Need for developing case definitions and guidelines for data collection, analysis, and presentation for small for gestational age (SGA) as an adverse event following maternal immunisation
Small for gestational age (SGA) fetuses or newborns are those smaller in size than normal for their gestational age, most commonly defined as a weight below the 10th percentile for the gestational age. This classification was originally developed by a 1995 World Health Organization (WHO) expert committee, and the definition is based on a birthweight-for-gestational-age measure compared to a gender-specific reference population [1], [2].
Successful pregnancy, including optimal growth of the fetus, relies on a careful balance between immune tolerance and suppression. Several mechanisms work together to protect the fetus from rejection [3]. During normal placentation, several changes occur, including differentiation of the endometrium to decidua, development of the fetal placental trophoplast to invade the decidua, migration and differentiation of trophoblast, and remodeling of the uterine arteries [4]. Current evidence suggests that the placenta creates a micro-environment that controls immune cell differentiation at the implantation site and trophoblastic cell-induced differentiation of the immune cells into a phenotype beneficial for the trophoblast [5]. Mor and Cardenas categorized pregnancy into three different immunological stages [6]. The first pro-inflammatory phase, occurring during the first trimester, includes implantation and placentation. It is associated with increased levels of interleukin (IL)-8, macrophage chemo-attractor protein 1 (MCP-1), and activated T cells. The second anti-inflammatory phase, occurring during mid-pregnancy, is a unique period of fetal growth and development. It is characterized by predominant anti-inflammatory cytokines (IL-4, IL10 and IL-13). The third pro-inflammatory phase is similar to the first phase, and it is a preparatory stage for delivery [3]. Furthermore, different Pattern Recognition Receptors (PRRs), including Toll-like receptors and Nod-like receptors, and the innate immune system play a vital role in this process.
Dysfunction of the maternal innate immune response may predispose to placentally mediated diseases such as pre-eclampsia (PET), fetal growth restriction (FGR), placental abruption, and intrauterine fetal death. The complement system can affect angiogenesis-related endothelial cell function. It can indirectly, through macrophages, upregulate the anti-angiogenic soluble vascular endothelial growth factor receptor-1 (SFlt-1). In addition, SFlt-1 can combine with soluble endoglin (sEnd) to induce PET, FGR, and coagulation defects [7], [8], [9], [10].
Traditionally, the causes for “pathological” growth restriction are subdivided into fetal, placental and maternal. Genetic and chromosomal disorders, fetal malformation, infection (e.g. rubella or cytomegalovirus), and toxic substances (e.g. alcohol, cocaine, or smoking) can contribute to FGR. Maternal diseases such as anemia and malnutrition may also affect fetal growth. However, classical utero-placental dysfunction accounts for the vast majority of cases of “placental” FGR, as well as to a variety of conditions such as pre-eclampsia and placental abruption [11]. The Brighton Collaboration fetal growth restriction manuscript addresses the impact of obstetric conditions on fetal growth restriction more fully [12].
Congenital infections by Toxoplasma gondii, rubella, cytomegalovirus, herpes simplex virus (HSV), varicella-zoster virus, Treponema, and HIV contribute to 5–10% of fetal growth restriction [13], [14]. Several investigators believe that congenital infection could be associated with a spectrum of disease, and it could be quite variable, ranging from severe clinical manifestations to mild disease only presenting with a small for gestational age fetus. Many clinicians think that TORCH screens should be performed on every SGA newborn infant [15], [16], [17].
Placental malaria is a major cause of fetal growth restriction. In a case-control study of 492 pregnant Malawian women, a significant increase of placental complement C5a levels was associated with an increased risk of delivering a small-for-gestational-age infant [18]. C5a was significantly increased in placental malaria and was negatively correlated with the angiogenic factor angiopoietin-1 and positively correlated with angiopoietin-2, soluble endoglin, and vascular endothelial growth factor [18].
Maternal vaccination during pregnancy has emerged as a recommended public health approach to prevent maternal and childhood infections. All current maternal vaccines were initially designed for and tested in non-pregnant populations, but the diverse immune modulations during pregnancy may cause pregnant women to respond sub-optimally or differently compared with non-pregnant populations [19]. In addition, vaccine efficacy could be affected by other factors including the dose, route, and timing of the vaccination. Limited data exist on the effect of vaccinations in high-risk pregnancies. In spite of the success of several maternal vaccines, many gaps exist in our knowledge of this promising public health strategy and impact on fetal growth during pregnancy.
