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Trainees Articles

A reflection on clinical research, minimal risk and informed consent

Brian Carter, MD, FAAP

The conduct of pediatric - and specifically neonatal - research is a necessary matter for all trainees and practicing neonatologists to be familiar with. Research is necessary to understand new therapies and management strategies, and to better understand practices - and practice variations - that are already commonplace. The vulnerability of children, as research subjects who largely cannot voice true informed consent due to developmental and cognitive realities, long ago prompted restraint on such research. In cases of neonatal research, the ethical principles that are most often applied are autonomy [respect for persons, even their future potential as autonomous agents], non-maleficence [avoidance of harm...minimizing risk], and justice [allowing a just and equitable representation of at-risk children to be research subjects]. The first two articles cited, below, address the general concepts of research ethics in pediatrics and neonatology and the gradations of what might constitute "minimal risk". They serve as somewhat foundational reading.

A Reflection on Clinical Research, minimal risk and informed consent »
Research Consent by Parents »
Minimal Risk in Pediatric Research »
Neonatal & Pediatric Research Ethics »

Predicting NICU Outcomes for VLBW Infants:
The Old, the New and the Yet to be Determined

Brian Carter, MD, FAAP

By now we are all familiar with the NICHD-NRN paper published by Jon Tyson, et al in the New England Journal of Medicine in 2008 that provide the “NICHD Calculator” for estimating survivability and presence of neurodisability in children born before 27 weeks’ EGA. What this study was not able to do, was inform us of what perinatal factors might influence NICU outcomes for these children. Tyson JE, Parikh NA, Langer J, Green C, Higgins RD; National Institute of Child Health and Human Development Neonatal Research Network. Intensive care for extreme prematurity—moving beyond gestational age. N Engl J Med. 2008;358(16):1672–1681.

Perinatal Arterial Ischemic Stroke

Potential understanding may mean potential interventions and improved outcomes
Brian Carter, MD, FAAP

In an article from Pediatrics in 2011, the International Pediatric Stroke Study (30 centers in 10 countries) reported on the conditions of 248 neonates with Perinatal Arterial Ischemic Stroke (PAIS). The authors reported that knowing what causes PAIS, and how, would require large-scale case-control studies. Only then might outcomes be improved. In some cases, PAIS may simply manifest as feeding problems, though these problems are not necessarily predictive of cerebral palsy or language disorders (J Child Neurol 2010; 25:867-872). Given that PAIS is a major contributor to perinatal brain injury, cerebral palsy and lifelong disability, all neonatologists should be interested in learning more about, and conceivably preventing, this condition (Pediatrics 2011;128:e1402-e1410). Now, two large case-control studies are available, one from the Netherlands and one from France.

For his full review »
Risk factors for perinatal arterial ischaemic stroke in full-term infants: a case-control study »
Antenatal factors associated with perinatal arterial ischemic stroke »

Decision Making by Parents of Critically Ill Children

Brian Carter, MD, FAAP

This month, two articles have been selected that yield insights into how parents of critically ill children make decisions. While not solely specific to the world of neonatal-perinatal medicine, these two studies are revealing and remind us that parental decision-making is phenomenally complex and requires time, listening, a bidirectional exchange of a broad array of information, and sensitivity.

1. What Is Known about Parents' Treatment Decisions? A Narrative Review of Pediatric Decision Making in the journal Medical Decision Making

They conducted a narrative review of the current research literature and report on 55 papers from 52 distinct studies. They found that most studies were descriptive of the decision-making process and were qualitative. Actual decision outcomes were far less reported. And while parents’ preferences for their own degree of participation in pediatric decision making varied, most parents appear interested in sharing the decision with their health care professional – especially in the inpatient setting. Additionally, parents were reportedly influenced in their decision making by (a) changes in their child’s health status, (b) other community members (e.g., family or school community, others with disease-specific knowledge or experience), (c) prior knowledge of their child’s condition (e.g., longevity of illness or prior experience with another sibling), and (d) personal factors, such as emotions and faith. It is apparent that parents struggle to balance such influences. The authors encourage research to address decision outcomes, interventions to improve outcomes, and prospective trials to better understand how to support parents through difficult treatment decisions for their children.

2. Decision Making Identified by Parents of Children Receiving Pediatric Palliative Care in the American Journal of Bioethics-Primary Research

Their NIH (NINR) sponsored study examined factors that 73 parents of 50 pediatric patients perceived as influencing their decision-making process. All patients in this study were receiving palliative care (1/3 of the children were in the NICU or PICU; roughly ¼ were < 1 year of age). The types of decisions that weighed heavily on these parents’ minds included where to deliver their baby and whether or not to have the baby admitted to an NICU, whether or not to get a G-tube placed, whether or not to get to get a 2nd opinion., whether or not to allow life extension devices, a blood transfusion, or provide an end-of-life directive, among others. Four themes were apparent: - those addressing their orientation and direction of care (including goals and hopes) - those which facilitated the discernment of what constitutes “what is good” for the child (including quality of life and suffering) - those addressing the importance of relationship, communication and support (the social and interactive nature of decision-making), and - those that addressed their own feelings and sense of personal accountability (their inward attention to their emotions and self-judgments). These influences obviously extend beyond what many caregivers consider the crux of decision-making: information exchange and some attention to risks and benefits. Accordingly, the authors suggest parental decision-support mechanisms should address these diverse influences.

Another perspective on neonatal caffeine therapy

Brian Carter, Vanderbilt University

A recently published report in JAMA on the 5-year outcomes from the CAP (Caffeine for Apnea of Prematurity) study is an excellent read for trainees and neonatologists alike. These investigators had previously reported their early outcomes at 18 months, including that caffeine improved the rate of survival without neurodevelopmental disability (OR adjusted for center, 0.77; 95% CI, 0.64-0.93) by reducing the risks of both cerebral palsy and cognitive delay. Recipients of caffeine were treated a median of 37 days. The primary outcome determinants at 5 years are a little different from the earlier trial

1. Schmidt B, et al. Survival Without Disability to Age 5 Years After Neonatal Caffeine Therapy for Apnea of Prematurity
2. Maitre NL & Stark AR. Neuroprotection for premature infants?: another perspective on caffeine. »
3. Rivkees S & Wendler C. Adverse and protective influences of adenosine on the newborn/embryo: implications for preterm white matter injury and embryo protection. »

Neonatal HSV Infection: Diagnosis, Acute and Suppresive Treatment

Herpes simplex virus infection is associated with significant morbidity and mortality. It is not uncommon in the US, and incidence figures suggest that it is higher than in much of the developed world. Recent attention to surveillance may improve our understanding of this particular disease burden and help to develop educational, preventive, and treatment interventions to minimize the acute and long-term concerns associated with it. In a recent report from New York City, evidence is presented that reminds clinicians of obstetrical procedures that may negate the potential protective impact of operative cesarean section delivery (e.g., delivery >4 hours after rupture of membranes, artificial rupture of membranes, vacuum extraction, and use of indwelling instruments such as a fetal scalp electrode or intrauterine pressure catheters, or the use of forceps), and underscores the value of early recognition of the disease and implememtation of treatment. [Handel, et al. 2011].

The longterm concerns for newborns affected by systemic or central nervous sytem HSV infection are considerable, with 20 to 70% having neurological sequelae that include developmental delay, cognitive, communicative and motoric neurodisability, and seizures. ln a report from Kimberlin, et al. for the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group, the resuilts of a placebo controlled randomized trial that followed an initial 14-21 days of parenteral acyclovir [standard therapy] using 6 months of oral acyclovir versus placebo in those infants with CNS involvement demonstrated a statistically significant improvement in developmental assessment at age 1 year using the Mental Development Index (MDI) of the Bayley Scales of Infant & Toddler Development (3rd Ed.) Additionally, the 12-month Bayley MDI scores were incrementally higher as infants received acyclovir suppression for longer periods of time. While some attrition in the follow-up was noted, the end results indeed suggest benefit and the safety of this suppresive therapy is seemingly acceptable (some infants with neutropenia). Condidering that any CNS function lost due to the neurotropic nature and toxicity of HSV cannot be regained, the clinical benefit underscored in this trial is bound to impact future practice for all neonatal HSV infected patients.

1. Handel S, Klingler EJ, Washburn K, Blank S, Schillinger JA. Population-based surveillance for neonatal herpes in New York City, April 2006-September 2010. Sex Transm Dis. 2011 Aug;38(8):705-11. PMID: 21844721
2. Kimberlin DW, et al., for the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Oral Acyclovir Suppression and Neurodevelopment after Neonatal Herpes. N Engl J Med 2011;365:1284-92. »
3. Gershon AA. Neonatal Herpes Simplex Infection and the Three Musketeers. N Engl J Med 2011;365:1338-1339. »

Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia - and its attendant pulmonary hypoplasia and pulmonary hypertension - presents a formidable management challenge to neonatologists, surgeons, respiratory therapists and others NICU clinicians. The associated respiratory failure is known to be minimally responsive to surfactant (generally not used unless the patient is < 35 weeks' EGA) or inhaled nitric oxide (NO). But some evidence exists that eNOS is up-regulated in affected newborns [see Sood et al, below] and the plausibility of new strategies to enhance pulmonary parenchymal and vascular growth requires investigation. The 2nd and 3rd articles are offered as recent evidence for looking into potentially new approaches to improving outcomes for this condition.

Sood BG, et al. Expression of eNOS in the lungs of neonates with pulmonary hypertension. Exp Mol Pathol. 2011 Feb;90(1):9-12. (Epub 2010 Nov 24). »
Luong C, et al. Antenatal sildenafil treatment attenuates pulmonary hypertension in experimental congenital diaphragmatic hernia. CIRCULATION 2011;123(19):2120-31. »
de Buys Roessingh A, et al. Nitric oxide activity through quanylate cyclase and phosphodiesterase modulation is impaired in fetal lambs with congenital diaphragmatic hernia. J Pediatric Surgery 2011;46(8):1516-22. »

Resuscitation of the Preterm Infants

Room-Air Versus Oxygen Administration for Resuscitation of Preterm Infants: The ROAR Study »
Accuracy of pulse oximeter readings from probe placement on newborn wrist and ankle »
Safety and efficacy of Trans-warmer mattress for preterm neonates: results of a randomized controlled trial »

Retinopathy of Prematurity (ROP)

Retinopathy of prematurity (ROP) remains a major cause of blindness in the developed world where premature infants are cared for in modern intensive care units. As more and more extremely premature infants (<28 weeks’ EGA and <1,000g) survive, the incidence of severe ROP (generally Stages 3 to 4, or associated with plus-disease) is increasing. It remains important for all neonatologists to ensure appropriate screening for ROP in at-risk infants and provide timely referral for treatment in order to preserve the patient’s visual function and reduce later complications. This being said, ocular complications of prematurity apart from ROP also need to be considered, especially in the first ten years after NICU discharge (such as visual acuity concerns, strabismus, and visual motor function problems), especially in those infants <25 weeks’ EGA or those with significant IVH/PVL.

  • A landmark study was recently published in the New England Journal of Medicine that will likely impact upon the type of treatment(s) offered certain patients. It is referred to you, along with an accompanying editorial, and a new update on ROP screening and treatment from Current Opinion in Pediatrics.

1. Mintz-Hittner HA, Kennedy KA, Chuang AZ for the BEAT-ROP Cooperative Group: Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity. N Engl J Med 2011; 364:603-615 (February 17, 2011). PMID: 21323540 »

2. Reynolds JD: Bevacizumab for Retinopathy of Prematurity. N Engl J Med 2011; 364:677-678 (February 17, 2011). »

3. Chen J, Stahl A, Hellstrom A, Smith LE: Current update on retinopathy of prematurity: screening and treatment. Curr Opinion Pediatr 2011; 23 (2): 173-178. »

Periventricular Leukomalacia (PVL) and
Hypoxic-Ischemic Encephalopathy (HIE)

This month’s readings address the infrequent, yet significant problem of perinatal cerebral white matter injury (PVL) in the premature infant, and HIE in the term neonate – which may include white matter injury in 20% (Li, 2009).

  • The fact cerebral white matter injury poses a significant risk for the development of cerebral palsy (CP) should be well known by all neonatologists. But these are difficult conditions to study in the laboratory, and even in the ICU or the clinic (Silbereis, 2011).
  • The value of cranial ultrasonography cannot be overstated in examining the presence and severity of white matter injury and even in providing a means to inform the prognosis for the infant, premature or term, as it pertains to the risk for cerebral palsy (Himpens, Eur J Pediatr 2010).
  • Diffusion weighted magnetic resonance imaging is also a useful tool when performed in a timely manner (Li, 2009).
  • While asphyxia is important to consider in discerning contributing factors to white matter injury, this appears to be of greater import in the term, compared to preterm, infant (van Iersel, 2010).
  • Severity of respiratory illness, however, may be of importance in the preterm population (van Iersel, 2010; Himpens, EHD 2010).
  • Further, early indications from human pathologic specimens suggest that a potential for white matter injury repair exists and may provide an avenue for facilitating healing in the future (Haynes, et al., 2010).

1. Haynes, RL, et al. Potential Neuronal Repair in Cerebral White Matter Injury in the Human Neonate. »

2. van Iersel, PAM, et al. Does perinatal asphyxia contribute to neurological dysfunction in preterm infants? »

3. Himpens, E, et al. Predictability of cerebral palsy and its characteristics through neonatal cranial ultrasound in a high-risk NICU population »

4. Himpens, E, et al. Predictability of cerebral palsy in a high-risk NICU population. »

5. Li, AM, et al. White Matter Injury in Term Newborns With Neonatal Encephalopathy »

6. Silbereis, JC, et al. Towards improved animal models of neonatal white matter injury associated with cerebral palsy »

Phenylketonuria (PKU)

This month's core reading is focused on a well-recognized genetic condition that unfortunately remains poorly managed and has considerable impact on both child and adult outcomes: phenylketonuria (PKU). While PKU was first described over 75 years ago, and dietary restrictions to manage it implemented over 50 years ago, it remains the most prevalent disorder of amino acid metabolism caused by common single-gene defect. An excellent review is currently available in The Lancet. Two current articles relevant for the neonatologist were published in the genetics and metabolism literature, and the American College of Obstetricians and Gynecologists issued a Committee Opinion on the matter as it pertains to maternal PKU within the past year.

Read more »

Sugar Highs and Lows

The selection for reading this month comes from the clinical literature and addresses an age-old concern for pediatricians and neonatologists alike: what do I do about hypoglycemia and hyperglycemia in my newborn patients? The major energy substrate for the fetus is maternal glucose transported across the placenta, increasing with gestational length and culminating in the eventual storage of third trimester glycogen and fat. Both the term and premature infant rely upon these substrates, and any stores, in transitioning from intrauterine to extrauterine life (with hormonal and metabolic adaptation as important as cardiopulmonary adaption to the success of the transition).

For sick newborns, those with growth restriction, and those born prematurely, abnormalities in glucose homeostasis should not be surprising. Hyperglycemia is a frequent concern in the first postnatal week of extremely low birth weight infants and often may reflect an iatrogenic complication in too great a glucose infusion rate. That either extreme of glycemic control may be concerning for short-term health in the ICU or long-term outcomes is well established and the reader is provided with one large cohort of hypoglycemic infants followed with neuroimaging and electrophysiologic testing as such an insight.

As with most things in neonatology, the significance of glucose irregularities has to be evaluated within context - of the pregnancy, the delivery, the transition to extrauterine life, and certain key concerns for active disease processes (eg sepsis, respiratory distress, surgery) - and it may turn on matters of definitions versus operational threshholds (to borrow a phrase from Bill Hay and Paul Rozance). An editorial by Hay & Rozance accompanies the paper by Harris, et al. in the Journal of Pediatrics and is worthy of the reader's consideration, as is yet another reflection shared in the journal Early Human Development.

Three articles are noted for your review (linked to abstracts):

Treatment for Infants With Neonatal Encephalopathy

Until recently, there has been no clinically proven treatment for infants with neonatal encephalopathy. The featured articles this month include a comprehensive review of therapeutic hypothermia including the author's recommendations for a policy statement and changes to the neonatal resuscitation guidelines. Also featured is a randomized clinical trial of erythropoietin for infants with HIE performed in Zhengzhou, China. This a rapidly evolving field of neonatal medicine where years of basic research are now being translated into clinical interventions with the hope of improved long-term neurologic outcomes for infants with HIE.

Therapeutic Hypothermia in Neonates. Review of Current Clinical Data, ILCOR Recommendations and Suggestions for Implementation in NICUs »

Erythropoietin Improved Neurologic Outcomes in Newborns With Hypoxic-Ischemic Encephalopathy »

Gestational Diabetes Mellitus

The following selections are pertinent in addressing:

  • Definitions, interventions and outcomes in gestational diabetes mellitus - a condition that broadly affects not only perinatal health (mother, fetus and newborn) but also infant and subsequent childhood-to-adult health as it pertains to body mass, excess growth in the first postnatal year, and programming for later obesity and diabetes;
  • how the MFMU network can provide substantive data, test hypotheses, and generate important findings - even when the most desired outcome (reduction in still birth and perinatal death) may not be realized, and
  • the added value of systematic reviews and meta-analyses in critically reviewing and pooling findings from various independent studies to give "new" evidence, or rationale, for promoting improved maternal, neonatal and infant health and nutrition.

A Multicenter, Randomized Trial of Treatment for Milk Gestational Diabetes »

Gestational Diabetes - Whom Do We Treat? »

Birth Weight, Early Weight Gain, and Subsequent Risk of Type 1 Diabetes: Systematic Review and Meta-Analysis »


This excellent review article gives an update on what we know, and don't know, about both the clinical and pathologic (histologic) definitions and implications of chorioamnionitis. The authors review important infectious etiologies, inflammatory biomarkers, and genetic associations of this condition which is likely responsible for more than 70% of preterm births. Significant considerations of genetic predisposition-including racial disparity, inflammatory responses, host immunomodulation, and apoptosis of membrance cells-are referenced and provide insights into candidate pathophysiologic processes that must be understood in order to make headway in both preventing preterm birth and minimizing fetal harm.

Chorioamnionitis-A complex pathophysiologic syndrome »

Using a surgical fetal lamb preparation, these investigators introduced LPS into the fetal respiratory and gastrointestinal systems and evaluated the inflammatory responses engendered in a 2-7 day period. Measurements included inflammatory cells, cytokine mRNA (IL-1b, IL-6, IL-8), mRNA for the acute phase raectant serum amyloid a(SAA), and TNF-alpha production of culture lung monocytes. This model clearly demonstrates a systemic fetal inflmmatory response, inducible alveolar macrophages, and modulated the function of monocytes. It appears from these studies that different organ systems (lung, gastrointestinal tract)respond to LPS in different manners, and the downstream ramifications for each (and for the yet unstudied CNS) remain to be elucidated.

Modulation of fetal inflammatory response on exposure to lipopolysaccharide by chorioamnion, lung, or gut in sheep »

Understanding Intestinal Vulnerability to Perforation in the
Extremely Low Birth Weight Infant

Our feature article this month is a recent review by Phillip Gordon published in Pediatric Research (Pediatr Res 65:138-144, February 2009) that provides a thorough overview of the perinatal risk factors and pathobiology of spontaneous intestinal perforation in ELBW infants. An excellent introduction to this vexing clinical entity, this review article raises many areas ripe for future clinical and laboratory-based research.

Full text of article »
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