Prenatal stress affects life expectancy in offspring


Extract from the birth certificate of a child given “orphan of the Nation” status (A) after being linked to the father’s military death certificate (B).

(A) Archives de Bordeaux / (B) Mémoire des Hommes.

Major prenatal stress reduces the lifespan of adult offspring by over 2 years. Inserm researchers have obtained these results by studying a cohort of children born between 1914 and 1916, some of whom lost their father in combat before they were even born. Stress suffered by the mother seems to weaken the fetus, at a developmental stage characterized by a high level of plasticity. These results were published in PNAS by a team from Inserm Unit 1169, “Gene Therapy, Genetics and Epigenetics in Neurology, Endocrinology, Cardiology, and Child Development”: Nicolas Todd, Pierre Bougnères, and Alain-Jacques Valleron.

Research has shown that early-life stress can have repercussions throughout an individual’s life. This is the case for example with exposure to famine during pregnancy, which increases the risk of cardiovascular, metabolic, and mental disorders in the offspring. However, the long-term consequences of such stress on mortality remain largely unknown. In an attempt to better understand this issue, Inserm researchers studied a cohort of children born in the period 1914-16, a group that has now passed away, and examined over 90,000 birth certificates. Following comparison with the French Ministry of Defense’s database of the 1.4 million soldiers killed in World War I, they identified 2,651 pupilles de la Nation (orphans of the Nation) whose fathers died in combat during this period.

Each war orphan was paired with a control child born at the same time, in the same commune, to a mother of comparable age, and their respective lifespans were compared. The lifespan of children whose father died after their birth was the same as that of their control counterparts. But the adult lifespans of children whose father died before their birth were shortened by 2.4 years, and by 4 years if this death took place in the final trimester of pregnancy. This historical study reveals for the first time that prenatal maternal stress weakens the fetus, at a stage of its development characterized by a high level of plasticity, and particularly of epigenetic plasticity.

The article describes the maternal, placental, and fetal mechanisms that may have contributed to the long-term impact of paternal death on prenatal orphans. These include, for example, variation in the level of cortisol, a steroid hormone that controls various stages of fetal development but which is also involved in the body’s response to stress in other periods of life.

Blood test developed to detect rare neurological disease

Groupe sanguin


Teams from the AP-HP Paris public hospitals network, in collaboration with researchers from the Brain & Spine Institute (ICM) (Inserm/CNRS/UPMC), and Metafora biosystems, a start-up with links to the CNRS, have recently developed a diagnostic blood test for a rare but treatable condition called De Vivo disease.

It was tested on 30 patients with the disease, which causes neurological deficits such as epilepsy and movement disorders.

Compared with current diagnostic tests that use an invasive procedure (lumbar puncture) or complex DNA analysis, this new test[1], the results of which have been published in Annals of Neurology, will be able to screen for the condition rapidly (within 48h) and with ease in both adults and children.

De Vivo disease or glucose transporter type 1 deficiency syndrome (GLUT1-DS) is most often characterized by developmental delay, epilepsy and/or movement disorders in children. Formes frustres[2] have been described in children (abnormal movement episodes) but also in adults. On the basis of an estimated prevalence of 1/83,000 in the Danish population, the number of those affected in the French population[3] is thought to be 800, a little over one hundred of whom will be diagnosed. Once diagnosed, metabolic therapies are available to alleviate the symptoms.

Dr Fanny Mochel from AP-HP Pitié-Salpêtrière University Hospital, along with teams from other hospitals of the AP-HP network (Bichat, Raymond-Poincaré and Robert-Debré) and the Brain & Spine Institute (Inserm/CNRS/UPMC), have developed a simple and rapid (within 48h) diagnostic blood test for De Vivo in collaboration with Metafora biosystems. Current diagnosis is restrictive because it involves an invasive procedure (lumbar puncture) and complex genetic analysis.

In this study, blood samples from 30 De Vivo patients, with profiles differing according to age and symptoms, were analyzed. Following comparison with samples from 346 healthy controls, the results show that the test is significantly conclusive in that it identified 78% of the De Vivo patients, including those for whom the genetic analysis was inconclusive.

Backed by these results, the researchers recommend the use of this new test in routine clinical practice in all neuropediatric and neurology departments. They suggest that its simplicity should enable more patients to be diagnosed in France.

Thanks to this innovative novel blood test, it will be possible to screen for the disease in all patients presenting with cognitive impairment, movement disorders, epilepsy or a combination of the three. The therapies at our disposal can considerably improve symptoms, including, for example, the control of epileptic seizures. However, since these are more effective when started early, timely diagnosis of the condition is crucial.


[1] Protected by patent CNRS WO2004/096841.

[2] When patients do not present all the characteristic symptoms of a disease or when such symptoms are mild

[3] [1] Larsen J, et al. The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia. 2015 Dec;56(12):e203-8.

We’re all a bit Neanderthal… or are we?


A study conducted by Inserm researchers at the Research Institute for Environmental and Occupational Health (Irset)[1] has shown that natural selection has “purged” our bodies of many of the traces of our ancient Neanderthal and Denisovan cousins in the genes responsible for the genetic mixing essential to reproduction. The researchers have shown that the genes expressed during meiosis in the cells that produce gametes (reproductive cells) are strongly deficient in genetic variations of Neanderthal origin that were the result of the interbreeding between Homo sapiens and Homo neanderthalensis. These results have been published in Molecular Biology and Evolution.

For decades, a question has preoccupied paleontologists regarding our now-extinct cousins, the Neanderthals and Denisovans:  what was the nature of the interactions between modern humans (Homo sapiens) and the other species of the Homo genus ?

Well, hundreds of thousands of years ago, a succession of human migrations from Africa to the other continents led to the coexistence in Eurasia of Homo sapiens with various other now-extinct species of the Homo genus. In 2014, the sequencing of a Neanderthal genome was made possible by the discovery of bone fragments containing DNA. With the very recent emergence of paleogenomics, it has been established that 1 to 3% of the genome of present-day Eurasians is inherited from the Neanderthals, whereas 3 to 6% of that of Oceanians is inherited from other ancestral cousins, the Denisovans. The women and men that populate our planet today are the result of many interbreeding events that have enabled human populations to expand thanks to the acquisition of characteristics favorable to climatic and environmental adaptations.

However, a surprising particularity recently came to light: the genetic variations inherited from interbreeding with these extinct species are not evenly distributed on the chromosomes. As such, Prof.  David Reich’s team demonstrated that these “archaic” genetic variations are present only to a very minor extent on the genes expressed specifically in the testis of modern humans.

Hence the key question studied by the researchers in Rennes: within the testis and ovary, to which specific functions are these genes, deficient in Neanderthal and Denisovan genetic variations, assigned ?

To answer that question, researchers from Inserm compared the genes present in the different cell types of the testis (germ line cells, Sertoli cells, Leydig cells, etc.).

The results obtained show that it is only those genes expressed specifically during meiosis, the process responsible for genetic mixing, that are highly deficient in ancestral alleles of Neanderthal and Denisovan origin. The conclusions were the same when the germ cells present in human fetal ovaries were studied. Since meiosis is a unique and fundamental process of spermatogenesis and oogenesis, natural selection has therefore “purged” our gene pool of the genetic variations that could have adversely affected its progression and thus prove harmful to the continuation of our species.

For the study’s coordinators Frédéric Chalmel and Bernard Jégou, this shows that “while interbreeding between modern humans and these extinct hominins has enabled us to acquire new adaptive traits important for our survival, it probably had a negative impact on the fertility of the initial hybrids. That is certainly why the genes involved in meiosis, a particularly sensitive biological process, have been purged of genetically archaic variations.  This is the first paleo-fertility study and it is likely to reveal evolutionary processes involved in certain present-day cases of infertility.”

[1]  Research Institute for Environmental and Occupational Health; Inserm; EHESP School of Public Health, Université de Rennes 1.

Cough syrup effective in stroke

cerveau avc apprentissage

© Fotolia

N-acetylcysteine (Mucomyst®, Exomuc®, Fluimucyl®) is commonly used as a treatment for clearing mucus from the airways, but researchers from Inserm Unit 1237, “Physiopathology and Imaging of Neurological Disorders” (Inserm/ UNICAEN), led by Denis Vivien, have shown that it is also capable of unblocking arteries obstructed by a blood clot. This study, coordinated by Maxime Gauberti and Sara Martinez de Lizarrondo, opens the way to a new treatment strategy in stroke. The work was published in May in Circulation.

Obstruction of an artery by a blood clot is the leading cause of death worldwide. Known as a thrombosis, it leads to ischemic strokes (deprivation of oxygen and other nutrients), myocardial infarction, and limb ischemia. When a thrombosis forms, it requires emergency care: the clot must be destroyed as quickly as possible in order to restore blood flow and prevent irreversible damage.

N-acetylcysteine (sold under the brand names Mucomyst®, Exomuc®, and Fluimucil®) is very widely used as a mucolytic drug: it helps thin out bronchial secretions, and assists with expectoration. Its mechanism of action is very simple: N-acetylcysteine breaks the molecular bonds between mucin proteins (the main component of mucus). In doing so, it breaks down the mucin macromolecules into smaller fragments, making the mucus more fluid and easier to expectorate.

Interestingly, the mucin in the pulmonary mucus is not the only protein in the human body that forms such molecular bonds. The same type of bonds can be found in blood vessels, resulting in the formation of thrombi. Rather than mucin, here it is Von Willebrand factor that is involved: the protein able to cause the accumulation of platelets and the formation of blood clots.

Researchers from Inserm Unit 1237 (in collaboration with researchers from Inserm Unit 1176 and the University of Pennsylvania) have now shown that intravenous injection of N-acetylcysteine enables the breakdown of blood clots and thus unblocks the arteries. In several ischemic stroke models, N-acetylcysteine was even more effective than currently available treatments.

According to the authors of the paper, “N-acetylcysteine is a low-cost treatment that is already used around the world as a cough medicine, and the demonstration of its thrombolytic effects could have very wide application in the management of stroke and myocardial infarction patients. We hope to build on this work and to have a clinical trial underway as soon as possible.”.

This work was supported by the Fondation pour la Recherche sur les AVC (the French Stroke Research Foundation).

Students at Increased Risk of Consuming Stimulants

studente medicina


With exam time looming, a certain number of students with intense workloads are succumbing to the use of stimulants to boost their intellectual capacities.

Classified as psychotropics, stimulants are medicinal doping agents that boost the brain’s function by increasing its capacity for alertness and performance.

A study by Inserm published in April 2016 showed that one third of the 1,700 medical students questioned were taking stimulants. Among them, 29.7% were consuming readily-available products (energy drinks, caffeine tablets), 6.7% prescribed stimulants, and 5.2% illicit drugs.

Used to enhance memory and concentration at exam time, the consumption of readily-available products such as caffeine tablets or energy drinks is a predictor of the use of medically-prescribed stimulants at a later date.

According to the French National Agency for Medicines and Health Products Safety (ANSM), the number of users of one such prescribed stimulant, methylphenidate (Ritalin), saw a 20% increase between 2008 and 2014. Prescribed to treat attention deficit hyperactivity disorder (ADHD) in children, this drug has proven extremely dangerous in patients with heart malformations or depression.

For Inserm researchers, this issue presents a new public health challenge.

Refractory cardiac arrest: an aggressive ECPR strategy significantly increases patient survival

© Fotolia

Multidisciplinary teams from the AP-HP Paris public hospitals network (SAMU75 emergency response dispatch centers and Hôpital européen Georges-Pompidou), as well as from Inserm, the Université Paris-Descartes, and the Paris BSPP medical emergency service, compared, in the French capital, two strategies of extracorporeal cardiopulmonary resuscitation (ECPR) used in patients suffering refractory cardiac arrest (defined as lack of return of spontaneous circulation after 30 minutes of resuscitation). The results of this study, which took place between November 2011 and December 2015 and involved 156 patients, were published on the website of the journal Resuscitation on April 14, 2017 and show that an aggressive strategy significantly increases patient survival following discharge from intensive care and with a favorable neurological prognosis.  It is the largest cohort to be studied in Europe and the United States.


Every year, approximately 50,000 adults in France die from cardiac arrest, which is fatal within minutes unless treated. At present, less than 5% of refractory cardiac arrest victims survive, hence the importance of an early and appropriate response.


In the Greater Paris region (Ile-de-France) at present, the emergency services dispatched by the SAMU75 hubs located within the AP-HP hospitals network use ECPR in the pre-hospital setting in patients with refractory cardiac arrest and potential for neurological recovery. These patients are selected according to a very precise algorithm in which, for example, they must have received chest compressions very soon after onset of the arrest and present signs of life (movement, breathing, etc.) – even in the absence of cardiac activity. If ECPR is indicated, it must be initiated within 60 minutes of onset of the cardiac arrest.


The role of ECPR, which is normally used in cardiac surgery, is to take over from the patient’s failing heart and lungs. A cannula is placed in the femoral vein through which the blood will pass into a machine that generates circulation and gas exchange to mimic heart and lung function, before being returned to the body via another cannula, this time in the femoral artery.


(Extracorporeal Cardiopulmonary Resuscitation (ECPR) in the Prehospital Setting: An Illustrative Case of ECPR Performed in the Louvre Museum.

Lamhaut L, Hutin A, Deutsch J, Raphalen JH, Jouffroy R, Orsini JP, Baud F, Carli P. Prehosp Emerg Care. 2017 May-Jun;21(3):386-389. doi: 10.1080/10903127.2016.1263372. Epub 2017 Jan 19. PMID: 28103127)



Teams from the AP-HP Paris public hospitals network (SAMU75 emergency response dispatch centers and Hôpital européen Georges-Pompidou), as well as from Inserm, the Université Paris-Descartes, and the Paris BSPP medical emergency service, conducted a single-center observational study involving 156 refractory cardiac arrest patients treated with ECPR by teams dispatched by SAMU75.


They compared two strategies that were used over two different periods:

> From November 2011 to December 2014, 114 patients received ECPR on arrival at hospital or directly at the site of the arrest, following 20 minutes of resuscitation by the emergency services.

> Throughout the year 2015, a team specialized in ECPR was deployed together with the initial response team for 42 cardiac arrests in patients under the age of 70 having already received chest compressions from bystanders immediately after onset. The ECPR was generally deployed before arrival at hospital. This pre-hospital ECPR was supplemented by other treatments, such as immediate coronary angiography.


This study shows that the second, more aggressive, ECPR strategy significantly increases survival following discharge from intensive care, with a favorable neurological prognosis. Without ECPR, these patients had virtually no hope of survival.


This study is supplemented by a European multicenter study which has been ongoing for several months.

Twin Pregnancies in France: is Vaginal Delivery Preferable After All?

Man Looking At Medical Team Operating Pregnant Woman


JUMODA, a prospective study sponsored by the Paris public hospitals (AP-HP) and conducted between 2014 and 2015 by teams of researchers and clinicians from Inserm, Université Paris Descartes and AP-HP, has shed new light on the mode of delivering twins.

According to the coordinators of JUMODA (“MOde D’Accouchement des JUmeaux”), Professors Thomas Schmitz and François Goffinet, vaginal delivery is associated with decreased neonatal morbidity and mortality rates for both twins. These results have been published in the June issue of Obstetrics & Gynecology.

While considerable progress has been made in recent years in perinatal healthcare, carrying and giving birth to twins are still high-risk situations. Indeed, sometimes serious complications can arise in both mother and children during pregnancy (hypertension, delayed growth, premature birth) and during the birth itself – especially that of the second twin (placental abruption, poor umbilical cord positioning, brutal uterine contractions during labor, etc.). Whereas the French neonatal mortality rate (death within 27 days of birth) is 2.3 per 1,000 live births for singletons (according to an Inserm study from 2013), it is 5 to 10 times higher for twins.

Until very recently, the practices of some French obstetricians were guided by the results of Anglo-Saxon retrospective studies that went against vaginal delivery in twin pregnancies, and particularly that of the second twin. In these studies, second twins enjoyed better neonatal health following Cesarean section than following vaginal delivery. Such data have contributed to the increased rate of Cesarean sections performed in France in this population over the past 20 years, and which in 2010 was 45%.

According to Prof. Schmitz, the methods of delivery, which differ considerably between France and Anglo-Saxon countries, may indeed be behind certain complications. It was therefore necessary to rigorously evaluate the obstetric practices involved in delivering twin pregnancies in France.

JUMODA, which stands for “Etude prospective comparative nationale sur le MODe D’Accouchement des femmes enceintes de JUmeaux” (national prospective and comparative study on the mode of delivery of twins), was initiated in 2014 by researchers from CRESS -Inserm/Université Paris Descartes/Paris public hospitals (AP-HP)- and coordinated by Professors Schmitz and Goffinet. Its objective was to measure the neonatal morbidity and mortality of twins, according to the planned mode of delivery (vaginal or Cesarean). To achieve this objective, the teams analyzed twin births in 176 French maternity units between February 2014 and March 2015. Approximately 8,800 women were enrolled, representing 75% of the total number of twin births in France during that period.

All in all, the study has shown that, in France, out of those women with twin pregnancies in the participating maternity units, 75% had an attempted vaginal delivery and 25% a planned Cesarean section. Most importantly, the attempted vaginal deliveries were associated with a low neonatal morbidity and mortality rate when the first baby was in the head-down position. For the first time, this rate of complications was even reported as being higher after a planned Cesarean section than after attempted vaginal delivery for children born at between 32 and 37 weeks.

While Cesarean section remains an essential emergency solution for certain complications arising during twin pregnancies, these recent results show that vaginal delivery is to be preferred in the large majority of cases. In addition to avoiding the surgical and psychological complications associated with Cesarean sections, vaginal delivery may also -thanks to the fetus coming into contact with the mother’s vaginal bacteria- trigger a number of protective immune mechanisms that are important for the child’s long-term health and development. “Our message to patients pregnant with twins is that twin pregnancy is not in itself an indication for delivery by Cesarean section. We think it is important to inform such patients of these results so that they can best discuss with their obstetrician how they will give birth.” concluded Prof. Schmitz.


This study was funded by the French national hospital clinical research program (PHRCN) in 2012.