Antepartum COVID-19 and Postpartum Autism

Abstract

A little over a year ago, a new viral disease appeared worldwide. Much like earlier pathologic RNA viruses, Covid-19 can cause distinctive harmful effects on pregnant women and their offspring. Because of the coexistent fever associated with a rise in pro-inflammatory interleukins in the most severe cases, there is a serious concern about the baby’s neurologic development. Although not yet observed in many Covid-19 pregnancies, it is anticipated particularly that the onset of autism in the child may be realized in a year or more postpartum. Prior studies have reported that exclusive breast-feeding which provides a good source of IGF1 for the baby may well reduce the incidence of autism in such cases.

Keywords: Cytokine storm; Interleukins; Respiratory distress; Proinflammatory; Alveoli

Introduction/Background

In the intrauterine development of a baby, the fetal stage is marked by varying levels of blood interleukins and IGF1 (insulin-like growth factor-1). If the baby is developing normally, without adverse influences in its environment, the trend over time is for serum interleukins to decrease and IGF1 to increase until delivery. On the other hand, if a maternal febrile cytokine storm occurs during the pregnancy, an overproduction of interleukins and reduction of IGF1 can take place. Such a phenomenon in the past has been associated with various bacterial and viral infectious diseases including cytomegalovirus, hemophagocytic lymphohistiocytosis, group A streptococcus, variola virus, influenza virus, SARS-CoV-1 (severe acute respiratory syndrome – a coronavirus), and avian H5N1 virus. Without fever, adverse manifestations are reduced [1-10].

Since 1918, orthomyxoviruses [single-stranded RNA viruses], such as influenza, have been the cause of epidemics and pandemics every few years. These viruses are spherical with distinctive surface spikes made of Hemagglutinin (HA) or Neuraminidase (NA) protein. Beginning with 2020, Covid-19, the newest member of this pathologic microbial group, has exhibited aspects of cytokine excesses in many cases. Much like the earlier pandemics of Spanish flu and H5N1, such a flare-up is characterized by fever, lethargy, and dyspnea. These zoonotic viruses are increasingly proliferative as the human population grows [3,6].

A consistent finding in patients with pulmonary complications is the overproduction of specific pro-inflammatory interleukins. Cytokines can elicit responses in cell proliferation and inflammatory reactions. Interleukin 1 (IL1), IL6, IL17, and TNF (tumor necrosis factor) in particular are central to the overt harmful features of acute viral diseases [7,11,12]. Especially with Covid-19, the most serious damage appears to be localized in the lung alveoli, where the viral spikes attach to ACE2 receptors. As the pathogenesis progresses, lung injury can lead to Acute Respiratory Distress Syndrome (ARDS) [6- 11,13].

Current therapy protocols for difficult cases of COVID-19 include drugs such as Tocilizumab (TCZ), a monoclonal antibody against IL6 receptor in patients with life-threatening cytokine storm [14-16]. In combination with methylprednisolone, this therapeutic agent is reported to successfully reduce cardiovascular collapse and major organ dysfunction in a number of severely ill coronavirus patients. Another relatively new agent, Allocetra, is effective in reprogramming macrophages and dendritic cells [17].Under normal postpartum conditions, the serum IGF1 level rises until the early teen years, after which it slowly decreases over time. In contrast, when a fetus had faced a fever-generating antepartum state such as a severe maternal coronavirus attack, the levels of serum IGF1 of the newborn are diminished and of pro-inflammatory Interleukins (e.g., IL6) are increased [18,19]. In a postmortem examination of human autistic brains, increased cytokines and pathologic signs of inflammation have been detected [1].

Maternal death often follows a failure to recover from immune paralysis and irreversible lung injury. As in similar cytokine enhancing events with other febrifacient viruses, one would anticipate an upsurge in the number of autistic children in the coming months or years with mothers who experienced febrile antepartum Covid-19 [12,20-23]. Antipyretics in gravidas have been somewhat successful in lowering the autism rate in viral illnesses [11].

Proposed Therapy

It has been reported with previous viral pandemics that gravidas suffering from microbe-induced fevers give birth to children who are more likely to exhibit autistic traits later. From various studies, this is apparently related to a deficiency of IGF1 and a persistence of enhanced IL6 in the baby after birth [5,7]. Such an IGF1 deficit reduces the rate of myelination and functional assembly of neoneuronal circuits in the baby’s brain (dysconnectivity) [24].

In laboratory fetal mice, increased serum IL6 is concomitant with low IGF levels in utero. In unaffected humans born at a mean gestational age of 27.8 weeks, for example, the average serum concentration of IGF1 is 46.6 ng/l, whereas the concentration of IGF1 is approximately double in full term neonates. In otherwise normal pregnancies, the serum IL6 at term is about a quarter of what it was in the middle of the gestation [25,26].

In pregnancies where the gravida had suffered a serious ARDS event before delivery, the newborns sustain IL6 levels at birth and beyond which are much higher than normal. Similarly, children with overt autism are typically found to have elevated serum IL17 [23,26,27]. In other words, autism is more likely to arise postpartum if the serum IGF1 level is depressed concurrently, as in severe COVID-19.

The hypothetical diagram (Figure 1) displays the typical fall in serum IL6 and the rise of IGF1 preceding the infected phase of a pregnancy, as well as the opposite trends following a Covid-19 infective/febrile event. Gross symptoms of autism in the baby usually become evident after the first year of postpartum life [23,26-28].

    

    

    Figure 1: Relationship between fetal/neonatal serum IL6 and IGF1 before
and after a febrile Covid-19 attack [5,7,21,25,26,35-40].