Epidemiology of Pregnancy Complications Through the Lens of Immunological Memory

Abstract

In the fifteen minutes it takes to read this short commentary, more than 400 babies will have been born too early, another 300 expecting mothers will develop preeclampsia, and 75 unborn third trimester fetuses will have died in utero (stillbirth). Given the lack of meaningful progress in understanding the physiological changes that occur to allow a healthy, full term pregnancy, it is perhaps not surprising that effective therapies against these great obstetrical syndromes that include prematurity, preeclampsia, and stillbirth remain elusive. Meanwhile, pregnancy complications remain the leading cause of infant and childhood mortality under age five. Does it have to be this way? What more can we collectively, as a biomedical community, or individually, as clinicians who care for women and newborn babies at high risk for pregnancy complications, do to protect individuals in these extremely vulnerable developmental windows? The problem of pregnancy complications and neonatal mortality is extraordinarily complex, with multiple unique, but complementary perspectives from scientific, epidemiological and public health viewpoints. Herein, we discuss the epidemiology of pregnancy complications, focusing on how the outcome of prior pregnancy impacts the risk of complication in the next pregnancy — and how the fundamental immunological principle of memory may promote this adaptive response.

Multiomic signals associated with maternal epidemiological factors contributing to preterm birth in low- and middle-income countries

“…Our results suggest that multiparous women might have an incrementally decreased up-regulation eNOS and CXCL13, reflecting a form of “pregnancy memory” ( 77 ) in which maternal adaptations to pregnancy affect future pregnancies. Pregnancy memory has previously been studied in the context of the prediction of PTB ( 59 ), specifically given that having a previous PTB and nulliparity are both risk factors of PTB ( 8 , 9 , 78 ).…”

Reproductive outcomes after pregnancy-induced displacement of preexisting microchimeric cells

“…S5) ( 22 ), highlighting fetal APC-controlled T reg cell differentiation along with maternal APC-primed CD4 cell expansion ( 26 ). Fetal-specific T reg cells reaccumulate with increased tempo upon fetal antigen restimulation, which is associated with enhanced resiliency against Lm prenatal infection and other perturbations in fetal tolerance that require MHC haplotype shared paternity in first and second pregnancies ( 7 , 12 ). These preclinical findings go along with reduced incidence of preeclampsia and other pregnancy complications in women with prior healthy pregnancy, and the partner specificity of these protective benefits ( 9 – 12 ).…”

“…Fetal-specific T reg cells reaccumulate with increased tempo upon fetal antigen restimulation, which is associated with enhanced resiliency against Lm prenatal infection and other perturbations in fetal tolerance that require MHC haplotype shared paternity in first and second pregnancies (7, 12). These preclinical findings go along with reduced incidence of preeclampsia and other pregnancy complications in women with prior healthy pregnancy, and the partner specificity of these protective benefits (9)(10)(11)(12). Given the plasticity of NIMA-specific tolerance, with MMc displacement and loss of resiliency against pregnancy complications after pregnancy sired by males without shared NIMAs, analogous experiments evaluated how a change in paternity affects preexisting FMcs and fetal-specific tolerance primed by primary pregnancy (Fig.…”

“…The necessity for FOXP3 + cells is further demonstrated in preclinical studies showing that fetal antigen stimulation primes maternal T reg cell expansion, and fetal wastage can be triggered by FOXP3 + cell depletion ( 5 – 8 ). Maternal T reg cells with fetal specificity remain expanded in mothers after parturition, and their accelerated reaccumulation in subsequent pregnancy represents an instructive framework for investigating how prior pregnancy confers partner-specific resiliency against complications in future pregnancy ( 9 – 12 ). However, memory features for fetal-specific T reg cells also raise questions as to whether low-level antigenic stimulation is required, similar to effector CD4 cells with microbial specificity ( 13 – 15 ), and the postpartum fetal antigen source, if such reminders are indeed necessary.…”

The vaginal microbiota of pregnant women varies with gestational age, maternal age, and parity

“…Specifically, parity was positively correlated with alpha diversity (Table 2). One potential explanation for the association between parity and increased alpha diversity is that there is a marked increase in the alpha diversity of the vaginal microbiota after live birth (85,104), and this phenomenon may be cumulative across multiple pregnancies, mirroring maternal-fetal immunological memory (105)(106)(107)(108). Notably, this phenomenon cannot be explained simply by advancing maternal age, since this covariate was not positively correlated with alpha diversity of the vaginal microbiota (Table 2).…”