Santé publique France reviews the key facts.

France has six registries of congenital malformations.

A registry is a system that conducts "a continuous and comprehensive collection of personal data pertaining to one or more health events within a geographically defined population, for research and public health purposes, by a team with the appropriate expertise1." They are therefore a valuable tool for Santé publique France’s health surveillance, monitoring, and alert missions.

The surveillance of congenital anomalies in France currently relies on six registries, covering approximately 20% of the French population. These are public institutions, primarily funded by health authorities (Santé publique France, the ANSM, and university hospitals) and research organizations (Inserm), although some may receive additional funding. Their funding, established under a contractual framework, is contingent upon compliance with specifications regarding data completeness and quality, as well as the related scientific work.

What is transverse agenesis of the upper limbs (ATMS)?

Transverse agenesis 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 registries, these malformations have an incidence in France of 1.7 cases per 10,000 births, or approximately 150 cases per year. They may be due to several known causes: chromosomal abnormalities, the teratogenic effect of certain medications such as thalidomide, or mechanical factors during pregnancy. There are likely other unknown causes, particularly those related to the environment.

Three clusters comprising 14 cases have been reported.

Reports from physicians to regional health agencies (ARS) and the registry system have identified three clusters of transverse agenesis of the upper limbs (TAUL) 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 cases were investigated. It should be noted that a cluster report is defined as the observation of a grouping of cases over time and within the same geographic area. All these reports were forwarded to Santé publique France. As with any cluster reported to the Agency, 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 definition.

• Next, an investigation was conducted along two lines:

1. An analysis of excess cases relative to the expected number, typically performed by epidemiologists and statisticians at Santé publique France;

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

Families were therefore interviewed and answered the same 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 was to determine whether there were one or more common exposures among the different cases. Environmental databases and, where applicable, veterinary services were also consulted.

All information from the excess case analyses and investigations was then compiled, and the results discussed in an investigation report for each cluster. Unfortunately, these investigations did not identify a common exposure that could be the cause of these severe malformations.

Regarding the Ain cluster, a debate arose over whether the number of cases exceeded the expected number. This concept, known as “statistical significance,” is merely one factor in the analysis of a cluster. In the present case of Ain, despite the debate over whether the observed number of cases exceeds the expected number, investigations were conducted to identify potential common causes among the 7 cases, including hypotheses regarding exposure to chemicals. These investigations did not identify a common exposure.

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, changing diets, 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 lead to memory lapses 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.

Santé publique France, a scientific agency dedicated to public health, has a duty to both the affected families and, more broadly, the population it protects, to provide all the information necessary to understand its scientific findings and to strive to propose new approaches for understanding and preventing potential impacts on human health from exposure, particularly to toxic products—pesticides or others.

Improving surveillance

The surveillance of congenital anomalies requires registries and the consolidation of their operations, with a focus on sound financial management and high scientific standards. To ensure its long-term viability, Santé publique France has announced the creation of a federation of congenital anomaly registries, with the aim of standardizing and consolidating data collection within a shared database. This federation will provide a strengthened and more consistent surveillance system, enable better investigation of signals, better support smaller organizations, and link them to larger-scale scientific research. The report that prompted this initiative is available here.

The Remera registry of the Hospices Civils de Lyon is long-standing. Because it failed to comply with its evaluation and the recommendations issued to it, certain funders suspended their contributions, making continued support contingent on compliance. Despite these deviations from the specifications, which led to its disqualification in 2011, Santé publique France has always maintained its funding for Remera due to the need, at the very least, to continue data collection.

Today, without waiting for new reports, we must strengthen our surveillance system by developing:

• a common registry database, by integrating registries in collaboration with research and linking them to the European surveillance system Eurocat;

• the analysis of information available in hospital databases covering the entire country;

In parallel with this consolidation, we must also develop mechanisms to monitor specific exposure to certain environmental risk factors that may serve as hypotheses to explain the onset of pathologies, including congenital malformations.

Better identifying environmental factors

The occurrence of these three clusters, for which investigations have not conclusively identified a common exposure, does not mean that environmental factors are not involved. Indeed, unlike epidemics, the investigation of clusters aims to confirm an excess of cases but very rarely allows for the identification of a common source. Other approaches involving much larger cohorts are necessary to identify common sources of exposure.

Santé publique France has included in its work program a population-level assessment of the risk of congenital malformations, based in particular on indicators of exposure to plant protection products.

For many years, the agency has developed systems to monitor the impact of plant protection products on human health:

• For example, Santé publique France has estimated the risk of developing Parkinson’s disease among residents living near crops who are exposed to plant protection products. In mid-October 2018, it published three studies highlighting chlordecone contamination in 90% of the population of the French West Indies, following the widespread use of this pesticide in French banana plantations until 1993, and establishing the link between this contamination and dietary and environmental exposures.

• For the specific population of pregnant women, Santé publique France has, for the first time, acquired exposure data representative of this population (Elfe study).

• Regarding exposure to and the impacts of plant protection products in agricultural areas, Santé publique France recently launched two nationwide epidemiological surveys. This work was proposed following an investigation into a cluster of pediatric cancers in a wine-growing town in Gironde.- A first study was launched with Inserm to better objectively assess the link between exposure to agricultural plots and pediatric cancers (Géocap-Agri study);- A second study, conducted jointly with ANSES and for which the protocol is currently being developed, will aim to better characterize environmental exposure and contamination among populations living near agricultural plots.

Santé publique France is a public agency dedicated to public health. It leverages its expertise, know-how, and resources to anticipate, understand, and address health risks. It is on the front lines for local investigations into the health impacts of contaminated sites and soils, or for responding to epidemics, threats, and exceptional health situations. The agency’s governance is based on two major principles: scientific excellence in its work, and openness and dialogue, which ensure transparency. It is organized around four councils: the Board of Directors, the Scientific Council, the Ethics and Professional Conduct Committee, and the Steering and Stakeholder Dialogue Committee. All ensure adherence to scientific rigor and professional ethics in all our work, in strict compliance with the missions entrusted to us and the populations we help protect.

¹ Decree of November 6, 1995, regarding the National Committee of Registries² Data from Santé publique France, based on data from the six French registries, 2011–2014