The benefits of antenatal steroids before preterm birth have been clearly demonstrated in the literature and have been nicely summarized in a Cochrane Review. From this report the evidence is clear. Treatment with antenatal corticosteroids prior to preterm birth is associated with an overall reduction in neonatal death (relative risk (RR) 0.69, 95% confidence interval (CI) 0.58 to 0.81, 18 studies, 3956 infants), RDS (RR 0.66, 95% CI 0.59 to 0.73, 21 studies, 4038 infants), cerebroventricular haemorrhage (RR 0.54, 95% CI 0.43 to 0.69, 13 studies, 2872 infants), necrotising enterocolitis (RR 0.46, 95% CI 0.29 to 0.74, eight studies, 1675 infants), respiratory support, intensive care admissions (RR 0.80, 95% CI 0.65 to 0.99, two studies, 277 infants) and systemic infections in the first 48 hours of life (RR 0.56, 95% CI 0.38 to 0.85, five studies, 1319 infants).
While it is clear that corticosteroid administration prior to 37 weeks has great benefit, the question is whether these benefits might actually extend to 37 and 38 weeks. It has been known for some time that having an elective c-section before 39 weeks exposes the infant to an increased risk of pulmonary morbidity and NICU admission. In 2009 Tita At et al studied 24077 repeat elective c-sections at term finding that 36% were performed prior to 39 weeks. The findings conclusively demonstrated that delivery at 37 and 38 weeks increased the likelihood of a composite outcome of death or respiratory complications, treated hypoglycemia, newborn sepsis and admission to the NICU. Interestingly one can also see that after 40 weeks these complications rose again. Post term deliveries are not without their consequences either.
Broken down by outcome, it is also clear that each component has an increased risk at both 37 and 38 weeks compared to delivery at 39 or 40 weeks.
With such increased risk this practice has been discouraged by many obstetrical organizations including the American College of Obstetricians and Gynecologists.
Knowing that there is clear benefit to providing corticosteroids before 37 weeks, it was only a matter of time before someone would test the hypothesis that treatment of women having an elective c-section in would reduce the incidence of respiratory complications such as TTN and RDS. Surprisingly there is really only one relevant study on this subject performed by P. Stutchfield et al in 2005 entitled Antenatal Betamethasone and Incidence of Neonatal Respiratory Distress After Elective Caesarean Section: A Pragmatic Trial. The trial provided betamethasone as a single course of two doses 24 hours apart starting 48 hours before a planned c-section with 998 participants in total.
The primary outcome in this trial was admission to NICU with respiratory distress. While the study was unblinded, the results were impressive and shown in the figure to the right indicating that below 39 weeks there was a significant difference in likelihood of admission for respiratory distress if women were treated with betamethasone prior to elective delivery via c-section. In terms of effectiveness this translates to the need to treat 37 women at 37-38 weeks with betamethasone to prevent one admission for respiratory distress to NICU. Eighty percent of the newborns in the control group had TTN versus RDS so I would expect you would need to treat about 200 women to prevent one case of RDS at this gestational age. Is it worth it? I suspect if you told parents that you could prevent hospital admission of their newborn at all many would choose to do so. There is another side to this though that one must consider and that side is the impact on neurodevelopment.
Corticosteroids work by overcoming the maternal capacity to break down cortisol by a placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HDS-2). Furthermore the corticosteroids used (betamethasone and dexamethasone) are resistant to degradation by this enzyme. In the brain this enzyme exists as well and has increased activity such that levels of active cortisol in the brain are at a minimum. In animal models, high levels of glucocorticoids cause decreased brain differentiation with reduced neurogenesis. These processes are likely to be similar in humans given the presence of the same enzyme which has little effect in inactivating these synthetic medications.
Even with this knowledge, we as health care providers freely recommend antenatal steroids to women at risk of preterm birth for all the benefits outlined at the start of this post. Preterm infants are at significant risk of IVH, PVL, NEC, PDA and many other conditions which in and of themselves have been linked with adverse neurodevelopment. It is the avoidance of these outcomes which likely explains why corticosteroid administration with it’s known effect on the developing brain leads to improved neurodevelopmental outcome. The challenge here is that can we extrapolate this to the 38 and 39 week fetus? I would suggest that this is not the case as the risks of the conditions leading to neurodevelopmental impairment are magnitudes less. We are then exposing these fetuses to the potential harm or glucocorticoids without the benefit of reducing the conditions that matter to outcome. On the other side of the scale is a reduction in TTN/RDS and admission to the NICU but is it worth treating 37 mothers to avoid this with the heavy weight on the other side?
If you believe I am making some unfair assumptions it is worth seeing what happened to the patients in the 2005 study by Stuchfield when they were followed up between 8 – 15 years of age. The study used a questionnaire to address a number of outcomes related to education, atopy and behaviour. The response rate for the study was only 51% of the original cohort so any conclusions must be taken with a grain of salt. That being said the authors state that there were no differences in outcome or difference in rates of asthma and atopy. In their conclusion they affirm that based on the lack of differences in long-term outcomes but with improved short-term respiratory status at birth steroids should be provided before elective c-sections. Curiously though the authors do not address an interesting finding shown in table 2 from the article.
Looking at the bottom section pertaining to the school’s assessment of a child’s academic ability, less children in the steroid group performed at the top quarter of the class and twice as many children were in the lower quarter of the class. To me at least it seems disingenuous to claim no differences were seen when clearly here is a difference based on a third-party (the teacher) that is significant. The academic purists will be quick to point out that this is a secondary analysis and not the primary outcome specifically of the study and that the numbers are small. Additionally one can also argue that at a 51% response rate we are missing a great deal of outcomes. Furthermore it may well be that when it comes to surveys, those who have concerns about their participation in the study may be more apt to complete it skewing the results.
I will allow all these arguments as it really helps to support my conclusion on all of this. There is very little data out there on the benefit of providing antenatal steroids at term before elective c-section. The data out there for long-term effects does show a concern regarding school performance and the exposure in this case is to medication which is known to have effects on the developing brain. That data though is suspect as well given the issues raised in the above paragraphGiven the number of women that need to be treated to avoid one admission for respiratory distress and with the above mentioned concerns I believe more studies are needed to determine whether this is worth instituting as standard practice. Finally, any future studies will need to address in a prospective manner using a large number of patients whether there is indeed any impact on development in the long-term from such practice.
A couple months ago on my Facebook Page (www.facebook.com/AllThingsNeonatal) I posted the shocking story of a 65 Grandmother Annegret Raunigk who received IVF and was carrying quadruplets. The post spawned outrage among my followers with statements that it was simply wrong while others argued that the risks of the mother giving birth to premature infants who would need extensive support was extremely high and that it was unethical to have done so. From my standpoint I agreed with the comments and so here you have it; the mother (or grandmother) has given birth.
She has delivered four premature infants < 26 weeks gestational age. Assuming they are 25 weeks each the outcomes for these babies may not be as dire as one might think. We would expect for singletons about a 70 – 80% survival with about 50% surviving without moderate or severe impairment. With quadruplets I would expect lower numbers so the reality is that at least two of these kids will have significant health care needs in the future. I would ask that we leave aside the arguments that may ensue at this point by bioethical purists who may argue that the babies’ perception of their quality of life in adolescence would be better that ours. The reality is that even if this were so, this single mother has now given birth to 17 children of which her last four are extremely low birth weight.
Who will be there to care for these children? What about the impact on society? in the next ten years will she have the energy to provide the stimulation, take the kids to all their appointments and so forth that will be needed to ensure an optimal outcome for them from a developmental standpoint?!
This is wrong on so many levels and it is not enough to say as they mention in the article that doctors encouraged her to undergo fetal reduction by one or two fetuses at an early stage. That excuses the IVF treatment in the first place by ignoring the fact that the opportunity to do something about this was missed at the first doctor’s appointment when she asked for the IVF treatment.
Nadya Suleman the “Octomom” give birth to eight premature infants and became known the world over in a sensational news story that followed her through her pregnancy and birth. It is another example of the medical community embarking on a path that lacks responsibility and ignores one of the founding principals of our Hippocratic Oath “To do no harm”. Nadya’s physician in her case suffered one of the most appropriate punishments that California could dole out. He lost his license (http://nydn.us/1d5rSxc), she went on to file bankruptcy, spoke out against the kids she wanted so much and finally resorted to pornography to pay the bills (http://huff.to/1AE5HsR). I can only wonder if the mainstream media’s obsession with Nadya’s story sparked desires for copycat sensational pregnancy stories elsewhere. Annegret Raunigk will not doubt receive a tremendous amount of attention as she already has so is there another agenda over and above to have children that is at work here?
As a medical practitioner it is generally ill advised by the local Colleges to speak out publicly against another physician but in this case this doctor who chose to implant embryos into the 65 year old mother should suffer the same fate and lose his license before he does such a thing again. He lacked judgement and any sensibility in creating a situation that would almost certainly lead to four extremely premature infants being born. I hope the German medical community acts to remove such a physician (I use the term lightly) before he can cause any further damage.
Its hard not to hear about probiotics these days. They are in our grocery stores as supplements to yoghurt and other foods and can be purchased in health food stores or at your local pharmacy. They appear to be everywhere as word spreads about the importance of your microbiome in maintaining good overall health.
It didn’t take long for clinician scientists to turn their attention to the neonate who is at risk of necrotizing enterocolits (NEC). It has been known for some time that formula feeding versus breast milk plays a role in the development of NEC as premature infants fed formula repeatedly were found across studies to have a higher incidence of NEC. The evidence is so strong in fact that the Cochrane review on the subject states “Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence strongly supports a change in practice.“ If you have read such reviews you know that they rarely come out this strong in their support of something! Furthermore, infants fed formula may have a different preponderance of more pathogenic bacteria in the colon and less lactobacillus and bifidobacterium species. The idea behind providing probiotics to neonates would therefore be to repopulate the intestine of these vulnerable infants with good bacteria and potentially reduce the incidence of a devastating condition like NEC.
If only it were that easy though
The issue of using Probiotics in preterm infants is a contentious one to say the least. While the evidence appears to indicate an overall benefit in terms of reducing rates of NEC there remain concerns regarding the safety of providing bacteria to this population even though the bacteria are thought to be beneficial. The people who urge caution in the use of probiotics say so due to a few reports of sepsis after the introduction of probiotics with the organism that the patient was provided or with a different species that was could be traced to a contaminated product. As noted in an article on CBC recently these products fall under the category of a nutritional product rather than a medication with Health Canada and therefore are not subject to the same rigorous quality control standards as other comparable medications would be.
Others while recognizing the potential for contamination and sepsis would argue that the risk is low compared to the benefit provided to the infants overall and therefore claim benefits outweigh risks.
Manipulating Breastmilk in a Double Bling RCT
Given the above concerns regarding administration of these products to neonates I was excited to see the randomized double blinded study by Benor S et al; Probiotic supplementation in mothers of very low birth weight infants. This study enrolled mother and infant pairs within 72 hours after birth to commence on maternal treatment with Lactobacillus acidodphilus and Bifidobatera lactis versus placebo until discharge. The rationale for giving probiotics to lactating mothers was based on a previous study showing less atopic dermatitis in the offspring of mothers who took such treatment while breastfeeding and in a study of breast milk demonstrating lower levels of the inflammatory cytokine transforming growth factor beta (TNF-B). Less inflammation might equate to less NEC.
The primary outcome was Bell Stage II NEC and the investigators required 90 mothers in each arm to show a difference in the incidence of NEC based on previous work in their centre. All included pairs needed to be providing >50% EBM in order to minimize any effect from formula. The overall incidence of NEC at the completion of the study was 27% in the placebo group vs 12% probiotic group and for NEC II 18% vs 4% in those treated with probiotics. The rates of NEC were quite high compared to what we typically see and the authors noted that even for their site (for uncertain reasons) there was a higher rate than they expected. Neither of the rates of NEC were statistically different (both reached p=0.15 levels) but there was a significant issue with this study.
The total recruitment was 25 in the probiotic and 33 in the control arm. This was a far cry from the estimated 90 needed per side. The reason for this goes back to the start of this blog entry. The study needed to be stopped due to poor enrolment. Why so low? The majority of mothers approached for this study did not want to risk not getting probiotics so they opted to simply take them due to the perceived health benefits that as adults they already believe exist. Sadly I think this problem would resurface in many places if the study was replicated. This loss of equipoise by the families will make obtaining consent for such studies very difficult and we may not get a satisfactory answer.
Interestingly the authors of this study also measured TNF-B and found a strong trend towards lower levels in the breast milk of the probiotic supplemented group matching the trend towards less NEC.
I sincerely hope that another study such as this can be done without such issues in recruitment as the strategy would address the issue of not providing the bacteria directly to the neonate while still potentially reaping the benefits of less NEC. For now we will have to wait and see.
The answer to this question seems to be quite elusive! In 2009 the American Society of Obstetricians and Gynecologists published a recommendation to avoid elective delivery of infants < 39 weeks gestational age.
Induction after 41 but before 42 weeks was advised, however due to the increased rates of complications after 42 weeks including mortality, asphyxia and complications of having a large infant to name a few. This was also supported by the Cochrane Review on the same topic that can be found here: http://1.usa.gov/1E2aq8a
The decision to avoid elective delivery prior to 39 weeks was secondary to many published reports demonstrating that such deliveries had a higher chance of having babies born with complications, the most likely of which was respiratory distress leading to increased rates of NICU admissions. That being said the incidence of asphyxia in the same group was lower than if one waited until a later gestational age.
Since that time, the recommendations have been to avoid these elective deliveries but a recent article has been receiving a lot of press that suggests we have it all wrong. Outcomes may be better if one delivers prior to 37 weeks.
In this study from Denmark (published Feb 18th in the British Journal of Obstetrics and Gynecology) an enormous sample of patients (832935) over a ten year period were studied to determine outcomes for each pregnancy when one compared elective delivery prior to 37 weeks with c-sections or planned vaginal birth. Despite an adoption in Denmark of the recommendations as outlined above from ACOG, the incidence of delivery prior to 37 weeks increased significantly. What makes this article so sensational is that during this time the number of NICU admissions decreased in this cohort delivered prior to 37 weeks vs the expectant vaginal births. Concurrently the risk of cerebral palsy decreased, large babies decreased and also less nerve injuries after birth but strangely with an increase in the incidence of shoulder dystocia. The original article abstract is found here: http://1.usa.gov/1MXaE2U
Before I go on I feel the need to state the obvious. As a man I have no idea what it is like to be pregnant although I do know that as women approach and then pass the 37 week mark of their pregnancy, many are enamoured with the idea of giving birth ASAP. I have no doubt there is an appeal to this research study explaining why so much press has been devoted to this paper. It suggests an action that many women I believe would be more than happy to accept but is it the right way to go?
The short answer is I don’t know for sure. The authors do a fairly good job of looking at variables that might have influenced outcomes such as maternal age, smoking rates, number of prior pregnancies etc but one has to question what variables may have influenced outcomes that were not measured? Looking at a massive number of patients gives a robustness to the results but it also means that you have collected a sample over a large period of time. Over a ten year period, practices can change, new technologies become implemented and new NICUs may be built all of which may account for an improvement in outcome over time. This is not to say that the authors are not on to something here but it does give one reason to pause and question how one study can have such a different result than many others that have come before it.
I think that the authors in this case took the right path and acknowledge at the end of the article that more work must be done in essence to confirm the findings. As a Neonatologist I am very interested to see if further work in the area will confirm these findings in a modern cohort.
If they do though will we have the capacity to deal with the increased number of admissions if it turns out they are wrong. Only time will tell.