For decades, the maternal–fetal interface was framed as an immunologic paradox: how does a mother’s immune system tolerate a fetus that is, in part, genetically foreign? Pregnancy was often described as a state of immune privilege, in which immune activity is dampened to protect the developing fetus.
Scott Gordon, MD, PhD, an attending neonatologist in the Division of Neonatology at Children’s Hospital of Philadelphia (CHOP) and principal investigator of the Scott Gordon Laboratory, is challenging that paradigm. His work positions pregnancy not as immunologic quietude, but as a period of intense and highly coordinated immune activity, one that is essential for placental development and, ultimately, neonatal outcomes.
Trained as a basic immunologist and practicing as a clinician in CHOP’s Harriet and Ronald Lassin Newborn/Infant Intensive Care Unit, Dr. Gordon studies how maternal immune cells shape the earliest stages of placental formation, and how disruptions in that process reverberate across pregnancy, contributing to preterm birth, fetal growth restriction, preeclampsia and neonatal morbidity.
In the Q&A below, Dr. Gordon explains how insights from basic immunology are reshaping our understanding of placental development, why events in the first trimester matter for neonatal outcomes, and how this work may inform future strategies to prevent — not just treat — the conditions that define modern neonatology.
What is the central question your lab is trying to answer?
At a high level, we’re trying to understand how maternal uterine immune cells promote healthy placental development.
The placenta is entirely fetal in origin, yet it must invade deeply into maternal tissue to establish the vascular and metabolic connections that support fetal growth. Most of that development happens during the first trimester of pregnancy.
If placental development is disrupted during that window, the consequences can be profound. Many of the outcomes we manage in neonatology — preterm birth, preeclampsia, fetal growth restriction, even fetal demise — are linked to abnormal placentation. The same is true for recurrent implantation failure in IVF. Understanding how a “good” placenta forms is therefore foundational to improving maternal and neonatal health.
What surprised me when I entered this field was the degree to which the uterine environment is immunologically active at the time of implantation. Rather than suppressing immune responses, pregnancy appears to depend on them.
How did your background in basic immunology lead you into placental and pregnancy research?
I’ve been interested in immunology since college, particularly how immune cells develop and acquire function. During my PhD, I studied natural killer (NK) cells, which are best known for their roles in antiviral and antitumor immunity.
At the time, I didn’t expect that work to resurface in my later career. But when I began focusing on pregnancy and neonatal outcomes, I found myself returning to NK cells in an entirely different context. It turns out that NK cells are the most abundant immune cell type in the uterine lining at the time of implantation, sometimes accounting for 75% to 80% of immune cells in that environment.
That observation fundamentally changed how I thought about pregnancy. The same immune programs that allow NK cells to fight infection are being repurposed to support placental development. My clinical training in neonatology made the relevance of that biology immediately clear.
What are uterine NK cells doing during early pregnancy?
That’s the central question we’re pursuing.
We know that uterine NK cells directly interact with fetal cells that form the placenta. They release signaling molecules into the local environment that support placental assembly and function. But we don’t yet understand which signals matter most, how those signals are regulated, or how they change under stress.
What makes your lab’s approach distinct within immunology research?
Much of immunology focuses on infection, cancer or vaccination. We still study infection, but always in the context of pregnancy.
Our lab is focused on how immune cells behave within the uterine environment. Uterine immune cells may share lineage markers with immune cells in blood or other organs, but functionally they are distinct. Understanding that specialization is critical.
Pregnancy research has historically lagged behind other areas of immunology. It’s technically challenging, samples are precious, and political and funding environments have had real effects on progress. But the need is enormous. We still lack a basic mechanistic understanding of reproductive immunology compared to other fields.
Can you describe a project that reflects the current direction of your work?
One major focus is defining the molecular signals that act on uterine NK cells early in pregnancy to support placental development. We’re trying to understand what distinguishes these cells at a molecular level and which pathways are essential for their function.
We’re also studying how perturbations in the maternal environment affect immune–placental communication. For example, hormonal stimulation prior to in vitro fertilization is a high-risk period, and we’ve shown that NK cells in that context can be reduced in number and altered in function.
Another line of work examines congenital viral infections. Some viruses cause only mild disease outside of pregnancy but can severely disrupt placental development during gestation, leading to poor fetal outcomes. Understanding which immune responses protect the placenta — and which inadvertently cause harm — is a major goal.
How does this bench work connect to neonatal care?
As neonatologists, we see the downstream consequences of placental failure every day. Whether it’s spontaneous preterm birth, severe preeclampsia or extreme prematurity after repeated IVF attempts, these outcomes are deeply connected to what happened early in pregnancy.
My long-term goal is prevention. If we can identify high-risk pregnancies early, understand whether placental development is threatened, and intervene appropriately, we could fundamentally change neonatal outcomes.
The vision — still long-term — is to identify targetable pathways and eventually develop interventions that support immune–placental communication. If that reduces the number of infants we care for in the NICU, that would be a success.
How does CHOP’s research environment support this work?
The CHOP–Penn ecosystem is essential. I collaborate closely with reproductive endocrinologists, bioengineers and other investigators working at the intersection of maternal and fetal health.
This work depends on interdisciplinary collaboration — neonatology, immunology, reproductive medicine, engineering. CHOP provides an environment where those connections are not only possible, but integral to the research mission.
What do you most want neonatologists and researchers to take away from your work?
Many of the conditions we manage in the NICU are consequences of events that occurred very early in pregnancy. Reframing neonatal disease through that lens opens new possibilities for prevention.
If this work encourages more clinicians and scientists to engage in reproductive and placental research, that’s critical. Improving pregnancy outcomes is one of the most powerful ways we can improve neonatal health.
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For decades, the maternal–fetal interface was framed as an immunologic paradox: how does a mother’s immune system tolerate a fetus that is, in part, genetically foreign? Pregnancy was often described as a state of immune privilege, in which immune activity is dampened to protect the developing fetus.
Scott Gordon, MD, PhD, an attending neonatologist in the Division of Neonatology at Children’s Hospital of Philadelphia (CHOP) and principal investigator of the Scott Gordon Laboratory, is challenging that paradigm. His work positions pregnancy not as immunologic quietude, but as a period of intense and highly coordinated immune activity, one that is essential for placental development and, ultimately, neonatal outcomes.
Trained as a basic immunologist and practicing as a clinician in CHOP’s Harriet and Ronald Lassin Newborn/Infant Intensive Care Unit, Dr. Gordon studies how maternal immune cells shape the earliest stages of placental formation, and how disruptions in that process reverberate across pregnancy, contributing to preterm birth, fetal growth restriction, preeclampsia and neonatal morbidity.
In the Q&A below, Dr. Gordon explains how insights from basic immunology are reshaping our understanding of placental development, why events in the first trimester matter for neonatal outcomes, and how this work may inform future strategies to prevent — not just treat — the conditions that define modern neonatology.
What is the central question your lab is trying to answer?
At a high level, we’re trying to understand how maternal uterine immune cells promote healthy placental development.
The placenta is entirely fetal in origin, yet it must invade deeply into maternal tissue to establish the vascular and metabolic connections that support fetal growth. Most of that development happens during the first trimester of pregnancy.
If placental development is disrupted during that window, the consequences can be profound. Many of the outcomes we manage in neonatology — preterm birth, preeclampsia, fetal growth restriction, even fetal demise — are linked to abnormal placentation. The same is true for recurrent implantation failure in IVF. Understanding how a “good” placenta forms is therefore foundational to improving maternal and neonatal health.
What surprised me when I entered this field was the degree to which the uterine environment is immunologically active at the time of implantation. Rather than suppressing immune responses, pregnancy appears to depend on them.
How did your background in basic immunology lead you into placental and pregnancy research?
I’ve been interested in immunology since college, particularly how immune cells develop and acquire function. During my PhD, I studied natural killer (NK) cells, which are best known for their roles in antiviral and antitumor immunity.
At the time, I didn’t expect that work to resurface in my later career. But when I began focusing on pregnancy and neonatal outcomes, I found myself returning to NK cells in an entirely different context. It turns out that NK cells are the most abundant immune cell type in the uterine lining at the time of implantation, sometimes accounting for 75% to 80% of immune cells in that environment.
That observation fundamentally changed how I thought about pregnancy. The same immune programs that allow NK cells to fight infection are being repurposed to support placental development. My clinical training in neonatology made the relevance of that biology immediately clear.
What are uterine NK cells doing during early pregnancy?
That’s the central question we’re pursuing.
We know that uterine NK cells directly interact with fetal cells that form the placenta. They release signaling molecules into the local environment that support placental assembly and function. But we don’t yet understand which signals matter most, how those signals are regulated, or how they change under stress.
What makes your lab’s approach distinct within immunology research?
Much of immunology focuses on infection, cancer or vaccination. We still study infection, but always in the context of pregnancy.
Our lab is focused on how immune cells behave within the uterine environment. Uterine immune cells may share lineage markers with immune cells in blood or other organs, but functionally they are distinct. Understanding that specialization is critical.
Pregnancy research has historically lagged behind other areas of immunology. It’s technically challenging, samples are precious, and political and funding environments have had real effects on progress. But the need is enormous. We still lack a basic mechanistic understanding of reproductive immunology compared to other fields.
Can you describe a project that reflects the current direction of your work?
One major focus is defining the molecular signals that act on uterine NK cells early in pregnancy to support placental development. We’re trying to understand what distinguishes these cells at a molecular level and which pathways are essential for their function.
We’re also studying how perturbations in the maternal environment affect immune–placental communication. For example, hormonal stimulation prior to in vitro fertilization is a high-risk period, and we’ve shown that NK cells in that context can be reduced in number and altered in function.
Another line of work examines congenital viral infections. Some viruses cause only mild disease outside of pregnancy but can severely disrupt placental development during gestation, leading to poor fetal outcomes. Understanding which immune responses protect the placenta — and which inadvertently cause harm — is a major goal.
How does this bench work connect to neonatal care?
As neonatologists, we see the downstream consequences of placental failure every day. Whether it’s spontaneous preterm birth, severe preeclampsia or extreme prematurity after repeated IVF attempts, these outcomes are deeply connected to what happened early in pregnancy.
My long-term goal is prevention. If we can identify high-risk pregnancies early, understand whether placental development is threatened, and intervene appropriately, we could fundamentally change neonatal outcomes.
The vision — still long-term — is to identify targetable pathways and eventually develop interventions that support immune–placental communication. If that reduces the number of infants we care for in the NICU, that would be a success.
How does CHOP’s research environment support this work?
The CHOP–Penn ecosystem is essential. I collaborate closely with reproductive endocrinologists, bioengineers and other investigators working at the intersection of maternal and fetal health.
This work depends on interdisciplinary collaboration — neonatology, immunology, reproductive medicine, engineering. CHOP provides an environment where those connections are not only possible, but integral to the research mission.
What do you most want neonatologists and researchers to take away from your work?
Many of the conditions we manage in the NICU are consequences of events that occurred very early in pregnancy. Reframing neonatal disease through that lens opens new possibilities for prevention.
If this work encourages more clinicians and scientists to engage in reproductive and placental research, that’s critical. Improving pregnancy outcomes is one of the most powerful ways we can improve neonatal health.
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