The paradox of the preterm fetus

The preterm fetus, and particularly the infant born very preterm, are considered life's most fragile creatures: tiny and not yet sufficiently developed for ex‐utero life. The baby born preterm is entirely dependent on a host of specialist clinicians and machines to ensure poorly developed lungs obtain oxygen and the cardiovascular system is supported. Meanwhile, life hangs in the balance, often for many months. Infants born very preterm (<32 weeks gestation) are at major risk for brain injury and subsequent motor, cognitive and/or behavioural deficits (Volpe, 2009; Keunen et al. 2012). Even those infants born moderate to late preterm (up to 36 weeks gestation) demonstrate increased rates of neurodevelopmental deficits compared to their term‐born counterparts (Kelly et al. 2016). Accordingly, preterm birth imposes the highest ranking risk factor for developing cerebral palsy – infants born very preterm have a 30‐fold increased prevalence of cerebral palsy over infants born at term (MacLennan et al. 2015).

But, while seemingly fragile once born, there is a complex ‘arsenal of physiological weapons’ that the preterm fetus has at its disposal to combat hypoxic episodes when in utero. These are reviewed by Bennet (2017) in this issue of The Journal of Physiology. We learn that the preterm fetus has an exceptional capacity to respond and adapt to hypoxic challenges and, indeed, very immature fetuses can survive a severe asphyxic event for much longer than term‐equivalent fetuses, in accordance with their basic metabolic demands.

As noted in Bennet's review, although the incidence of hypoxia–ischaemia (HI) at birth is significantly greater in preterm infants compared to term infants, it is likely that the greatest burden of HI events occurs antenatally and remote from birth, with epidemiological evidence supporting that the origins of cerebral palsy are primarily prior to labour (MacLennan et al. 2015). It is therefore critical that we understand how the fetus that is destined for preterm delivery responds to hypoxic episodes, whether moderate or severe, and the mechanisms initiated by antenatal HI that lead to organ damage. In turn, such knowledge will inform strategies for antenatal monitoring, neonatal care and the development of protective therapies for very preterm infants.

Bennet brings together a large body of information that examines the physiological responses of the preterm fetus to acute hypoxic challenge. The preterm fetus mounts a set of robust and highly organised processes to counter severe hypoxia, characterised by three phases – acute compensation (maximal cardiovascular response), adaptive compensation (an active attempt to limit organ injury), and subsequent slow decompensation (to prevent cardiovascular failure). We might expect that such a coordinated reaction should provide relative protection for the preterm brain and other organs against injury. For example, while it is generally considered that the cerebral autoregulatory response is poorly developed in the preterm fetus and infant, data presented by the author support that cerebral blood flow is maintained despite profound hypertension during the acute hypoxia in phase 1, followed by a relatively slow fall in cerebral perfusion during phase 2 (Fig. 1 in Bennet, 2017). Indeed, during phase 2 the preterm fetus has better control of cerebral perfusion than term fetuses and this appears to be managed in such a way as to ensure the metabolic needs of the brain are met. During phase 3, the preterm fetus also demonstrates a slower fall in blood pressure and cerebral perfusion than in term fetuses.

The defence system of the preterm fetus to hypoxia is principally driven by the metabolic need of individual organs, together with selective sparing of perfusion to essential organs (heart and brain). Combined, this means that the preterm fetus is able to counter the dangerous hypoxic environment with a complex and integrated set of physiological reactions and, as a result, preterm fetuses can survive relatively long periods of asphyxia without injury when compared to term infants. But why, then, is the preterm fetus at high risk for organ injury, and in particular, perinatal brain injury? This is likely to be due to a combination of factors: (i) periods of acute HI are commonly experienced by the preterm fetus; (ii) preterm birth is often complicated by infection, or fetal growth restriction; (iii) brain development, and notably white matter development, is at a critical and particularly vulnerable stage; (iv) preterm perinatal interventions (e.g. steroids) may impact brain development; and (v) postnatal intensive care accompanied by periods of instability probably exacerbate brain injury. We are therefore urged to consider the development of treatments and therapies that will protect brain and other organ development in infants born preterm. In the first instance the knowledge of the cardiovascular and cerebrovascular response to antenatal hypoxia or asphyxia in the preterm fetus provides an opportunity for detection of at‐risk fetuses, potentially via fetal heart rate monitoring (Lear et al. 2016). For those fetuses who are born very preterm, we must now optimise neonatal care strategies, and implement novel therapies to reduce and/or prevent brain injury, potentially using stem cell treatments (Li et al. 2016).

The review by Bennet in this issue of The Journal brings together many decades of clinical and animal experimental investigation of the preterm fetus and infant, highlighting that, while the preterm infant may be perceived to be fragile once born, it is certainly not physiologically immature. Herein the paradox is apparent – the preterm fetus shows a robust ability to tolerate long periods of severe hypoxia with a coordinated phasic response, but infants born preterm have significantly greater likelihood of suffering brain injury and long‐term developmental deficits than term infants, most likely originating from antenatal compromise. Researchers and clinicians must now extend this knowledge, implementing detection and treatment strategies to reduce the burden of neurodevelopmental and other complications arising after preterm birth.

Additional information

Competing interests

The author does not have any conflicts of interest on the submission.

Funding

The author is funded via an Australian Research Council Future Fellowship (FT130100650) and the Victorian Government Operational Infrastructure Support Program.