Premature Infants Born: History
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Subjects: Pediatrics
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After birth, infants born after <25 weeks’ gestation develop respiratory and hemodynamic instability due to their immature physiology and anatomy. Successful stabilization at birth has the potential to reduce morbidities and mortalities, while suboptimal DR care could increase long-term sequelae. 

  • threshold of viability
  • postnatal stabilization
  • umbilical cord management
  • respiratory support
  • cardio-circulatory support
  • premature infants born after <25 weeks’ gestation

1. Introduction

The impending birth of periviable infants born after 22 + 0 to 24 + 6 weeks’ gestation is associated with anxiety and uncertainty for family members and healthcare teams [1]. Parental beliefs and values need to be incorporated into the decision-making process to provide the optimal approach and outcome for the parent–infant dyad. These options include active or comfort (palliative) care. The decision of active management leaves clinicians in a challenging position. Despite the advances that have been achieved in perinatal and neonatal care, there is a lack of strong evidence in delivery room (DR) studies which have included infants at 22 + 0 to 24 + 6 weeks’ gestation [2].

In recent decades, gestational age has continuously shifted lower. However, the stabilization of premature infants born after <25 weeks’ gestation in the DR remains challenging [3]. The current neonatal resuscitation guidelines are designed for term and premature infants born after <32 weeks’ gestation [4,5,6,7], thereby potentially not providing the optimal DR management for infants born after <25 weeks’ gestation.

2. Decision Making at <25 Weeks’ Gestation

Decision making about active or comfort (palliative) care in infants to be delivered between 22 + 0 to 24 + 6 weeks’ gestation is challenging. Gestational age (despite the uncertainty of the accuracy of an infant’s gestation determined by fetal ultrasound) is used as the main determinant for decision-making due to its association with outcomes [8,9]. Current recommendations vary widely and decision making should use a guided approach including parents and care-givers at each hospital. Factors that might influence the decision-making process include birth weight, multifetal pregnancy, sex [10], presence of intra-amniotic infection [11] or the presence of congenital anomalies. In addition, antepartum corticosteroid [12,13] and magnesium sulfate [14] administration could influence outcomes. Survival predicting tools such as the Neonatal Research Network Extremely Preterm Birth Outcome Model are widely used for prediction by care-givers and thereby may support the decision-making process [15]. However, systematic analyses investigating the impact on neonatal outcome by incorporating survival predicting tools into the decision-making process are lacking.

Survival rates among periviable infants born after 22 + 0 to 24 + 6 weeks’ gestation increase for deliveries that occur in hospitals with NICUs that have both a high level of care and a high volume of such patients [16]. Different perinatal management among hospitals and countries may have a further impact on outcome. In centers with a more proactive perinatal resuscitation strategy in premature infants born after <25 weeks’ gestation, the number of live births increased and survival rates improved when compared to those with a more selective approach, potentially resulting in increased morbidity among survivors [17,18]. Most importantly, there is an open discussion about the parents’ wishes, the capability of the perinatal center and NICU and their outcomes to provide the best decision-making options for the parents.

3. Umbilical Cord Clamping

Immediate cord clamping (ICC) has been used for several decades. However, evidence suggests that ICC might cause an acute reduction in left atrial, filling leading to an abrupt drop in left ventricular output [19]. In contrast, delayed cord clamping (DCC) might improve blood pressure stability and placental transfusions in premature infants [19,20]. A meta-analysis including 3514 premature infants born after <34 + 0 weeks’ gestation from 23 studies reported that DCC may improve neonatal survival or reduce neonatal mortality with a survival risk ratio of 1.02, a 95% confidence interval (CI) of 1.00–1.04 with a number needed to benefit: 50, 95% CI: 25 to no benefit [21]. However, most studies included in the meta-analysis only enrolled infants born between 32 and 34 weeks’ gestation. The trial by Tarnow-Mordi et al. included 518 premature infants born after < 27 + 0 weeks’ gestation and reported no differences in the composite of death or major morbidity ( p = 0.23) [22]. While the evidence is limited in premature infants born after <25 weeks, recent guidelines recommend that DCC be performed irrespective of gestational age [4,5,6].

Intact umbilical cord milking (I-UCM) has been advocated as an alternative to DCC, particularly in infants who do not breathe at birth [19]. Animal studies reported that I-UCM promotes placental transfusion, however, this causes large fluctuations in mean carotid artery pressures and carotid artery blood flows (with each milking along 10 cm of cord, carotid artery blood flow increased and decreased by 15% ± 2% and 8% ± 1%, respectively) [23]. A pilot trial comparing I-UCM with DCC reported higher superior vena cava flow and right ventricular output during the first 12 h of life [24] with higher cognitive composite score (100 ± 13 vs. 95 ± 12, p = 0.031) and language composite score (93 ± 15 vs. 87 ± 13, p = 0.013) at 22–26 months of corrected age compared with those randomized to DCC [25]. However, a recent large randomized trial comparing I-UCM with DCC reported a significant increase in the rates of severe intraventricular hemorrhage (IVH) after I-UCM in a subgroup of 182 premature infants born after <28 weeks’ gestation (20 vs. 5; p = 0.02) [26]. This led to an early termination of the trial, and currently I-UCM is not recommended in premature infants born after <28 weeks’ gestation [6].

An alternative approach of umbilical cord milking is cut-umbilical cord milking (C-UCM), which is performed by early cord clamping and retaining a long segment of the umbilical cord that then can be milked while initiating ventilation [27]. In extremely low-birth-weight (ELBW) infants, C-UCM increases the mean blood volume by 17.7 (±5.5) mL/kg birthweight per 30 cm of umbilical cord [28] and has similar effects on placental transfusion and the need for red blood cell transfusions compared to I-UCM [27]. In premature infants, C-UCM may increase peak hematocrit within 24 h after birth compared to ECC, but the study population only included six (10%) ELBW infants [21,29]. Prospective trials in premature infants born after <25 weeks’ gestation are warranted to prove the safety and effects of C-UCM on short- and long-term outcomes.

4. Respiratory Support in the Delivery Room

Tactile maneuvers might stimulate breathing and thereby improve oxygenation in premature infants [32,46,47]. Katheria et al. have shown that gentle tactile stimulation in premature infants during DCC promotes the establishment of spontaneous breathing and provides a similar placental transfusion compared to CPAP and/or PPV during DCC [32]. Baik-Schneditz et al. reported that oxygenation improved after tactile stimulation (before 61.9 (53.1–76.0) versus after stimulation 67.8 (58.1–77.1), p < 0.001) in late premature infants [47]. Repetitive tactile stimulation compared with standard stimulation (based on clinical indication) in premature infants 27–32 weeks’ gestation resulted in significantly improved oxygenation with a lower fraction of inspired oxygen (FiO 2), but did not result in differences in respiratory effort between groups [46]. Several additional studies reported on tactile stimulation in premature infants > 30 weeks’ gestation. However, only the study by Katheria et al. included premature infants at <25 weeks’ gestation. Future trials are required to assess whether tactile maneuvers improve respiratory function as well as to identify the best tactile stimulation strategy (i.e., stimulation area, duration, frequency, etc.) with a special focus on premature infants born after <25 weeks’ gestation [48].

In addition to face masks and bi-nasal prongs, nasal tubes might be equivalent alternative interfaces for PPV at birth in ELBW infants [63]. Other supraglottic airways such as oropharyngeal airways or laryngeal masks are currently not recommended in premature infants born after <25 weeks’ gestation, since oropharyngeal airways significantly increased the incidence of airway obstruction and appropriately sized laryngeal masks are not available for those patients [6,64,65]. Administering ventilation at birth with a T-piece resuscitator compared with a self-inflating bag reduces the duration of PPV and the risk of bronchopulmonary dysplasia [66].

A meta-analysis of seven trials (<500 total patients) in premature infants born after ≤28 weeks’ gestation reported no differences in mortality, major morbidity, or neurodevelopmental outcomes when respiratory support was started with low (0.21–0.3) compared with higher oxygen (0.6–1) [69]. Recent resuscitation guidelines recommend an initial FiO 2 of 0.21–0.3 [5,7] or 0.3 [4,6] for premature infants born after <28 weeks’ gestation, which reflects a preference to prevent exposure to additional oxygen beyond what is necessary to achieve oxygen saturation targets. However, a subgroup analysis of premature infants born after <25 weeks’ gestation is not available. Since the current recommendations for oxygen therapy in premature infants come from low-quality evidence, the optimal FiO 2 to initiate respiratory support in those patients after birth remains a hot topic for future research [67]. In particular, studies of intermediate oxygen concentrations (e.g., 0.4–0.5%) to initiate resuscitation in premature infants are urgently required.

Endotracheal intubation and the subsequent invasive ventilation should be reserved for premature infants not responding to PPV during DR stabilization, and they should then receive surfactant via the endotracheal tube [4].

5. Cardio-Circulatory Support

5.1. Chest Compressions and Epinephrine Administration

None of the international resuscitation guidelines endorse withholding chest compressions and/or epinephrine administration from the subgroup of premature infants born after <25 weeks’ gestation [5,6,7], although there are concerns over whether extensive cardiopulmonary resuscitation should be performed in such premature infants, as both have been associated with high mortality and neurodevelopmental impairment rates [88,89,90,91]. A Canadian cohort study included 190 ELBW infants with a mean (SD) gestational age of 25.4 (1.7) weeks and 29% of subjects born after ≤24 weeks’ gestation who received chest compressions and/or epinephrine administration in the DR. Overall, 60% survived with 78% of the survivors not severely impaired at 18–24 months corrected age [91]. A Vermont Oxford Network study reported a higher survival rate in a subgroup of premature infants weighing between 401 and 500 g who received extensive cardiopulmonary resuscitation compared to neonates who did not receive chest compressions and/or epinephrine administration. These findings were attributed to a more aggressive ventilation and resuscitation approach in the investigated cohort [92]. In the absence of evidence to justify a different approach in ELBW infants, the standard newborn resuscitation algorithms, including chest compressions and/or epinephrine administration, should also be used in premature infants born after <25 weeks’ gestation, if advanced resuscitation was considered appropriate prior to birth [93].

5.2. Vascular Access

The current neonatal resuscitation guidelines recommend vascular access if infants require chest compressions or fluid administration [6]. Vascular access could be achieved with either umbilical venous catheterization, peripheral, or intraosseous access [6,7]. While umbilical venous catheterization is most commonly used, the success rates and adverse effects attributable to emergency umbilical venous catheterization are unknown. Peripheral venous access has been described in premature infants (mean gestational age of 31 ± 2 weeks) with a high success rate at 5 (IQR 4–9) minutes after birth [94]. However, the study did not include premature infants born after <25 weeks’ gestation, which might result in lower success rates.
More recently, intraosseous access has been advocated as an alternative to umbilical venous catheterization [6]. A total of 80 newborns have been described in case series [95,96], with varying success rates and severe complications such as bone fracture, osteomyelitis, compartment syndrome, and amputation [95]. There have been reports on the successful use of a Cook needle (Cook Medical, Bloomington, IN, USA) or butterfly needle in five infants at 25 weeks’ gestation and a lowest birth weight of 515 g [97,98], but none in premature infants born after <25 weeks’ gestation. While there are currently no data to support intraosseous lines in premature infants born after <25 weeks’ gestation, it might be considered during neonatal resuscitation if other access routes have failed.

This entry is adapted from the peer-reviewed paper 10.3390/children8100882

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