I still haven’t found the best term for babies who are born so immature that their chances of survival are significantly reduced. Extremely Low Gestational Age Newborn, or ELGAN is a term which is not pretty but has the advantage of being accurate and not being associated with any value judgement, it is, however, now very strongly associated with Dr Alan Leviton (and many others)’s cohort study, almost becoming a trade mark! “Threshold of viability”, (or infants born at the…) has the disadvantage of being a moving target and not being clear as to how viability is determined; as we will soon see, if you decide a baby in this gestational age range is not viable, they will die. “The periviable period” is, I think a reasonable term for the time between 20 and 24 weeks, but I really don’t like “periviable neonates” for the same reasons I just mentioned, and “infants born during the periviable period” is unwieldy. Maybe “profoundly immature” is a better term, no values involved, and clear to everyone what we are talking about…

Two very recent publications and their accompanying editorials are worth discussing. They have different methods and conclusions as you will see:

The first is a study from France, part of the EPIPAGE-2 study. Perlbarg J, et al. Delivery room management of extremely preterm infants: the EPIPAGE-2 study. Archives of disease in childhood Fetal and neonatal edition. 2016.

This study was a high quality prospective cohort study of very preterm deliveries in all but one of the administrative regions of France. To clarify, France is divided into 22 metropolitan regions (that is, mainland France) and 4 overseas regions (Guadeloupe, Martinique, La Réunion, et Guyane (French Guyana)), or at least it was, as the number of regions has been decreased recently, it seems. All but one of the metropolitan regions was included in EPIPAGE-2, and all of the overseas regions. The timing of inclusion overlapped but wasn’t exactly the same for each region, which is a shame; but given the enormous nature of this study we can forgive a few logistic problems.

The protocol publication (Ancel PY, Goffinet F. EPIPAGE 2: a preterm birth cohort in France in 2011. BMC pediatrics. 2014;14:97) notes the following :

The babies in the study were born between May and December 2011, in some regions the time periods of data collection were not exactly the same, but they all overlapped.

This particular publication is about what happened in the delivery room for babies who were thought to be between 22 and 26 weeks gestation. It includes just over 2000 births, and is a good description of French practices during that period.

One of the problems with large regional cohort studies like this is that they include very acute unexpected extremely preterm deliveries in small general medical centers, as well as controlled deliveries in tertiary teaching hospital centers. There are many layers of subtlety that are difficult to grasp from afar.

Nevertheless, there are a number of findings worthy of discussion. At 22 weeks gestation there were 421 deliveries, of which 52 were “terminations of pregnancy” we don’t know from the paper what the indications for the termination were; (some “terminations” are performed because of preterm labour, which is quite different to terminations performed because of life-threatening malformations, for example). Of the remaining pregnancies, most led to stillbirth (74%, of the original group, but 85% after excluding terminations of pregnancy) and, among the others, only one of the live born babies received active intervention with oxygen and intubation, that baby died, leading to a survival of zero.

Even stillbirth, however, is not necessarily a hard endpoint; what I mean is that an attitude of active management of profoundly immature delivery will dramatically increase the number of babies born alive, compared to those born without a heart rate. It is also the case that some babies who are classified as stillbirths may be apneic, and, as a decision for comfort care has already been made, no-one seeks a heart rate. They may thus be resuscitatable, but are classified as stillborn.

If we try and contrast these results to the Swedish national cohort (EXPRESS), that study excluded pregnancy terminations, and at 22 weeks gestation there were 142 deliveries with 91 still births or 64% were stillborn, of the 51 liveborn infants there were 23 admitted to the NICU with 6 surviving to discharge.

There are differences between the 2 cohorts at 23 weeks also, in the EXPRESS study there were 183 deliveries and 82 were stillbirths, or 45%; they also report the intrapartum deaths, that is those stillbirths for whom the baby was known to have had a heart rate prior to labour, which were 19, or 10%. There were 16 deaths in the delivery room, leaving 81 admitted to the NICU, with 53 survivors (or 65% of NICU admissions). The EXPRESS study does not give the proportion of babies who had a decision for comfort care before delivery, but almost all of those born at a level 3 hospital had a neonatologist present at birth, and most were intubated.

In the French cohort there were 361 deliveries at 23 weeks that were not terminations, 270 were stillbirths, or 75%. That leaves 89 who were born alive, most did not have active intervention in the delivery room, seven of the babies were admitted to the NICU and 1 survived.

At 24 weeks there are still major differences between the 2 cohorts, many more stillbirths, and delivery room deaths, and NICU deaths, in the French cohort than the Swedish.

At 25 weeks there are smaller differences in the delivery room, but NICU deaths remained higher, 65% survival of NICU admissions at 25 weeks in France compared to 82% in Sweden.

In the French study, they examined what factors were associated with the decision-making regarding withholding or withdrawing intensive care, in addition to gestational age, babies under 600g were more likely than larger babies to have care withheld or withdrawn, babies from IVF were less likely to have this, but there was no difference between boys and girls. We know that smaller babies at any gestational age have lower survival, so to take that into account in decision-making is reasonable, but IVF has no known effect on survival, and sex certainly does, effect at least as important as birth weight. Which points out that decision-making is driven by values and not just by data, even if national guidelines have, until recently, uniquely spoken about the risks of death or disability as the driving force for decision-making.

The authors of the article point out that survival rates to discharge are lower in France, than in Sweden, the USA, Japan or Australia, at 23 up to 26 weeks gestation. Part of which difference is associated with the relative rarity of active intensive care below 25 weeks, but intensive care was given to the majority of babies at 25 and 26 weeks, yet survival rates were still lower. The authors speculate that later withdrawal of intensive care may be more frequent, given how frequent it is before NICU admission in the profoundly immature, and also that places who give intensive care to the most profoundly immature babies have lower mortality for more mature infants. That second explanation is supported by results from the NICHD NRN (Smith PB, et al. Approach to infants born at 22 to 24 weeks’ gestation: relationship to outcomes of more-mature infants. Pediatrics. 2012;129(6):e1508-16), and I think it likely that both are important.

The accompanying editorial Janvier A, Lantos J. Delivery room practices for extremely preterm infants: the harms of the gestational age label. Archives of disease in childhood Fetal and neonatal edition. 2016;101(5):F375-6. points out the same issues and wonders if there is any other place in modern medicine where interventions are universally denied in one high-income country, and almost universally applied in another.

I have asked the same thing about these differences, which also occur even within the USA. Is there any other condition in modern medicine, where one university center has 0% rates of intervention, and another, even in the same network, has 100%? And yet all of us claim to be practicing shared decision-making! I think the share is clearly not equally divided.

The second article is a regional study using administrative databases from New South Wales, Australia. (Haines M, et al. Population-based study shows that resuscitating apparently stillborn extremely preterm babies is associated with poor outcomes. Acta Paediatrica. 2016. Which is the kind of title that makes me sarcastically say “what a surprise!”) Between 1998 and 2011 they examined the outcomes of over 2000 babies of 22 to 27 weeks and 6 days who were born with a 1 minute Apgar of 0.  As far as I can tell, and this still isn’t quite clear to me after re-reading, the babies were classified as stillborn or live-born by the local personnel at the time who filled in the official  documents. The abstract states “We classified 2173 infants….. as stillborn” but I don’t see any methods for the authors to have done that. Of the infants classified as stillborn there were 40 who had an attempt at resuscitation, none were admitted to NICU, one surviving 51 days, but none surviving to discharge. I thought at first when I saw that all the stillborn resuscitated babies had died, that a baby who never responded during resuscitation and never had a heart rate might be considered to be stillborn, I think it’s weird that a baby who lives for 51 days would be called stillborn! I guess when you look at over 2000 records you are bound to find weird things, some of which might just be errors.

We also don’t know from these data which babies had a fetal heart rate detected in the hospital before delivery, and how many of the non-resuscitation babies were already known to have deceased in utero.

Of the 89 infants who were classified as live-born 48 had a resuscitation attempt, 13 were stabilized enough for NICU admission and 11 were discharged alive. The survivors ranged from 23 to 27 weeks gestation.

None of the infants in this study who still had an APGAR recorded as 0 at 5 minutes of age survived.

The conclusion of the study states that even with resuscitation attempted, “almost all of the babies died”. I don’t agree that 11 survivors out of 88 resuscitation attempts is “almost all”. The comparison group, babies with 1 minute Apgar 0 and no resuscitation attempt, had zero survivors.

The data on the lack of response when the babies were still pulseless at 5 minutes is useful I think, it is consistent with a somewhat different data set that we published a few years ago (Janvier A, Barrington KJ. The ethics of neonatal resuscitation at the margins of viability: informed consent and outcomes. The Journal of pediatrics. 2005;147(5):579-85) where we showed that if the babies at 23 weeks needed extensive resuscitation, and still were bradycardic by 3 minutes, they usually died, or may have survived but with major short-term complications. Extending this out to being pulseless at 5 minutes might give us enough certainty for these extremely preterm babies that they aren’t going to make it, and potentially stop resuscitative efforts.

La Gamma EF, et al. Resuscitation of potentially stillborn periviable neonates: who lives, who dies and who gets missed? Acta Paediatr. 2016;105(11):1252-4. The editorial accompanying the Australian study puts the results of the study differently; they state the following : “active resuscitation of ELGANs with a zero Apgar… increases survival”. They suggest that active intervention and a trial of therapy is the preferred approach for babies such as these, but that such an approach should be accompanied by an understanding by the neonatal team (which I hope includes the parents) and when futility is achieved. I think “futility” is not the best term to use here, it is indefinable and slippery. I would prefer that we just talk about frequent re-evaluations of the status of the baby, with an honest re-consideration of the goals of care. Trying to pre-establish limits of interventions or of acceptable complications is helpful but difficult, and also tends to slip away.

My take on these 2 articles is that, as I have said many times before, making a decision and having strict intervention guidelines based on gestational age alone makes no sense. We usually do not know gestational age with accuracy, and even if we did, there is a huge range of potential outcomes at any gestational age, which overlap by much more than 2 weeks. Babies with a significant chance of survival, taking into account all of the prognostic information available, should be offered a trial of therapy, which should include extensive delivery room resuscitation if required. What “significant chance” means is different for different families, and a major part of the antenatal consultation should be involved with establishing a relationship of trust with the parents and exploring their values in order to define what that means for them.

I’d encourage everyone to read also a new “viewpoint article” from 2 members of our team,  Gaucher N, Payot A. Focusing on relationships, not information, respects autonomy during antenatal consultations. Acta Paediatr. 2016.  which discuss the relational aspects of the antenatal consultation, based on research that has been done in Québec, and elsewhere, over the last several years, including the latest publication that I discussed recently on this blog.