Neonatal Fc receptor is a major histocompatibility complex class I (MHC)-related molecule that plays a central role in the regulation of IgG homeostasis and transport across the placental barrier [8]. Expression of FcRn on syncytiotrophoblast cells appears to be decisive for efficient IgG-mediated phagocytosis [9], whereas expression on endothelial cells is important to prolong IgG half-life by recycling internalized IgG back to the surface [10].

The interaction between the Fc domain of IgG and FcRn is influenced by pH changes, presenting high affinity at acidic pH level < 6.5 and low affinity at physiologic pH [11]. During pregnancy, IgG is transferred from mother to fetus at the level of syncytiotrophoblasts through a process called transcytosis, which starts with internalization of maternal IgG into endosomes. At this level, the pH is acidified and it allows IgG to bind to FcRn present on the internal surface of the endosome [12]. The complex is then carried towards the basal cell membrane of the syncytiotrophoblast, where the IgG is released upon exposure to normal pH (7.4) and it enters the fetal circulation (Figure 1). It is not yet fully understood how maternal IgG is carried through villous stroma to the fetal endothelial cells as FcRn are not expressed on stromal cells [13,14]. Some evidence shows that Fc receptors type II and III are expressed in term placentas and could be involved in transplacental transfer of IgG [15]. It remains controversial whether FcRn are expressed or not on fetal endothelial cells, but Fc receptors II could be identified at this level and are considered to be linked with IgG passage into the fetal circulation [16,17].

In humans, FcRn are also expressed on both endothelial and bone marrow-derived cells, playing a role in prolonging the half-life of IgG and albumin [18,19] by preventing their catabolism. This finding might have a great impact in clinical practice: by modulating this IgG–FcRn interaction, one could improve the pharmacokinetics of therapeutic antibodies, or by inhibiting FcRn function in some autoimmune conditions, a reduced level of harmful antibodies could be achieved [20,21,22].

The transplacental transfer of maternal antibodies to the fetus begins during the first trimester of pregnancy. Very little maternal IgG reaches the embryo and could be found in the coelomic fluid and villous stroma as early as 6 weeks [23]. Approximately 10% of maternal IgG concentrations are transferred to the fetus by 17–22 weeks’ gestation, and the levels show a continuous rise between 17 and 41 weeks, exceeding maternal levels by 37–40 weeks of gestation [24] (Figure 2). Due to this marked transfer of antibodies in the third trimester, closer to term, preterm neonates especially those born before 32 weeks have a considerably lower level of IgG compared to full term neonates and therefore higher susceptibility to infections [25,26,27]. Preterm infants also show a more rapid and earlier decrease in IgG in the postpartum period than term infants [28]. As passive immunization through transplacental maternal IgG transfer is not enough for preterm neonates, administration of intravenous immunoglobulin (iv IgG) after birth has been considered, although with limited benefits in reducing mortality or morbidity. A recent Cochrane meta-analysis tested the hypothesis that intravenous immunoglobulin supplementation in preterm or low birth weight neonates might reduce the risk of infections and any complications related to nosocomial infections. Data from more than 5000 infants enrolled showed that prophylactic use of iv IgG resulted in 3% reduction in sepsis and 4% reduction in severe infection, but without having a significant impact on neonatal mortality or other important neonatal outcomes such as length of hospital stay. Consequently, there is no general recommendation on prophylactic use of iv IgG in preterm neonates and there should be an individualized decision based on local resources. These results were consistent with previous data published in 2013 [29].

The immunoglobulin rise in the fetal circulation is different between the four types of IgG. The fastest transfer was observed for IgG1 and the slowest for IgG2. At term, in the fetal circulation IgG1 level was seven times higher than IgG2 level. There are also differences between the two IgG types compared to maternal levels: fetal IgG1 level exceed the maternal concentration near term or after birth, while fetal IgG2 remain below maternal level [24,30]. These differences were considered to be due to a preferential transfer of natural killer (NK) cell-activating antibodies, which could be explained through different affinities of neonatal Fc receptors towards specific components (glycans) in the Fc region [31].

Serum maternal immunoglobulin levels correlate to the placental transfer and neonatal IgG levels. Higher maternal IgG levels, above 15 g/L, have a negative influence on transplacental IgG passage and correlate to lower neonatal IgG levels, although in normal conditions fetal IgG levels in the third trimester surpass the maternal concentration. Paradoxically, when maternal level is too high, as is the case in maternal hypergammaglobulinemia, FcRn are oversaturated and unbound IgG molecules are destroyed [7], leading to decreased fetal antibody transfer. A similar effect is observed in black women, who normally have a higher level of total IgG than white women; therefore, one could say that transplacental transfer is correlated to maternal race [32].

On the other hand, in immunocompromised women secondary to HIV infection, reduced humoral immune response and reduced antibody production are linked with poor transfer of antibodies against specific pathogens such as group B streptoccocus, pertussis or Haemophilus influenzae [33,34]. In women with primary immunodeficiency with underlying specific gene mutation, exogenous IgG administration is essential to prevent severe maternal and fetal infections. It was observed that in these cases, immunoglobulin transfer across the placenta is similar to the transfer of endogenous antibodies [35].

With an unclear mechanism of impairment, placental malaria has been associated with reduced IgG transplacental transfer [34].