August 4th, 2020 – Since this post was originally published I have published in this area with one of our former trainees and current fellow in Toronto M. Durst. Her paper Atypical case of preterm ovarian hyperstimulation syndrome is available through the link in full text via open access!
Thus far in my career, I have been called to the bedside to look at a female ex-preterm infant several times due to the complaint of swelling that usually extends from the lower abdomen to the upper thighs. Usually the clitoris and hood are swollen as well and at times raises the suspicion of cliteromegaly. The enlarged clitoris then prompts the question of whether the patient could be virilized from Congenital Adrenal Hyperplasia or perhaps even be male in extreme cases. As I think back on some of these babies, nursing often has expressed concerns that the infants are uncomfortable and have either been treated with furosemide (unsuccessfully) or pain medication for the perceived discomfort.
As you might expect from the first paragraph I believe I have found the answer which came to me through a circuitous route. We had a patient in the hospital recently whose phallus was small for his gestational age. After consulting the Pediatric Endocrinologist on service we performed a hormonal workup which excluded hypogonadotropic hypogonadism (small phallus due to a lack of male hormones) and insensitivity to testosterone. Our Neonatal service was advised that this child would likely experience penile growth during “Mini Puberty” I don’t know about you but I had never heard of the term so I began a search that culminated in me writing this post to hopefully bring others up to speed.
Mini puberty is secondary to the normal rise in testosterone that occurs after delivery. In utero both estrogen and testosterone inhibit GNRH with estrogen from the placenta being the most potent inhibitor. Once the placenta is removed this inhibition is lost leading to LH and FSH levels rising which peak between the 4th to 10th week that finally begin to decline after 7 months of age. The level of testosterone similarly peaks by 3 months and reaches pre-pubertal levels by 6-9 months. During this time there is an increase in testicular volume and less so penile length but a patient such as ours might reach a normal length with such stimulation if the length was not extremely short before “Mini Puberty”.
In female infants it is somewhat different in that pre-pubertal levels of estradiol are reached by two months of age. Given the lack of stimulation from excessive levels of estradiol how can we tie this back to the question of genital swelling?
In 1985 Sedin G et al published a case series of 4 premature infants who demonstrated swelling of the lower abdomen, labia and upper thighs. In each case the etiology was found to be the same; estradiol producing ovarian cysts. In one case the cyst was removed and with it the edema resolved and in the other cases progesterone was utilized to suppress production of Gonadotropin Releasing Hormone (GNRH) and with it production of FSH and LH, thereby reducing the estradiol levels. Ultrasound in each case also revealed uterine enlargement consistent with over stimulation. What is it that causes this phenomenon is unknown for sure but it is certainly curious that the condition only seems to affect preterm infants born at < 29 weeks. Furthermore the timing of the edema is consistently at 36 – 39 weeks CGA. Sedin postulates that the reason for this is that the hypothalamic pituitary axis is immature in these preterm infants and does not provide the negative feedback to reduce LH and FSH compared to the term infant in which such sensitivity is present.
Additionally another theory is that vascular endothelial growth factor released from ovarian granulosa and thecal cells may be involved. Since the report by Sedin, Starzyk et al have reported an additional 9 patients with such edema and ovarian cysts http://www.ncbi.nlm.nih.gov/pubmed/19039238
I suspect that many Neonatal units across the World have encountered such patients and tried a collection of treatments including furosemide or other diuretics along with fluid restriction. Unfortunately there has not been widespread description of such patients and it is my hope that with this post, awareness will increase of both “Mini Puberty” and “Genital Edema in females”. What is really needed in the latter is consultation with Endocrinology to perform provocative Hypothalamic Pituitary Axis testing and an ultrasound to confirm the presence of uterine hypertrophy and cysts. Treatment with progesterone or some other inhibitor of the GNRH will likely bring about resolution in a timely fashion without exposing the infant to a multitude of testing. Lastly such infants are often described as appearing uncomfortable which may be related to the ovarian cysts or the swelling but in either case adequate analgesia should be provided.
This truly is a post that I hope is shared with others so that we can increase awareness as there are certain to be cases in units right now that might do well to understand this condition.
In the modern day NICU thermoregulation is something that we are concerned with but due to the availability of servo controlled warmers in delivery suites hypothermia is becoming a rarer event. Add to that we have access to polyurethane plastic wraps for our smallest infants and admission into servo controlled environments with additional humidity control and we have all the tools available to prevent hypothermia and it’s consequences. Such adverse effects include hypoglycemia and lethargy the latter being a common cause of septic work-ups leading to increased antibiotic usage. Such interventions are both painful and put the infant at risk of complications related to antibiotic use such as increased resistance, or altered microbiome with puts them at an increased risk of NEC. Just published online today in fact, researchers from the Canadian Neonatal Network have shown a U shaped relationship between admission temperature and outcome (morbidity and mortality including ROP, BPD and NEC etc) from being hypo or hyperthermic on admission. http://bit.ly/1H2384x. Clearly there is harm from being hypothermic so maintaining normothermia must be of prime importance in the care of our patients.
Sadly such technology does not exist everywhere and in developing nations the common alternatives may be non-servo controlled warmers, warmed blankets, cribs or Kangaroo Care (Skin to Skin). There is no question that Skin to Skin (STS) care provides excellent thermoregulation and bonding for the parent and child but what do you do when the mother or father is unavailable (ill after delivery) or unwilling? The benefits of STS to prevent hypothermia and infant mortality are striking and were first described in 1978 by Drs Rey and Martinez. A brief history of the practice following their description can be found here http://bit.ly/1CgDm9t.
This month Bhat SR et al published the following article (http://1.usa.gov/1HRRZoo) Keeping babies warm: a non-inferiority trial of a conductive thermal mattress. Arch Dis Child Fetal Neonatal Ed. 2015 Mar 19
This study compared the above mentioned modes of warming infants with a warming mattress over a four hour period in a non-inferiority trial of temperature regulation. The concept here is that the authors were simply trying to show that the use of the mattress as a thermoregulation device was just as good as the other means of controlling temperature. For a video demonstrating this technology please look at http://embraceglobal.org/. Briefly the system involved a containment device that has a paraffin based material that when preheated with an inexpensive electric heater absorbs the heat and then when placed in a pouch provides constant temperature regulation for a 4-6 hour period. The pouch was subsequently placed in a mattress with wrap as shown in the video to yield the desired temperature regulation. The authors of this study looked at a total of 160 infants with a birthweight between 1500 – 2499g in four centres located in India and observed infant temperatures hourly over a four hour period. Temperatures were compared in each case between those randomized to the standard temperature regulation strategies in each centre versus the warming mattress. The findings were in agreement with the hypothesis of the study in that the mattress was equivalent to the other methods of regulating temperature.
Specifically the temperature of the infants during the 4 hour trial period was 0.11 +/1 0.03 degrees higher than the other methods. None of the infants developed hypothermia during the trial and while 5 of the infants randomized to the mattress were withdrawn from the study it was due to the temperature of the infants being in the upper range of an acceptable level between 37.5 – 37.9 degrees.
My first reaction when I read this paper was that it was interesting but did it really apply to our population? As the authors suggest it was not a blinded intervention and over time, temperature regulation improved so could the Hawthorne effect be at play? The infants in this study were larger (1500 – 2499g) than the infants that we would typically put at highest risk. Also how useful is an intervention that only lasts 4-6 hours when we need to care for these kids for weeks? Lastly, I live in North America and work in an intensive care unit with access to state of the art equipment for thermoregulation and also have a team that proudly promotes STS care so is this really needed? Despite all of these concerns the conclusion I have come to is that the technology provides reasonable thermoregulation for a 4-6 hour period. Can this be applied to our patients in the end? I think there may be a role.
I would see the role being in managing newly born infants in remote communities prior to the arrival of a Neonatal Transport Team. In our own centre about 75% of our patients or about 230 patients are transferred from outside of the city borders. On occasion, a premature infant will be born in such places and hypothermia on arrival of the team is not an uncommon occurrence. In Manitoba and many parts of Canada there are communities that are quite isolated from tertiary care centres. These centres have limited equipment and even then it can often be quite outdated if functioning properly at all. Given that the average time to arrival for such infants is less than the 4-6 hours that the mattress provides warmth for, this would seem to be a very beneficial tool to have in such communities. It appears to be the ideal product as the website indicates the following
Special phase change material in WarmPak maintains a temperature of ~37 °C for at least 4 hours
Does not require a constant supply of electricity Portable for in-clinic or transport usage
Reusable and easy to sanitize and reuse
Enables mother-to-child bonding
As I write this I wonder how many other centres not just in Canada but also in the USA would benefit from looking into such technology. Providing servo controlled infant warmers for each centre that delivers infants is certainly the gold standard and in fact is recommended for all neonates undergoing resuscitation at 10 minutes of age. While ideal we need to acknowledge that some centres do not have such resources so this could very well serve a useful purpose particularly in the Northern US and Canada. According to the Embrace website the concept for this came out of a student project at Stanford University with the goal of designing an infant warmer with a cost of <1% of a traditional infant warmer (about $20000). If the cost is then $200 for the warmer for a completely reusable warming mattress I think they have hit the mark.
Finally, it must be pointed out again that the smallest infants treated in this way have been 1500g. We do not know if smaller infants would remain normothermic or become hypothermic if the same paraffin sized material was utilized. It will be interesting to see if Embrace releases a smaller unit for infants under 1500g. If proven to be successful in maintaining normothermia in this population I believe the use of this device will become widespread. Such a simple concept to treat a big problem in Neonatal Transport!
To quote Malcolm Gladwell, I think I witnessed a “Tipping Point” yesterday. The standard of practice for determining the presence or absence of pneumonia and pneumothorax has always been a chest radiograph. Determination of fluid collections by ultrasonography in the chest or abdomen, the domain of the Pediatric Radiologist.
Yesterday however, I was introduced to the use of bedside Point of Care Ultrasound (POC U/S) for the diagnosis of all of these aforementioned conditions. I spent the morning at a course on POC U/S for the Neonatologist and with that became comfortable much sooner than I expected with making such diagnoses based on some very straightforward criteria. Now before you think I am getting ahead of myself, I do not believe for a second that I am now competent to use U/S to replace radiographs as the “gold standard” in my practice. It has led me to consider though how one might go about reaching this level of confidence but I will share more on that later.
An example of how one can use ultrasound to exclude a pneumothorax is shown here https://www.youtube.com/watch?v=ws7DI4ZGQCo. The presence of bilateral “lung sliding” of the parietal and visceral pleura accompanied by “comet trails” excludes a pneumothorax. The absence of these findings is suggestive of a pneumothorax although other pathological findings can be present necessitating a chest x-ray. Think of how many times a patient develops a sudden increase in FiO2 and you do a chest x-ray to exclude a pneumothorax before increasing PEEP. This could change with acquisition of such technology.
The first question to really ask before taking the leap to replace or augment the classic chest radiograph is to look at the literature. With respect to the Neonate, the body of literature is not large but there are a couple of recent papers that are worth mentioning. The first is by Pereda MA et al. Lung Ultrasound for the Diagnosis of Pneumonia in Children: A Meta-analysis. (http://1.usa.gov/1CM24Sv) The review examined 9 studies of which 2 were in the neonatal population. The findings were intriguing. The sensitivity was 96% and specificity 93% when compared to the “Gold Standard” of either CXR or CXR with clinical diagnosis. To put this into context, there were 765 children who would have had thousands of x-rays during their hospital stay. This technology could reduce the number to ionizing radiation exposure by an extraordinary amount given the accuracy of the test compared to standard x-rays. The benefit of such reduction can be immediately appreciated when one considers that children are at an increased risk of malignancy compared to adults from ionizing radiation. Free supporting publication here.
The second paper to highlight is by Lovrenski J. Lung Ultrasonography of pulmonary complications in preterm infants with respiratory distress syndrome. Free supporting publication here
In this paper 120 patients with respiratory distress syndrome had U/S performed in the first 24 hours of life and then follow-up as indicated. Of this sample, 47 had complications including hemorrhage, pneumothorax, pneumonia, atelectasis and bronchopulmonary dysplasia. Of this group 45 were detected by ultrasound with the only two failures being small pneumothoraces. There were 512 ultrasounds performed compared to 612 clinically indicated chest x-rays during the same period. Again the potential reduction in ionizing radiation is astounding!
To be clear I am not suggesting that we do away with the chest x-ray but rather there is a great potential for reducing the need for the urgent chest x-ray when patient status changes. Depending on the situation in the unit you work in, an x-ray from the time it is ordered till the time it is performed and processed can be 15-30 minutes or more. The time it takes to perform a bedside ultrasound exam is 2-3 minutes at most making this modality at least in my mind a great first line option.
As I mentioned earlier though I am not an expert but merely an enthusiastic Neonatologist. This is not meant to replace the Pediatric Radiologist and in fact I would like to stress that I believe it is best suited to questions in which a binary yes/no answer is being asked. Does the patient have a pneumothorax, atelectasis, fluid in the abdomen or chest; all yes/no. Does the patient have a tumour in the liver and if so what type? That is a different kettle of fish and deserving of a Pediatric Radiologist’s opinion.
How do we go from “good to great” and utilize this technology accurately and safely. Clearly we are in need of practice, which can only come through training by qualified people who have demonstrated proficiency in the field. Thankfully in our situation we have access to individuals who have taught courses internationally and are willing to provide the training locally to us. Our strategy will include monthly U/S rounds supervised by these two experts who will provide a small group of us “superusers” with the training and ultimately confidence to put this into routine clinical practice. As confidence rises, the use of POC U/S to obtain vascular access will develop as will performance of such procedures as a bladder tap under direct visualization to improve our success rate. I suspect new uses will develop over time as we are at the forefront of this technology. There are courses offered abroad but like the paucity of Neonatal research in the area there are very few if any such programs for the Neonate specifically.
What I can say for sure is that the benefits of POC U/S are vast and I believe our patients will benefit both during their hospital stay and into adulthood due to the reduction in ionizing radiation that I see coming for these fragile infants. I for one am excited and energized by the future of this field and look forward to an expanding body of literature on the topic.
I came across an article from the BBC about a company in Israel that has developed a kit which can determine the presence of bacteria or virus in the blood of a patient within a two-hour window. More than that the kit has a point of care device as shown below.
Imagine for a moment the impact of being able to determine the presence or absence of sepsis within a two-hour window. Infants who have respiratory distress with a plan to assess in four-hours to determine need for antibiotics would never receive a dose. Other infants who were given one dose of ampicillin and gentamicin at birth would not need any further doses if the test indicated no bacteria or viruses present. Now you might say what is the harm in providing 48 hours of antibiotics or even 5 days if you are unsure of the presence of sepsis? There probably is little harm in a couple of days but the practice of prolonging antibiotics for fear that a patient has suspected sepsis is quite common in Neonatal circles. A recent article by Greenwood C et al (http://1.usa.gov/1Ex4qlH) examined stools at 1, 2 and 3 weeks of premature infants exposed to either short 1-4 day or longer 5-7 day courses of antibiotics. The results were quite striking in that the neonates exposed to the longer duration experienced less bacterial diversity than the other group and a preponderance of Enterobacter. Curiously levels of Lactobacillus and Bifidobacteria were low in all groups which might suggest a role for probiotics or explain why they might have been shown to reduce NEC. In fact in this study higher rates of NEC, sepsis and death were noted in the group receiving prolonged courses!
I have written other posts in which I have commented on Probiotics so to be clear I am not advocating that we use them routinely but one does have to wonder if it would be worthwhile repopulating the intestine of an infant who legitimately needed a 7 day course for a proven infection. Perhaps this post will stimulate someone to do that very study.
Aside from the perturbed microbiome leading to NEC, sepsis and death we also now have evidence of many long-term effects from antibiotics. The one creating the most alarm in press is no doubt the emergence of “superbugs” but more recently evidence has started to mount that repeated courses of antibiotics in infancy may lead to adult obesity (http://bit.ly/18JIIj7) and childhood allergy (http://bit.ly/1LwBmBc).
Getting back to this new technology it would still seem to be in the early stages. Looking through the company’s website they are allowing people to apply to be an early adopter. Additionally the links to their publications are really presentations at this time. A Pubmed search failed to come up with any specific articles regarding these products to I would have to say we are still in this products infancy. That being said it is certainly exciting to speculate about the impact that this innovation could have especially the point of care device pictured above which would bring the diagnosis to the bedside! I would encourage you to look at MeMeds website as it has a lot of very good information and if you check in from time to time who knows, you might be the first to hear that the two-hour test for sepsis is ready for use in your unit somewhere.
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.