# Parity, paternity and pregnancy outcomes

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $575,901

## Abstract

Abstract. Prematurity remains the leading cause of infant mortality, responsible for well over 1 million deaths
each year. Another 1.9 million babies are estimated to die in utero from stillbirth. We do not have effective
cures because our understanding of how pregnancy works remains rudimentary. Important clues come from
human epidemiological studies highlighting protective benefits of prior pregnancy against complications in
future pregnancy, and the partner specificity of these effects. For example, the risk of preeclampsia is sharply
reduced in women with prior healthy pregnancy, but rebounds with a change in paternity in subsequent
pregnancy. Partner-specific resiliency against pregnancy complications is reproduced in mice using inbred
strains expressing defined MHC haplotype or other model antigens for siring first and subsequent pregnancies.
These parallels establish our scientific premise that investigating how fetal-expressed antigens are recognized
and remembered by mothers will efficiently unveil essential new knowledge on how pregnancy works, and
urgently needed strategies for improving pregnancy outcomes. Pregnancy in humans and mice each stimulate
expansion of immune suppressive maternal CD4 T cells that express the FOXP3 transcriptional regulator,
called regulatory T cells (Tregs). Tracking maternal CD4 cells using antigen-specific tools show selective Treg
expansion among cells with fetal-specificity. In turn, resiliency against pregnancy complications is associated
with postpartum persistence fetal-specific “memory” Tregs, establishing an instructive framework for
investigating how mothers immunologically remember their children. Our recent studies tracking maternal CD4
cells using FOXP3 lineage fate tracking reporter mice further show a large proportion (40-70%) of fetal-specific
Tregs loose FOXP3 expression after parturition. These FOXP3-negative “exTregs” are essential for enhanced
resiliency against complications in future pregnancy, because their depletion overrides the protective benefits
of adoptively transferred postpartum donor splenocytes. At the same time, these findings also highlight exciting
new gaps in knowledge regarding the interplay between FOXP3 expression plasticity, fetal tolerance and
pregnancy outcomes. These knowledge gaps, directly aligned with the goals of RFA-AI-23-027, Immune
mechanisms at the maternal-fetal interface, will be addressed through the following specific aims designed to
further investigate our overall hypothesis that mothers remember not only through fetal-specific FOXP3+ Treg
memory, but also via exTregs with distinct phenotypic and functional features: Establish the suppressive
molecules utilized by exTregs and FOXP3+ Tregs for enhanced resiliency against pregnancy complications
(Aim 1), Investigate maternal CD4 cell differentiation after fractured fetal tolerance induced pregnancy
complications (Aim 2), and Determine whether pregnancy primed exTregs are committed for FOXP3 re-
expressi...

## Key facts

- **NIH application ID:** 10946865
- **Project number:** 1R01AI184537-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Sing Sing Way
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $575,901
- **Award type:** 1
- **Project period:** 2024-06-10 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10946865

## Citation

> US National Institutes of Health, RePORTER application 10946865, Parity, paternity and pregnancy outcomes (1R01AI184537-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10946865. Licensed CC0.

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