with a birth defect, concurrent with its release to the press.

This eighth case had not previously been recorded by the registry, even though it is supposed to maintain a comprehensive registry. This comprehensiveness must cover all cases in the Ain department, regardless of whether the births occurred in that department or not.

A total of 11 additional suspected cases

As Santé publique France had committed to doing, additional analyses were initiated based on hospital data (PMSI). This work is currently underway.

On October 30, Santé publique France announced that it had identified in the PMSI database, in the department of Ain:

• Between 2000 and 2008: 7 suspected cases (upper limb deformities, including ATMS);

• Between 2009 and 2014: 4 additional suspected cases, among which the case reported by Remera appears to be included. These 4 cases are in addition to the 7 cases identified and reported by the Registry.

In the Ain department, over the period from 2000 to 2014, Santé publique France has therefore identified 11 additional suspected cases in addition to the 7 cases reported by the Remera registry. It is first necessary to assess, among these 11 suspected cases of upper limb reduction, which ones actually correspond to transverse agenesis of the upper limbs; this is why investigations are still ongoing.

Limitations of case investigations

The difficulty in identifying a common exposure among a cluster of cases of the same disease stems from several factors, some of which include:

1. the small number of cases limits the power of analytical methods;

2. exposures throughout life are numerous and varied (lifestyle habits, variable diet, multiple environmental exposures, etc.). It is therefore difficult to trace them all retrospectively;

3. the long time lag (often several years) between the investigation and the periods of exposure under investigation can introduce memory bias and affect the quality of the information collected.

However, investigating clusters alone does not provide answers to the hypotheses that could shed light on their origin. This is why Santé publique France continues to improve surveillance and relies on advances in research.

Broader studies in environmental health, particularly regarding exposure to pesticides or toxic substances, are also being conducted to identify potential health risks.

Surveillance of congenital anomalies: a rigorous methodology

To monitor congenital anomalies, Santé publique France coordinates a network of six registries covering 19% of births in France and contributes to their funding.

The surveillance conducted by the registries enables the production of surveillance indicators, the study of their trends, and the investigation of reports of suspicious clusters.

In this context, the Agency, together with the French network of registries, pays particular attention to the occurrence of new cases in these regions and in the rest of France.

Toward a federation of congenital anomaly registries

Surveillance of congenital anomalies is therefore based on registries that need to be consolidated, with the imperative of sound financial management and high scientific standards.

At the October 4 conference, Santé publique France also published a report on improving the surveillance system, proposing the creation of a federation of congenital anomaly registries to standardize and consolidate data collection within a shared database. This federation will provide a stronger and more consistent surveillance system, enable better investigation of signals, better support smaller organizations, and link them to larger-scale scientific research.

For more information:

• Surveillance of Congenital Anomalies (press release of October 4, 2018)

• Congenital anomalies linked to drug and environmental exposures (report)

• Investigation of a report of forearm agenesis in a municipality in Morbihan (report)

• Investigation of a suspected spatio-temporal cluster of congenital malformations in the department of Ain (report)

• Investigation of a spatio-temporal cluster of congenital malformations in a municipality in Loire-Atlantique (report)

• Transverse agenesis of the upper limbs: Santé publique France reviews the key facts (news update from October 29, 2018)

• Transverse agenesis of the upper limbs: Santé publique France continues its investigations and has identified, at this stage, 11 additional suspected cases in the Ain department between 2000 and 2014 (news update of October 30, 2018)

• Congenital malformations and chromosomal abnormalities (report)

• Speech by François Bourdillon on November 6 in Guidel (public meeting)

• 10 Questions and Answers on ATMS

¹ Transverse agenesia of the upper limbs (ATMS) is the failure of a hand, forearm, or arm to form during embryonic development. These are rare malformations in France. According to records, these malformations have an incidence in France of 1.7 cases per 10,000 births, or approximately 150 cases per year. They can be caused by several known factors: chromosomal abnormalities, the teratogenic effects of certain medications such as thalidomide, or mechanical causes during pregnancy. There are likely other unknown causes, particularly those related to the environment.

² A cluster report refers to the observation of a concentration of cases over time and within the same geographic area.