Chaur-Dong Hsu

Interests

Teaching

Maternal-Fetal Medicine, Preeclampsia, High Risk Pregnancy Disorders

Research

Great Obstetrical Syndromes, Personalized Obstetrics, Preeclampsia, Intra-amniotic infection during pregnancy, Hypertension in Pregnancy

Courses

No activities entered.

Scholarly Contributions

Journals/Publications

• Hsu, C., Ahmed, M., Casanova, N., Zaghloul, N., Gupta, A., Rodriguez, M., Robbins, I. R., Kempf, C. L., Sun, X., Song, J. H., Hernon, V. R., Sammani, S., Camp, S. M., Moreira, A., & Garcia, J. G. (2023).

  The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes.

  . Frontiers in Physiology. doi:10.3389/fphys.2023.1129413
• Alhousseini, A., Romero, R., Benshalom-Tirosh, N., Gudicha, D., Pacora, P., Tirosh, D., Kabiri, D., Yeo, L., Thachil, J., Hsu, C. D., Hassan, S. S., & Erez, O. (2022). Nonovert disseminated intravascular coagulation (DIC) in pregnancy: a new scoring system for the identification of patients at risk for obstetrical hemorrhage requiring blood product transfusion. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 35(2), 242-257.
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  Nonovert disseminated intravascular coagulation (DIC) is a subclinical hemostatic dysfunction that has not yet reached the decompensation stage. The detection of pregnant patients at this stage may assist in the identification of those who will develop severe obstetrical hemorrhage, as it is one of the leading causes for preventable maternal mortality. Currently, nonovert DIC is diagnosed by a scoring system based on nonpregnant patients, originally generated by the International Society on Thrombosis and Hemostasis (ISTH), which does not address the physiologic changes of the hemostatic system during pregnancy.
• Bhatti, G., Romero, R., Gomez-Lopez, N., Chaiworapongsa, T., Jung, E., Gotsch, F., Pique-Regi, R., Pacora, P., Hsu, C. D., Kavdia, M., & Tarca, A. L. (2022). The amniotic fluid proteome changes with gestational age in normal pregnancy: a cross-sectional study. Scientific reports, 12(1), 601.
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  The cell-free transcriptome in amniotic fluid (AF) has been shown to be informative of physiologic and pathologic processes in pregnancy; however, the change in AF proteome with gestational age has mostly been studied by targeted approaches. The objective of this study was to describe the gestational age-dependent changes in the AF proteome during normal pregnancy by using an omics platform. The abundance of 1310 proteins was measured on a high-throughput aptamer-based proteomics platform in AF samples collected from women during midtrimester (16-24 weeks of gestation, n = 15) and at term without labor (37-42 weeks of gestation, n = 13). Only pregnancies without obstetrical complications were included in the study. Almost 25% (320) of AF proteins significantly changed in abundance between the midtrimester and term gestation. Of these, 154 (48.1%) proteins increased, and 166 (51.9%) decreased in abundance at term compared to midtrimester. Tissue-specific signatures of the trachea, salivary glands, brain regions, and immune system were increased while those of the gestational tissues (uterus, placenta, and ovary), cardiac myocytes, and fetal liver were decreased at term compared to midtrimester. The changes in AF protein abundance were correlated with those previously reported in the cell-free AF transcriptome. Intersecting gestational age-modulated AF proteins and their corresponding mRNAs previously reported in the maternal blood identified neutrophil-related protein/mRNA pairs that were modulated in the same direction. The first study to utilize an aptamer-based assay to profile the AF proteome modulation with gestational age, it reveals that almost one-quarter of the proteins are modulated as gestation advances, which is more than twice the fraction of altered plasma proteins (~ 10%). The results reported herein have implications for future studies focused on discovering biomarkers to predict, monitor, and diagnose obstetrical diseases.
• Garcia-Flores, V., Romero, R., Xu, Y., Theis, K. R., Arenas-Hernandez, M., Miller, D., Peyvandipour, A., Bhatti, G., Galaz, J., Gershater, M., Levenson, D., Pusod, E., Tao, L., Kracht, D., Florova, V., Leng, Y., Motomura, K., Para, R., Faucett, M., , Hsu, C. D., et al. (2022). Maternal-fetal immune responses in pregnant women infected with SARS-CoV-2. Nature communications, 13(1), 320.
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  Pregnant women represent a high-risk population for severe/critical COVID-19 and mortality. However, the maternal-fetal immune responses initiated by SARS-CoV-2 infection, and whether this virus is detectable in the placenta, are still under investigation. Here we show that SARS-CoV-2 infection during pregnancy primarily induces unique inflammatory responses at the maternal-fetal interface, which are largely governed by maternal T cells and fetal stromal cells. SARS-CoV-2 infection during pregnancy is also associated with humoral and cellular immune responses in the maternal blood, as well as with a mild cytokine response in the neonatal circulation (i.e., umbilical cord blood), without compromising the T-cell repertoire or initiating IgM responses. Importantly, SARS-CoV-2 is not detected in the placental tissues, nor is the sterility of the placenta compromised by maternal viral infection. This study provides insight into the maternal-fetal immune responses triggered by SARS-CoV-2 and emphasizes the rarity of placental infection.
• Goshgarian, G., Jawad, R., O'Brien, L., Muterspaugh, R., Zikos, D., Ezhuthachan, S., Newman, C., Hsu, C. D., Bailey, B., & Ragina, N. (2022). Prenatal Buprenorphine/Naloxone or Methadone Use on Neonatal Outcomes in Michigan. Cureus, 14(8), e27790.
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  Background Maternal opioid exposure during pregnancy has various effects on neonatal health. Buprenorphine/naloxone and methadone are examples of medications for opioid use disorder (MOUD) used for the treatment of opioid use disorder (OUD). Research comparing the impacts of these MOUD modalities on neonatal outcomes when used to treat pregnant people with OUD remains limited. We evaluated the differences in outcomes between neonates with in-utero exposure to buprenorphine/naloxone versus methadone. Methodology We performed a retrospective cohort chart review between October 15, 2008, and October 15, 2019, evaluating mother/neonate dyads at two medical centers in Michigan. The charts of female patients, aged 18+, with OUD and buprenorphine/naloxone or methadone treatment, were examined. The charts of the corresponding neonates were also examined. Multiple regression analysis was performed. Results In total, 343 mother/infant dyads were included: 99 patients were treated with buprenorphine/naloxone and 232 patients were treated with methadone. The buprenorphine/naloxone group had significant differences in maternal age, hepatitis status, asthma, gestational age in weeks, neonatal intensive care unit (NICU) length of stay (LOS), neonatal opioid withdrawal syndrome (NOWS) peak score, birth head circumference, and birth weight compared to the methadone group at baseline. Adjusted multivariable regression analysis demonstrated neonates with exposure to buprenorphine/naloxone had a NOWS peak score 3.079 points less (95% confidence interval (CI): -4.525, 1.633; p = 0.001) and NICU LOS 8.955 days less (95% CI: -14.399, -3.511; p = 0.001) than neonates exposed to methadone. Conclusions Neonates with in-utero exposure to buprenorphine/naloxone had significantly lower NOWS scores and shorter NICU LOS compared to neonates with in-utero exposure to methadone. These findings demonstrate that buprenorphine/naloxone is potentially a more favorable treatment for the reduction in metrics representing adverse neonatal outcomes in pregnant people with OUD than methadone.
• Helmi, H., Siddiqui, A., Yan, Y., Basij, M., Hernandez-Andrade, E., Gelovani, J., Hsu, C. D., Hassan, S. S., & Mehrmohammadi, M. (2022). The role of noninvasive diagnostic imaging in monitoring pregnancy and detecting patients at risk for preterm birth: a review of quantitative approaches. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 35(3), 568-591.
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  Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. The ability to predict patients at risk for preterm birth remains a major health challenge. The currently available clinical diagnostics such as cervical length and fetal fibronectin may detect only up to 30% of patients who eventually experience a spontaneous preterm birth. This paper reviews ongoing efforts to improve the ability to conduct a risk assessment for preterm birth. In particular, this work focuses on quantitative methods of imaging using ultrasound-based techniques, magnetic resonance imaging, and optical imaging modalities. While ultrasound imaging is the major modality for preterm birth risk assessment, a summary of efforts to adopt other imaging modalities is also discussed to identify the technical and diagnostic limits associated with adopting them in clinical settings. We conclude the review by proposing a new approach using combined photoacoustic, ultrasound, and elastography as a potential means to better assess cervical tissue remodeling, and thus improve the detection of patients at-risk of PTB.
• Para, R., Romero, R., Gomez-Lopez, N., Tarca, A. L., Panaitescu, B., Done, B., Hsu, R., Pacora, P., & Hsu, C. D. (2022). Maternal circulating concentrations of soluble Fas and Elabela in early- and late-onset preeclampsia. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 35(2), 316-329.
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  The Fas/Fas ligand (FASL) system and Elabela-apelin receptor signaling pathways are implicated in the pathophysiology of preeclampsia. The aim of the current study was to investigate whether a model combining the measurement of sFas and Elabela in the maternal circulation may serve as a clinical biomarker for early- and/or late-onset preeclampsia more effectively than measures of each biomarker individually.
• Pique-Regi, R., Romero, R., Garcia-Flores, V., Peyvandipour, A., Tarca, A. L., Pusod, E., Galaz, J., Miller, D., Bhatti, G., Para, R., Kanninen, T., Hadaya, O., Paredes, C., Motomura, K., Johnson, J. R., Jung, E., Hsu, C. D., Berry, S. M., & Gomez-Lopez, N. (2022). A single-cell atlas of the myometrium in human parturition. JCI insight, 7(5).
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  Parturition is a well-orchestrated process characterized by increased uterine contractility, cervical ripening, and activation of the chorioamniotic membranes; yet, the transition from a quiescent to a contractile myometrium heralds the onset of labor. However, the cellular underpinnings of human parturition in the uterine tissues are still poorly understood. Herein, we performed a comprehensive study of the human myometrium during spontaneous term labor using single-cell RNA sequencing (scRNA-Seq). First, we established a single-cell atlas of the human myometrium and unraveled the cell type-specific transcriptomic activity modulated during labor. Major cell types included distinct subsets of smooth muscle cells, monocytes/macrophages, stromal cells, and endothelial cells, all of which communicated and participated in immune (e.g., inflammation) and nonimmune (e.g., contraction) processes associated with labor. Furthermore, integrating scRNA-Seq and microarray data with deconvolution of bulk gene expression highlighted the contribution of smooth muscle cells to labor-associated contractility and inflammatory processes. Last, myometrium-derived single-cell signatures can be quantified in the maternal whole-blood transcriptome throughout pregnancy and are enriched in women in labor, providing a potential means of noninvasively monitoring pregnancy and its complications. Together, our findings provide insights into the contributions of specific myometrial cell types to the biological processes that take place during term parturition.
• Uzianbaeva, L., Yan, Y., Joshi, T., Yin, N., Hsu, C. D., Hernandez-Andrade, E., & Mehrmohammadi, M. (2022). Methods for Monitoring Risk of Hypoxic Damage in Fetal and Neonatal Brains: A Review. Fetal diagnosis and therapy, 49(1-2), 1-24.
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  Fetal, perinatal, and neonatal asphyxia are vital health issues for the most vulnerable groups in human beings, including fetuses, newborns, and infants. Severe reduction in oxygen and blood supply to the fetal brain can cause hypoxic-ischemic encephalopathy (HIE), leading to long-term neurological disorders, including mental impairment and cerebral palsy. Such neurological disorders are major healthcare concerns. Therefore, there has been a continuous effort to develop clinically useful diagnostic tools for accurately and quantitatively measuring and monitoring blood and oxygen supply to the fetal and neonatal brain to avoid severe consequences of asphyxia HIE and neonatal encephalopathy. Major diagnostic technologies used for this purpose include fetal heart rate monitoring, fetus scalp blood sampling, ultrasound imaging, magnetic resonance imaging, X-ray computed tomography, and nuclear medicine. In addition, given the limitations and shortcomings of traditional diagnostic methods, emerging technologies such as near-infrared spectroscopy and photoacoustic imaging have also been introduced as stand-alone or complementary solutions to address this critical gap in fetal and neonatal care. This review provides a thorough overview of the traditional and emerging technologies for monitoring fetal and neonatal brain oxygenation status and describes their clinical utility, performance, advantages, and disadvantages.
• Wolf, H. M., Romero, R., Strauss, J. F., Hassan, S. S., Latendresse, S. J., Webb, B. T., Tarca, A. L., Gomez-Lopez, N., Hsu, C. D., & York, T. P. (2022). Study protocol to quantify the genetic architecture of sonographic cervical length and its relationship to spontaneous preterm birth. BMJ open, 12(3), e053631.
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  A short cervix (cervical length
• Bhatti, G., Romero, R., Gomez-Lopez, N., Pique-Regi, R., Pacora, P., Jung, E., Yeo, L., Hsu, C. D., Kavdia, M., & Tarca, A. L. (2021). The amniotic fluid cell-free transcriptome in spontaneous preterm labor. Scientific reports, 11(1), 13481.
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  The amniotic fluid (AF) cell-free RNA was shown to reflect physiological and pathological processes in pregnancy, but its value in the prediction of spontaneous preterm delivery is unknown. Herein we profiled cell-free RNA in AF samples collected from women who underwent transabdominal amniocentesis after an episode of spontaneous preterm labor and subsequently delivered within 24 h (n = 10) or later (n = 28) in gestation. Expression of known placental single-cell RNA-Seq signatures was quantified in AF cell-free RNA and compared between the groups. Random forest models were applied to predict time-to-delivery after amniocentesis. There were 2385 genes differentially expressed in AF samples of women who delivered within 24 h of amniocentesis compared to gestational age-matched samples from women who delivered after 24 h of amniocentesis. Genes with cell-free RNA changes were associated with immune and inflammatory processes related to the onset of labor, and the expression of placental single-cell RNA-Seq signatures of immune cells was increased with imminent delivery. AF transcriptomic prediction models captured these effects and predicted delivery within 24 h of amniocentesis (AUROC = 0.81). These results may inform the development of biomarkers for spontaneous preterm birth.
• D'Mello, R. J., Hsu, C. D., Chaiworapongsa, P., & Chaiworapongsa, T. (2021). Update on the Use of Intravenous Immunoglobulin in Pregnancy. NeoReviews, 22(1), e7-e24.
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  Intravenous immunoglobulin (IVIG) was first administered to humans in the 1980s. The mechanism of action of IVIG is still a subject of debate but the pharmacokinetics have been well characterized, albeit outside of pregnancy. IVIG has been used in pregnancy to treat several nonobstetrical and obstetrical-related conditions. However, current evidence suggests that IVIG use during pregnancy can be recommended for 1) in utero diagnosis of neonatal alloimmune thrombocytopenia; 2) gestational alloimmune liver disease; 3) hemolytic disease of the fetus and newborn for early-onset severe intrauterine disease; 4) antiphospholipid syndrome (APS) when refractory to or contraindicated to standard treatment, or in catastrophic antiphospholipid syndrome; and 5) immune thrombocytopenia when standard treatment is ineffective or rapid increase of platelet counts is needed. All recommendations are based on case series and cohort studies without randomized trials usually because of the rare prevalence of the conditions, the high incidence of adverse outcomes if left untreated, and ethical concerns. In contrast, IVIG therapy cannot be recommended for recurrent pregnancy loss, and the use of IVIG in subgroups of those with recurrent pregnancy loss requires further investigations. For non-obstetrical-related conditions, we recommend using IVIG as indicated for nonpregnant patients. In conclusion, the use of IVIG during pregnancy is an effective treatment in some obstetrical-related conditions with rare serious maternal side effects. However, the precise mechanisms of action and the long-term immunologic effects on the fetus and neonate are poorly understood and merit further investigations.
• Garcia-Flores, V., Romero, R., Xu, Y., Theis, K., Arenas-Hernandez, M., Miller, D., Peyvandipour, A., Galaz, J., Levenson, D., Bhatti, G., Gershater, M., Pusod, E., Kracht, D., Florova, V., Leng, Y., Tao, L., Faucett, M., Para, R., Hsu, C. D., , Zhang, G., et al. (2021). Maternal-Fetal Immune Responses in Pregnant Women Infected with SARS-CoV-2. Research square.
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  Pregnant women are a high-risk population for severe/critical COVID-19 and mortality. However, the maternal-fetal immune responses initiated by SARS-CoV-2 infection, and whether this virus is detectable in the placenta, are still under investigation. Herein, we report that SARS-CoV-2 infection during pregnancy primarily induced specific maternal inflammatory responses in the circulation and at the maternal-fetal interface, the latter being governed by T cells and macrophages. SARS-CoV-2 infection during pregnancy was also associated with a cytokine response in the fetal circulation (i.e. umbilical cord blood) without compromising the cellular immune repertoire. Moreover, SARS-CoV-2 infection neither altered fetal cellular immune responses in the placenta nor induced elevated cord blood levels of IgM. Importantly, SARS-CoV-2 was not detected in the placental tissues, nor was the sterility of the placenta compromised by maternal viral infection. This study provides insight into the maternal-fetal immune responses triggered by SARS-CoV-2 and further emphasizes the rarity of placental infection.
• Gomez-Lopez, N., Romero, R., Panaitescu, B., Miller, D., Zou, C., Gudicha, D. W., Tarca, A. L., Para, R., Pacora, P., Hassan, S. S., & Hsu, C. D. (2021). Gasdermin D: evidence of pyroptosis in spontaneous labor at term. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 34(4), 569-579.
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  Pyroptosis is an inflammatory form of programmed cell death that is mediated by the activation of the inflammasome and depends on the pore-forming function of gasdermin D. Therefore, the detection of gasdermin D represents evidence of pyroptosis. We recently showed that there is intra-amniotic inflammasome activation in spontaneous labor at term; however, evidence of pyroptosis is lacking. The objectives of this study were to investigate (1) whether gasdermin D is detectable in the amniotic fluid of women who delivered at term; (2) whether amniotic fluid gasdermin D concentrations are associated with the process of spontaneous labor at term; and (3) whether gasdermin D is expressed in the chorioamniotic membranes from these patients. This retrospective cross-sectional study included amniotic fluid samples from 41 women who underwent spontaneous labor at term ( = 17) or delivered at term without labor ( = 24). As a readout of pyroptosis, gasdermin D was determined in amniotic fluid samples using a specific and sensitive ELISA kit. The 90th percentile of amniotic fluid gasdermin D concentrations was calculated among women without spontaneous labor at term (reference group). The association between high amniotic fluid gasdermin D concentrations (≥90th percentile in the reference group) and spontaneous labor at term was tested using the Fisher's exact test. A value  3.4 ng/mL were significantly associated with the presence of spontaneous labor in women who delivered at term (odds ratio 6.0, -value .048); and (5) the protein expression of gasdermin D is increased in the chorioamniotic membranes of women who underwent spontaneous labor at term and is colocalized with caspase-1 and IL-1β. Gasdermin D is increased in the amniotic fluid and chorioamniotic membranes of women who underwent spontaneous labor at term compared to those without labor. These data provide evidence implicating pyroptosis in the mechanisms that lead to the sterile inflammatory process of term parturition.
• Hsu, C. (2021). Prediction of preeclampsia throughout gestation with maternal characteristics and biophysical and biochemical markers: a longitudinal study. American Journal of Obstetrics & Gynecology.
• Hsu, C. (2021). Update on the Use of Intravenous Immunoglobulin in Pregnancy.. Neoreviews. doi:10.1542/neo.22-1-e7
• Hsu, R., Tong, A., & Hsu, C. D. (2021). Hypervolemic Hyponatremia as a Reversible Cause of Cardiopulmonary Arrest in a Postpartum Patient with Preeclampsia. Case reports in obstetrics and gynecology, 2021, 8850725.
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  Although the incidence of preeclampsia complicated by hyponatremia is reportedly rare, the effects on the maternal outcome are severe and life-threatening. Here, we describe a case of a patient with preeclampsia who coded postpartum and was discovered to have hypervolemic hyponatremia and subsequently recovered after fluid diuresis and resolution of hyponatremia. While hyponatremia in preeclampsia is rare, it is even more unique for it to lead to cardiopulmonary arrest consequently. Therefore, sodium levels and fluid status should be monitored closely and promptly corrected without delay to prevent cardiopulmonary arrest in patients with preeclampsia.
• Jaiman, S., Romero, R., Pacora, P., Erez, O., Jung, E., Tarca, A. L., Bhatti, G., Yeo, L., Kim, Y. M., Kim, C. J., Kim, J. S., Qureshi, F., Jacques, S. M., Gomez-Lopez, N., & Hsu, C. D. (2021). Disorders of placental villous maturation are present in one-third of cases with spontaneous preterm labor. Journal of perinatal medicine, 49(4), 412-430.
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  Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65-70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity.
• Jung, E., Romero, R., Yoon, B. H., Theis, K. R., Gudicha, D. W., Tarca, A. L., Diaz-Primera, R., Winters, A. D., Gomez-Lopez, N., Yeo, L., & Hsu, C. D. (2021). Bacteria in the amniotic fluid without inflammation: early colonization vs. contamination. Journal of perinatal medicine.
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  Intra-amniotic infection, defined by the presence of microorganisms in the amniotic cavity, is often accompanied by intra-amniotic inflammation. Occasionally, laboratories report the growth of bacteria or the presence of microbial nucleic acids in amniotic fluid in the absence of intra-amniotic inflammation. This study was conducted to determine the clinical significance of the presence of bacteria in amniotic fluid samples in the absence of intra-amniotic inflammation.
• Motomura, K., Romero, R., Galaz, J., Tarca, A. L., Done, B., Xu, Y., Leng, Y., Garcia-Flores, V., Arenas-Hernandez, M., Theis, K. R., Gershater, M., Jung, E., Hsu, C. D., & Gomez-Lopez, N. (2021). RNA Sequencing Reveals Distinct Immune Responses in the Chorioamniotic Membranes of Women with Preterm Labor and Microbial or Sterile Intra-amniotic Inflammation. Infection and immunity, 89(5).
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  Preterm labor precedes premature birth, the leading cause of neonatal morbidity and mortality worldwide. Preterm labor can occur in the context of either microbe-associated intra-amniotic inflammation (i.e., intra-amniotic infection) or intra-amniotic inflammation in the absence of detectable microorganisms (i.e., sterile intra-amniotic inflammation). Both intra-amniotic infection and sterile intra-amniotic inflammation trigger local immune responses that have deleterious effects on fetal life. Yet, the extent of such immune responses in the fetal tissues surrounding the amniotic cavity (i.e., the chorioamniotic membranes) is poorly understood. By using RNA sequencing (RNA seq) as a discovery approach, we found that there were significant transcriptomic differences involving host response to pathogens in the chorioamniotic membranes of women with intra-amniotic infection compared to those from women without inflammation. In addition, the sterile or microbial nature of intra-amniotic inflammation was associated with distinct transcriptomic profiles in the chorioamniotic membranes. Moreover, the immune response in the chorioamniotic membranes of women with sterile intra-amniotic inflammation was milder in nature than that induced by microbes and involved the upregulation of alarmins and inflammasome-related molecules. Lastly, the presence of maternal and fetal inflammatory responses in the placenta was associated with the upregulation of immune processes in the chorioamniotic membranes. Collectively, these findings provide insight into the immune responses against microbes or alarmins that take place in the fetal tissues surrounding the amniotic cavity, shedding light on the immunobiology of preterm labor and birth.
• Nguyen, T., Khaksari, K., Khare, S. M., Park, S., Anderson, A. A., Bieda, J., Jung, E., Hsu, C. D., Romero, R., & Gandjbakhche, A. H. (2021). Non-invasive transabdominal measurement of placental oxygenation: a step toward continuous monitoring. Biomedical optics express, 12(7), 4119-4130.
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  This study aimed to assess transabdominal placental oxygenation levels non-invasively. A wearable device was designed and tested in 12 pregnant women with an anterior placenta, 5 of whom had maternal pregnancy complications. Preliminary results revealed that the placental oxygenation level is closely related to pregnancy complications and placental pathology. Women with maternal pregnancy complications were found to have a lower placental oxygenation level (69.4% ± 6.7%) than those with uncomplicated pregnancy (75.0% ± 5.8%). This device is a step in the development of a point-of-care method designed to continuously monitor placental oxygenation and to assess maternal and fetal health.
• Pacora, P., Romero, R., Jung, E., Gudicha, D. W., Hernandez-Andrade, E., Musilova, I., Kacerovsky, M., Jaiman, S., Erez, O., Hsu, C. D., & Tarca, A. L. (2021). Reduced fetal growth velocity precedes antepartum fetal death. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology, 57(6), 942-952.
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  To determine whether decreased fetal growth velocity precedes antepartum fetal death and to evaluate whether fetal growth velocity is a better predictor of antepartum fetal death compared to a single fetal biometric measurement at the last available ultrasound scan prior to diagnosis of demise.
• Romero, R., Pacora, P., Kusanovic, J. P., Jung, E., Panaitescu, B., Maymon, E., Erez, O., Berman, S., Bryant, D. R., Gomez-Lopez, N., Theis, K. R., Bhatti, G., Kim, C. J., Yoon, B. H., Hassan, S. S., Hsu, C. D., Yeo, L., Diaz-Primera, R., Marin-Concha, J., , Lannaman, K., et al. (2021). Clinical chorioamnionitis at term X: microbiology, clinical signs, placental pathology, and neonatal bacteremia - implications for clinical care. Journal of perinatal medicine, 49(3), 275-298.
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  Clinical chorioamnionitis at term is considered the most common infection-related diagnosis in labor and delivery units worldwide. The syndrome affects 5-12% of all term pregnancies and is a leading cause of maternal morbidity and mortality as well as neonatal death and sepsis. The objectives of this study were to determine the (1) amniotic fluid microbiology using cultivation and molecular microbiologic techniques; (2) diagnostic accuracy of the clinical criteria used to identify patients with intra-amniotic infection; (3) relationship between acute inflammatory lesions of the placenta (maternal and fetal inflammatory responses) and amniotic fluid microbiology and inflammatory markers; and (4) frequency of neonatal bacteremia.
• Tarca, A. L., Pataki, B. Á., Romero, R., Sirota, M., Guan, Y., Kutum, R., Gomez-Lopez, N., Done, B., Bhatti, G., Yu, T., Andreoletti, G., Chaiworapongsa, T., , D. P., Hassan, S. S., Hsu, C. D., Aghaeepour, N., Stolovitzky, G., Csabai, I., & Costello, J. C. (2021). Crowdsourcing assessment of maternal blood multi-omics for predicting gestational age and preterm birth. Cell reports. Medicine, 2(6), 100323.
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  Identification of pregnancies at risk of preterm birth (PTB), the leading cause of newborn deaths, remains challenging given the syndromic nature of the disease. We report a longitudinal multi-omics study coupled with a DREAM challenge to develop predictive models of PTB. The findings indicate that whole-blood gene expression predicts ultrasound-based gestational ages in normal and complicated pregnancies (r = 0.83) and, using data collected before 37 weeks of gestation, also predicts the delivery date in both normal pregnancies (r = 0.86) and those with spontaneous preterm birth (r = 0.75). Based on samples collected before 33 weeks in asymptomatic women, our analysis suggests that expression changes preceding preterm prelabor rupture of the membranes are consistent across time points and cohorts and involve leukocyte-mediated immunity. Models built from plasma proteomic data predict spontaneous preterm delivery with intact membranes with higher accuracy and earlier in pregnancy than transcriptomic models (AUROC = 0.76 versus AUROC = 0.6 at 27-33 weeks of gestation).
• Yeo, L., Romero, R., Chaiworapongsa, T., Para, R., Johnson, J., Kmak, D., Jung, E., Yoon, B. H., & Hsu, C. D. (2021). Resolution of acute cervical insufficiency after antibiotics in a case with amniotic fluid sludge. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 1-11.
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  Cervical insufficiency generally refers to a condition in which there is mid-trimester cervical dilatation or protruding chorioamniotic membranes in the absence of uterine contractions. Such condition is a risk factor for spontaneous mid-trimester abortion or early preterm birth, and is associated with adverse neonatal outcomes. Both intra-amniotic infection and inflammation ascertained by amniocentesis have been identified in patients with cervical insufficiency, and are poor prognostic factors. A subset of patients with intra-amniotic inflammation will have no demonstrable microorganisms detected via cultivation or molecular methods, and therefore represent cases of sterile intra-amniotic inflammation. Amniotic fluid sludge (free-floating hyperechogenic material within the amniotic fluid in close proximity to the uterine cervix) identified on sonography is a biomarker for intra-amniotic infection and inflammation. Recent evidence suggests that intra-amniotic infection, as well as sterile intra-amniotic inflammation can be treated successfully using antimicrobial agents. We report a unique case in which administration of antibiotics in the presence of mid-trimester cervical insufficiency, sterile intra-amniotic inflammation, and amniotic fluid sludge was associated with resolution of the cervical findings, as demonstrated on both sonographic and speculum examination. The patient successfully underwent elective cesarean delivery at 36-2/7 weeks of gestation. This case illustrates that antibiotic therapy may be effective despite the presence of several high-risk pregnancy conditions, and that successful outcome is possible.
• Florova, V., Romero, R., Tarca, A. L., Galaz, J., Motomura, K., Ahmad, M. M., Hsu, C. D., Hsu, R., Tong, A., Ravel, J., Theis, K. R., & Gomez-Lopez, N. (2020). Vaginal host immune-microbiome interactions in a cohort of primarily African-American women who ultimately underwent spontaneous preterm birth or delivered at term. Cytokine, 137, 155316.
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  Recent studies suggest that alterations in the vaginal microbiome allow for the assessment of the risk for spontaneous preterm birth (PTB), the leading cause of neonatal morbidity and mortality worldwide. However, the associations between the local immune response and the vaginal microbiome are still poorly understood. Herein, we characterize the vaginal host immune-microbiome interactions in women who ultimately underwent PTB and in those who delivered at term.
• Galaz, J., Romero, R., Xu, Y., Miller, D., Levenson, D., Para, R., Varrey, A., Hsu, R., Tong, A., Hassan, S. S., Hsu, C. D., & Gomez-Lopez, N. (2020). Cellular immune responses in amniotic fluid of women with a sonographic short cervix. Journal of perinatal medicine, 48(7), 665-676.
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  Objectives A sonographic short cervix is one of the strongest predictors of preterm delivery. However, the cellular immune composition of amniotic fluid in women with a short cervix has not yet been described. Herein, we determined cellular and soluble immune responses in amniotic fluid from pregnant women with a mid-trimester asymptomatic short cervix. Methods Amniotic fluid samples (n=77) were collected from asymptomatic women with a cervical length between 15 and 25 mm (n=36, short cervix) or ≤15 mm (n=41, severely short cervix) diagnosed by ultrasound. Flow cytometry and multiplex measurement of cytokines/chemokines were performed. Results (1) The cellular immune composition of amniotic fluid did not differ between women with a severely short cervix (≤15 mm) and those with a short cervix 15-25 mm; (2) amniotic fluid concentrations of multiple cytokines/chemokines were higher in women with a severely short cervix (≤15 mm) than in those with a short cervix 15-25 mm; (3) the cellular immune composition of amniotic fluid did not differ between women with a severely short cervix (≤15 mm) who ultimately underwent preterm delivery and those who delivered at term; and (4) amniotic fluid concentrations of IL-2, but not other immune mediators, were increased in women with a severely short cervix (≤15 mm) who ultimately delivered preterm compared to those who delivered at term. Conclusions Women with a severely short cervix (≤15 mm) have increased concentrations of pro-inflammatory mediators in the amniotic cavity; yet, these do not translate to changes in the cellular immune response.
• Gomez-Lopez, N., Arenas-Hernandez, M., Romero, R., Miller, D., Garcia-Flores, V., Leng, Y., Xu, Y., Galaz, J., Hassan, S. S., Hsu, C. D., Tse, H., Sanchez-Torres, C., Done, B., & Tarca, A. L. (2020). Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes. Cell reports, 32(1), 107874.
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  Regulatory T cells (Tregs) have been exhaustively investigated during early pregnancy; however, their role later in gestation is poorly understood. Herein, we report that functional Tregs are reduced at the maternal-fetal interface in a subset of women with idiopathic preterm labor/birth, which is accompanied by a concomitant increase in Tc17 cells. In mice, depletion of functional Tregs during late gestation induces preterm birth and adverse neonatal outcomes, which are rescued by the adoptive transfer of such cells. Treg depletion does not alter obstetrical parameters in the mother, yet it increases susceptibility to endotoxin-induced preterm birth. The mechanisms whereby depletion of Tregs induces adverse perinatal outcomes involve tissue-specific immune responses and mild systemic maternal inflammation, together with dysregulation of developmental and cellular processes in the placenta, in the absence of intra-amniotic inflammation. These findings provide mechanistic evidence supporting a role for Tregs in the pathophysiology of idiopathic preterm labor/birth and adverse neonatal outcomes.
• Gudicha, D. W., Romero, R., Kabiri, D., Hernandez-Andrade, E., Pacora, P., Erez, O., Kusanovic, J. P., Jung, E., Paredes, C., Berry, S. M., Yeo, L., Hassan, S. S., Hsu, C. D., & Tarca, A. L. (2021). Personalized assessment of cervical length improves prediction of spontaneous preterm birth: a standard and a percentile calculator. American journal of obstetrics and gynecology, 224(3), 288.e1-288.e17.
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  A sonographic short cervix (length
• Hsu, C. (2020). Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?. Elife.
• Hsu, C. (2020). Pregnancy-specific transcriptional changes upon endotoxin exposure in mice. J Perinate Med. doi:10.1515/jpm-2020-0159
• Hsu, C. (2020). The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications. Semin Fetal Neonatal Med.
• Jung, E. J., Romero, R., Gomez-Lopez, N., Paredes, C., Diaz-Primera, R., Hernandez-Andrade, E., Hsu, C. D., & Yeo, L. (2020). Cervical insufficiency, amniotic fluid sludge, intra-amniotic infection, and maternal bacteremia: the need for a point-of-care test to assess inflammation and bacteria in amniotic fluid. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 1-7.
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  Acute cervical insufficiency is frequently associated with subclinical intra-amniotic inflammation and intra-amniotic infection. Amniotic fluid analysis has been recommended prior to the placement of a cervical cerclage given that preexisting infection is associated with adverse pregnancy outcome. We report a case for which commonly available laboratory tests-amniotic fluid Gram stain, white blood cell count, and glucose concentration-did not detect either intra-amniotic inflammation, diagnosed by elevated amniotic fluid interleukin-6, or intra-amniotic infection, diagnosed by cultivation. Following cerclage placement, the patient developed clinical chorioamnionitis and bacteremia and experienced a spontaneous mid-trimester pregnancy loss. This case illustrates the need for a rapid and sensitive point-of-care test capable of detecting infection or inflammation, given recent evidence in support of treatment of intra-amniotic infection and intra-amniotic inflammation with antimicrobial agents.
• Jung, E., Romero, R., Yeo, L., Diaz-Primera, R., Marin-Concha, J., Para, R., Lopez, A. M., Pacora, P., Gomez-Lopez, N., Yoon, B. H., Kim, C. J., Berry, S. M., & Hsu, C. D. (2020). The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications. Seminars in fetal & neonatal medicine, 25(4), 101146.
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  The fetus can deploy a local or systemic inflammatory response when exposed to microorganisms or, alternatively, to non-infection-related stimuli (e.g., danger signals or alarmins). The term "Fetal Inflammatory Response Syndrome" (FIRS) was coined to describe a condition characterized by evidence of a systemic inflammatory response, frequently a result of the activation of the innate limb of the immune response. FIRS can be diagnosed by an increased concentration of umbilical cord plasma or serum acute phase reactants such as C-reactive protein or cytokines (e.g., interleukin-6). Pathologic evidence of a systemic fetal inflammatory response indicates the presence of funisitis or chorionic vasculitis. FIRS was first described in patients at risk for intraamniotic infection who presented preterm labor with intact membranes or preterm prelabor rupture of the membranes. However, FIRS can also be observed in patients with sterile intra-amniotic inflammation, alloimmunization (e.g., Rh disease), and active autoimmune disorders. Neonates born with FIRS have a higher rate of complications, such as early-onset neonatal sepsis, intraventricular hemorrhage, periventricular leukomalacia, and death, than those born without FIRS. Survivors are at risk for long-term sequelae that may include bronchopulmonary dysplasia, neurodevelopmental disorders, such as cerebral palsy, retinopathy of prematurity, and sensorineuronal hearing loss. Experimental FIRS can be induced by intra-amniotic administration of bacteria, microbial products (such as endotoxin), or inflammatory cytokines (such as interleukin-1), and animal models have provided important insights about the mechanisms responsible for multiple organ involvement and dysfunction. A systemic fetal inflammatory response is thought to be adaptive, but, on occasion, may become dysregulated whereby a fetal cytokine storm ensues and can lead to multiple organ dysfunction and even fetal death if delivery does not occur ("rescued by birth"). Thus, the onset of preterm labor in this context can be considered to have survival value. The evidence so far suggests that FIRS may compound the effects of immaturity and neonatal inflammation, thus increasing the risk of neonatal complications and long-term morbidity. Modulation of a dysregulated fetal inflammatory response by the administration of antimicrobial agents, anti-inflammatory agents, or cell-based therapy holds promise to reduce infant morbidity and mortality.
• Para, R., Romero, R., Miller, D., Panaitescu, B., Varrey, A., Chaiworapongsa, T., Hassan, S. S., Hsu, C. D., & Gomez-Lopez, N. (2020). Human β-defensin-3 participates in intra-amniotic host defense in women with labor at term, spontaneous preterm labor and intact membranes, and preterm prelabor rupture of membranes. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 33(24), 4117-4132.
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  Human β-defensin-3 (HBD-3) has a broad spectrum of antimicrobial activity, and activity and, therefore, plays a central role in host defense mechanisms against infection. Herein, we determined whether HBD-3 was a physiological constituent of amniotic fluid during midtrimester and at term and whether the concentration of this defensin was increased in amniotic fluid of women with spontaneous preterm labor and intact membranes and those with preterm prelabor rupture of membranes (pPROM) with intra-amniotic inflammation or intra-amniotic infection. Amniotic fluid was collected from 219 women in the following groups: (1) midtrimester who delivered at term ( = 35); (2) with or without spontaneous labor at term ( = 50); (3) spontaneous preterm labor with intact membranes who delivered at term ( = 29); (4) spontaneous preterm labor with intact membranes who delivered preterm with or without intra-amniotic inflammation or intra-amniotic infection ( = 69); and (5) pPROM with or without intra-amniotic infection ( = 36). Amniotic fluid HBD-3 concentrations were determined using a sensitive and specific ELISA kit. (1) HBD-3 is a physiological constituent of amniotic fluid; (2) the amniotic fluid concentration of HBD-3 did not change with gestational age (midtrimester versus term not in labor); (3) amniotic fluid concentrations of HBD-3 were higher in women with spontaneous labor at term than in those without labor; (4) in the absence of intra-amniotic inflammation, amniotic fluid concentrations of HBD-3 were similar between women with spontaneous preterm labor who delivered preterm and those who delivered at term; (5) among patients with spontaneous preterm labor who delivered preterm, amniotic fluid concentrations of HBD-3 were greater in women with intra-amniotic infection than in those without this clinical condition; (6) among patients with spontaneous preterm labor, amniotic fluid concentrations of HBD-3 were higher in women with intra-amniotic inflammation or intra-amniotic infection who delivered preterm than in those without these clinical conditions who delivered at term; and (7) women with pPROM and intra-amniotic infection had higher median amniotic fluid concentrations of HBD-3 than those without this clinical condition. Human β-defensin-3 is a physiological constituent of amniotic fluid and increases during the process of labor at term. Amniotic fluid concentrations of HBD-3 were increased in women with spontaneous preterm labor with intact membranes or pPROM with intra-amniotic inflammation or intra-amniotic infection, indicating that this defensin participates in the host defense mechanisms in the amniotic cavity against microorganisms or danger signals. These findings provide insight into the soluble host defense mechanisms against intra-amniotic inflammation and intra-amniotic infection.

Presentations

• Hsu, C. (2020, October). Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?. Cathay General Hospital (Virtual). Taipei, Taiwan: Taipei Medical University.
• Hsu, C. (2019, June). Cervical insufficiency, amniotic fluid sludge, intra-amniotic infection, and maternal bacteremia. Cathay General Hospital. Taipei, Taiwan: Taipei Medical University.
• Hsu, C. (2014, May). Pacing Event: Vulnerable Populations. Reduction of Surgical Site Infection in Cesarean Delivery. America's Essential Hospital Engagement Network. Webinar.

Case Studies

• Hsu, C., Blohm, J. E., & McMahon, L. R. (2023. Disseminated Coccidioidal Meningitis Occurring in Two Subsequent Pregnancies Requiring Ventriculoperitoneal Shunt(pp 1-6).
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  Recurrent disseminated coccidioidal meningitis in two subsequent pregnancies is rare and can pose a clinical challenge in ensuring the health of both mother and baby. We reported a 29-year-old G4P1021 with a history of disseminated coccidioidomycosis in a previous pregnancy two years ago. She presented to the service at 8 weeks gestation with nausea and emesis, headache, night sweats, and neck pain for one day. Both cerebrospinal fluidanalysis and serology were positive for recurrent coccidioidal infection. She was subsequently started on Amphotericin B and discharged. She improved until 30 weeks’ gestation. She then presented with phonophobia and photophobia, emesis, neck pain and swelling, similar to her previous admission. MRI showed evidence of ventriculomegaly with communicating hydrocephalus that was new from her last imaging. She was treated with a series of therapeutic lumbar punctures throughout her pregnancy, with plans to place a ventriculoperitoneal shunt following delivery. The patient had a spontaneous vaginal delivery at 38 weeks and 3 days with no complications.