Prematurity

The field of perinatology may be more comprehensively viewed as part of the broader field of maternal-fetal-neonatal medicine, a continuum which incorporates the intricate and dynamic relationships among obstetrics, perinatology, and neonatology. It is this multidisciplinary and collaborative symphony that the Journal of Perinatal Medicine supports as highlighted by this month’s issue with a focus on “Prematurity” in its 11 papers on various perinatal and neonatal topics. In the interest of weaving an editorial narrative, our comments on these articles are not in the order of their published appearance.

In the popular layperson concept of maternal-fetal-neonatal care, maternal experiences can be readily transmitted to feto-neonatal experiences. In the case of auditory experiences, such as music or voices, pregnancy music belts (audio speakers applied to the maternal abdominal wall) have been used in the hope that such stimulation will provide positive cognitive and neurobehavioral fetal and neonatal benefits. These devices have been used despite the lack of proven benefit of this approach while transmission of external neurosensory stimuli might actually interfere with the physiologic neurobehavioral processes of the developing fetus [1]. In this issue of the journal, Jahn et al. [2] used a porcine uterine model to demonstrate that frequency-dependent sound pressure levels generated by external abdominal audio speakers are essentially undetectable due to attenuation by interposed organic layers. Although one must be cautious when attempting to apply findings of animal studies, especially uterine models, to humans, these findings suggest that commercial abdominal speakers may not effectively transmit sounds to the fetus above that of the maternal basal metabolic noise floor, especially given the rising incidence of maternal obesity.

The effect of music on maternal cardiac physiology, however, may be a different matter, as highlighted in the paper by Rhomberg et al. [3]. The risk for maternal arrhythmia is increased during pregnancy, especially for re-entry tachycardias, drug-induced torsades de pointes, and symptomatic long QT syndrome. In the study on the electrophysiologic effects of music on QTc intervals of women with term gestation pregnancies, Rhomberg et al. found that QTc increased by an average of 10.1 ms during fast music (>150 bpm), compared to quiescence. Interestingly, other maternal cardiac parameters and fetal heart rate were unaffected by music exposure. Although it is unclear whether the effect on QTc was due to the amplitude, frequency, or cadence of the music, the authors speculate that the prolongation of QTc intervals may be an important factor in the cumulative exhaustion of repolarization reserves which precede arrhythmias. While these preliminary findings require confirmation, it might be advisable to consider them when caring for a pregnant woman with pre-existing QTc prolongation or on QTc-prolonging medication.

Moving from the maternal to fetal heart, the “area behind the heart” between the left atrium and the descending aorta has gained increased attention as a potential marker for congenital structural heart disease. The study by Akkurt et al. [4] in this issue of the journal provides baseline data for the use of the post-left atrium space index as a potential fetal sonographic marker for total anomalous pulmonary venous connection at 20–24 weeks’ gestation. By assessing fetuses with normal heart structure and function, the authors report a normal LD/DA ratio of 0.65±0.13, a value by which increased LD/DA ratios can be assessed. Of note is that this relatively simple measurement showed robust inter- and intraobserver agreements even among less experienced practitioners. Further validation of the finding is required, however, and the changes in LD/DA ratio over time and its potential utility in the detection of other conotrucal defects remain to be investigated.

Although little or no fetal interventions can be offered for most types of congenital heart disease at present, several management options exist for monozygotic twin pregnancies complicated by twin reverse arterial perfusion (TRAP) sequence, including conservative management, umbilical cord ligation, and intrafetal ablative therapy. Mone et al. [5] conducted a systematic review of these options and found that intervention, whether by ligation or ablation, was associated with significant survival benefit to the pump twin (OR 2.22, 95% CI 1.23–4.01). However, in the presence of comorbidities, such as hydrops, only laser ablation was associated with improved pump twin survival. Although the “truth half-life” of conclusions reached by meta-analyses is debatable [6], Mone et al., provide a thorough summation of the evidence to date on the survival benefit associated with intervention for the pump twin.

The decision to pursue fetal intervention, however, is never an easy one. Blumenthal-Barby et al. [7] share insights from their qualitative research focusing on complex information-exchange and shared decision-making processes for maternal-fetal interventions for myelomeningocele (MMC) and congenital diaphragmatic hernia (CDH). Recurring themes were identified through iterative grounded theory analyses of consultations between families and maternal-fetal physicians. Physicians typically spoke in qualitative, not quantitative, terms and favored positive frames (e.g. chances of survival) more than negative ones. Families spoke for only a minority of the time (15%), usually limited to clarifying questions, and never used the term “fetus”. The inclusion of neonatologists, psychologists, nursing staff, and others who actively participate in family consultations will further expand approaches to more effectively facilitate shared decision-making for fetal interventions.

The defining condition of maternal-fetal-neonatal medicine remains preterm birth, although the use of effective prophylactic therapies for preterm labor continues to elude the field. Perinatal progesterone supplementation has shown therapeutic promise, even if the mechanisms by which it reduces preterm labor remain unclear. In this context, Areia et al. [8] introduce information within the framework of a possible regulatory role which CD4⁺ T cells (Tregs) play in maternal immune tolerance to the developing fetus. After initiation of vaginal progesterone prophylaxis for women in preterm labor, they report markedly increased peripheral Treg counts, but as no clinical outcome data were provided, it remains to be seen if Tregs are among the potentially effective therapeutic targets in the management of preterm labor.

Once preterm delivery is imminent, either spontaneously or by induction, assessment of fetal lung maturity can be helpful in predicting readiness of the fetus for extrauterine life. Beamon et al. [9] offer a technologically simplified approach to fetal lung maturity testing based on lamellar body counts (LBCs) in uncentrifuged amniotic fluid. Given that lamellar body morphology approximates those of platelets, LBCs can be determined using platelet channels of hematology instruments. In their study of premature infants, they report that an LBC under 35,000/μL in the amniotic fluid was associated with an increased risk for neonatal respiratory morbidity. Furthermore, they provide gestational age-specific probability curves for neonatal respiratory morbidity based on LBCs. Confirmation of the study’s findings and evaluation of comparative accuracies of different automated hematology analyzer systems for LBC determination remains to be evaluated before this approach can be considered for clinical use.

For infants with respiratory distress from lung immaturity or other etiologies, continuous positive airway pressure (CPAP) remains a foundational therapy for the support of functional residual capacity and reduction of airway resistance. Both bubble and ventilator CPAP methods are used in the clinical arena. Yet little evidence supports the superiority of one modality over the other, despite the hypothesized beneficial oscillatory effects of bubble CPAP. In their crossover study of premature infants supported with nasal CPAP, Guerin et al. [10] found no differences in basic physiologic or cerebral oxygenation parameters associated with bubble versus ventilator modalities. Importantly, they found no adverse events associated with either approach. If a true clinical difference exists between bubble and ventilator CPAP, it is likely that only randomized clinical trials starting at the initiation of CPAP support and continued over a prolonged time period will identify it. This is, however, with the caveat that without understanding and identifying differences among subpopulations of preterm neonates or individual characteristics that affect cardiorespiratory function, even larger randomized clinical trials might not be able to provide this answer.

Among the most severe forms of neonatal cardiorespiratory disease is meconium aspiration syndrome (MAS). Neonatal MAS management varies by institution but, in appropriately selected cases, it may include postpartum tracheal aspiration and selective exogenous surfactant replenishment. Using their well-described MAS newborn porcine model, Henn et al. [11] provide evidence supporting the effectiveness of bronchoalveolar lavage with saline-diluted surfactant (BAL) followed by an exogenous surfactant bolus, compared to tracheal aspiration or surfactant replacement therapy alone. Improvements in oxygenation, ventilation, and pulmonary mechanics after BAL and a secondary surfactant bolus were sustained up to 6 h after therapy. Conversely, there were no differences in outcomes between tracheal aspiration and surfactant alone. Interestingly, a subset of study subjects was resistant to respiratory failure after MAS induction; one wonders if Beamon’s approach [9] would have identified a relatively higher lamellar body count in this subset (i.e. higher rate of underlying surfactant production and lung maturity). Adverse sequelae associated with BAL are not insignificant, including iatrogenic hypoxemia, bradycardia, and hypotension, but perhaps the time has come for a randomized clinical trial of dilute surfactant BAL with surfactant bolus for MAS in neonates.

MAS and other severe neonatal cardiorespiratory disease culminate in hypoxic respiratory failure (HRF). For term and late preterm infants with HRF, inhaled nitric oxide (iNO) remains a key therapy in reducing the need for extracorporeal membrane oxygenation and mortality. However, up to half of HRF infants will have little to no response to the selective pulmonary vasodilatory effects of iNO. In their case review report, Almanzar Morel et al. [12] identify clinical characteristics of iNO non-responders, including lower Apgar scores, lower initial pH, elevated oxygen index, and the use of vasopressor support prior to initiation of iNO therapy. Identifying this subset earlier in their clinical course may allow for more aggressive management strategies but the mechanisms underlying iNO-recalcitrant pulmonary vascular resistance remain to be elucidated.

This brings us to our final point. Maternal-fetal-neonatal medicine extends beyond the perinatal and neonatal spectrum and into the field of fetal programming and the developmental origins of disease, of which intrauterine growth restriction (IUGR) is the classic example. In their study of IUGR biomarkers regulating energy homeostasis, Aydin et al. [13] report reduced adropin levels in both maternal and fetal cord blood samples and reduced fetal adiponectin, a finding likely related to reduced adiponectin levels in formerly IUGR adolescents. Of interest might be the serial assessment of these biomarkers through perinatal, neonatal, and postnatal time points to better describe the evolution and timing of the pathophysiologic processes underlying fetal IUGR and developmental origins of diseases such as the metabolic syndrome, type-2 diabetes, hypertension and atherosclerotic heart disease.

We hope that the reader will enjoy critically reading this special issue of the Journal of Perinatal Medicine as much as we have and continue to participate in the journey in our shared maternal-fetal-neonatal and postnatal profession. It is a dynamic field which continues to grow, even beyond its original realm of perinatology into the human lifespan itself.