Confirmation of Morbihan Cluster of Cases in French Birth Defects Investigation

Aude Lecrubier

July 22, 2019

France - New evidence has been reported in the 'babies without arms' investigation in three regions in France.

After re-examination of all the files, a committee of independent scientific experts (comité d'experts scientifiques or CES), set up by France's national health agency (Santé Publique France or SPF) and the agency for food, environmental and occupational health & safety (Agence nationale de sécurité sanitairede l’alimentation, de l’environnementet du travail or ANSES), came to the conclusion that there was indeed an excess of cases of transverse agenesis of the upper limb (ATMS in its French acronym), a rare type of congenital malformation of the arms, in the Morbihan department but not in the Ain department.

Cases located in the Loire-Atlantique department are still being investigated. The results should be published by the end of the year.

The report by CES was issued last week after it was presented to representatives of the families of the children involved.

Putting an End to the Controversy

Approximately 150 cases of ATMS are recorded in France every year, but several clustered cases of limb reduction anomalies were seen in three districts in France, Ain, Morbihan, and Loire-Atlantique, between 2007 and 2014. Investigations were later launched.

The first alert regarding these birth defect cases was given in 2010, relayed by the registry of malformations in Rhône-Alpes (Registre des Malformations en Rhône-Alpes or REMERA) to the authorities in 2011.

Following a lack of action from the health authorities, REMERA launched a new alert in 2018. Since then, experts have disagreed over the existence or not of a statistically significant case cluster in Ain.

For REMERA, this is a certainty: "There is no longer any doubt about the fact that between 2009 and 2014, abnormal concentrations of cases (which epidemiologists call 'clusters' or 'aggregates') of very rare malformations in otherwise healthy children have occurred in three regions of France", wrote the registry working group on its website in early April.

On the other hand, at the end of 2018, SPF estimated that in Ain, according to its statistical analysis based on a different method to the one used by the REMERA registry, there was no excess of cases "in comparison with the national average".

To clarify the situation, at the request of the ministers of health and agriculture, SPF and ANSES set up an independent multidisciplinary committee of scientific experts that carried out a new analysis using the same statistical method as REMERA, a method promulgated by Harvard professor Martin Kulldorff, an expert in disease surveillance methodology. This compares the number of cases observed in the region where an excess is suspected with the number of cases in the rest of the registry's territory. The CES experts called Prof Kulldorf to check with him that the statistical technique could be used on samples of only three cases.

Before the statistical analysis, the CES reviewed all medical records of children reported as having transverse agenesis of the upper limb recorded in Guidel in Morbihan and in the villages of Ain.

It also conducted 11 hearings with scientific experts and members of a steering and monitoring committee that included stakeholders, families with affected children, and concerned members of the public.

Confirmation of the Cluster in Morbihan

Eventually, the committee concluded that there was no cluster in Ain but there was a cluster in the municipality of Guidel in Morbihan.

The review of patient files, which was anonymised without any geographical links, made it possible to identify that some reported cases (notably in Ain) were not upper limb reduction.

Based on this review, the CES validated three cases of upper limb reduction in Brittany (Guidel) over a period of 18 months between 2011 and 2013 and confirmed the cluster suspicion for these cases. "Further investigations will therefore be carried out in this region to deepen the search for possible common exposures," SPF said in a statement.

For Ain, the CES confirmed six cases of upper limb reduction between 2011 and 2015 but, after statistical analysis, did not conclude that it was a cluster.

For Loire-Atlantique, which does not have a register of malformations, cases are being collated and examined.

"Basically, we find the same results as SPF, even if it's not exactly the same number of cases, and with a different technique," commented Professor Alexandra Benachi, head of the gynaecology-obstetrics department at the hospital Antoine Béclère in Clamart and President of the CES, stating that "the CES was able to work independently".

How can we explain the differences observed, with the same statistical method, between the REMERA register and the CES?

"Eventually, in Ain, half of the cases were not ATMS, according to the best specialists in the subject," said Professor Benachi, adding that "in Morbihan, it is a question of three cases over 18 months in the same village, whereas in Ain, with a broad estimate, there are 13 cases in 13 different villages  occurring between 2006 and 2015. However, a cluster is an association of temporality and geographical location which, for Ain, was not the case. In Loire-Atlantique, three cases are reported in the same village 22 months apart which, in contrast, might seem a lot like what is seen in Morbihan."

The SPF commented: "This analysis showed the importance, in the event of [early warning] signals, of a precise diagnosis of the nature of the congenital malformation. This diagnosis must be made by a medical geneticist within one of the reference centres for rare diseases that are approved [to assess] developmental abnormalities."

Confirmed Cases

Cases of upper limb reduction validated and considered by CES experts:

  • Ville de Guidel (Morbihan, 11,000 inhabitants): three births over 18 months between 2011 and 2013

  • Village of Mouzeil (Loire-Atlantique, 1800 inhabitants): three births over a 22-month period between 2007 and 2008

  • Villages in Ain: six births between 2011 and 2015

Additional Investigations Launched

Following the confirmation of a case cluster in Guidel, further investigations were announced to look for possible common environmental exposures in Morbihan.

At the same time, a thorough review of the literature was set up (21,000 scientific publications identified), which takes into account, in particular, citizens' hypotheses, in order to look for any currently unidentified risk factors for ATMS, particularly environmental ones.

"This is very exhaustive research. We are not at risk of missing a signal", commented Prof Benachi.

The results of the literature review will be subject to a second CES report which should be available before the end of 2020.

"If we find a given substance (a chemical, a pesticide or another toxic agent) that has been associated with the anomaly, we will first seek to discover if it is found in the cluster identified in Morbihan and if we discover a signal, we will look in all places where there are children afflicted by ATMS," said Prof Benachi.

It should be noted that given the current absence of known risk factors for ATMS, and because of the rarity of these malformations, a large-scale epidemiological survey would have required several decades of observations. Therefore the CES did not recommend it. On the other hand, the CES considers that knowledge of the causes of developmental anomalies, in particular environmental influences, is currently insufficient to recommend increased allocation of resources for research on this subject.

CES Recommendations: New Register, Better Follow-up 

Among recommendations from the CES following this work, the committee did not advocate creating a national register, but advocated a [local] register in an area with interesting characteristics for study and the strengthening of the quality, evaluation and cooperation of existing registers.

The CES also advocated reinforcing the reporting of malformations in the pre- and post-natal periods by health professionals, particularly sonographers, obstetricians and paediatricians, and recommended that multidisciplinary pre-natal diagnosis centres set up an alerting system covering the whole area to warn of suspicions of clustered groups.

The CES recommends the simultaneous creation of a national scientific committee for congenital malformations.

Finally, it stresses the need to improve the management, monitoring and support of families.

No Reports From Neighbouring Countries

Excess incidents of malformations in general or of ATMS in particular have not been observed in Europe or in France in recent years, the CES said in a news conference.

Also, at a European level, EUROCAT, a network of population-based registries for the epidemiological surveillance of congenital anomalies, told the CES that in the last 10 years, it had been alerted to 171 suspicions of malformation clusters (of any type), all of which had been overturned.

"Note that for EUROCAT, the threshold for defining a cluster is five cases, whereas in our French analysis we opted for a threshold of three cases to be sure we hadn’t missed anything," Prof Benachi told Medscape French Edition.

Isolated Transverse Agenesis of the Upper Limb (ATMS)

Isolated transverse agenesis of the upper limb is present in 1.7 births per 10,000 and represents about a quarter of limb reduction abnormalities.

An ATMS is an isolated anomaly of a single arm, with a transverse amputation appearance, most often in the upper third of the forearm and sometimes associated with the presence of hints of finger buds.

It may be difficult to diagnose because it may be confused with other abnormalities of a different nature and of known origins, genetic or mechanical, such as amniotic band syndrome, in which bands within the amniotic fluid may be responsible for the amputation of distal extremities.

For diagnosis, the opinion of a geneticist specialised in syndromology is needed to carry out family and environmental investigations and to rule out differential diagnoses. Research on possible teratogenic factors is also important, since limb malformations have been linked to the teratogenic effect of various molecules, the best example being that of thalidomide. However, in these cases, the malformations usually affect more than one limb.

Translated and adapted from Medscape French Edition .

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