Integrated Research Center for Fetal Medicine

Baltimore, MD, United States

Integrated Research Center for Fetal Medicine

Baltimore, MD, United States
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Bustamante Helfrich B.,Center on the Early Life Origins of Disease | Bustamante Helfrich B.,University of the Incarnate Word | Chilukuri N.,Center on the Early Life Origins of Disease | He H.,Center on the Early Life Origins of Disease | And 7 more authors.
Placenta | Year: 2017

Introduction The associations of maternal conditions, before or during pregnancy, with placental lesions have not been adequately studied in populations. Methods In the Boston Birth Cohort, we evaluated associations between three maternal medical conditions (hypertensive disorders [HDs], gestational/pre-gestational diabetes and obesity), and placental histological findings, using a standardized classification system proposed by the Amsterdam Placental Workshop Group. Placental pathology diagnoses and clinical data from 3074 mothers with clinical indications who delivered singleton live births at the Boston Medical Center between October 1998 and November 2013 were evaluated. Associations between each maternal condition and maternal vascular malperfusion (MVM) of the placental bed and its standardized subgroups were examined using multivariate logistic and multinomial regressions. Results Women with HDs (chronic hypertension, eclampsia, preeclampsia, HELLP syndrome) had significantly increased odds of MVM lesions when compared to women with no HD (aOR 2.08 95% CI 1.74–2.50), after adjusting for demographics, substance use, diabetes and body mass index. No significant differences in frequencies or aORs were seen in women with and without diabetes, or across body mass index categories. Co-morbid condition patterns that included HDs were more likely to be associated with MVM than those without. Discussion Using a standardized classification system, we showed that MVM is strongly and specifically associated with maternal HDs, but not other maternal conditions. Additional studies are needed to confirm and validate our findings, and evaluate the role of maternal vascular lesions of the placental bed in relation to postnatal growth and development of the offspring and effect modifiers. © 2017 Elsevier Ltd


Burd I.,Integrated Research Center for Fetal Medicine
Journal of Assisted Reproduction and Genetics | Year: 2016

Zika transmission from mother to fetus and its possible sexual transmission have become a media focus in the past months as a major public health concern. While mother-to-fetus transmission, fetal neurologic manifestations or sexual transmission have never been documented for this virus before, other viruses that belong to the same family are very well known to reproductive health workers, clinicians, and researchers. As a member of Flaviviridae family, including hepatitis C and bovine viral diarrhea virus (BVDV), Zika’s pathogenesis may have some parallels with these infections which may pose future questions for public health and research. Vertical transmission of hepatitis C virus from mother to child is known to occur in up to 10 % of pregnancies. BVDV, a member of Pestivirus genus of Flaviviridae family is not known to be transmitted to humans but is known for its vertical transmission in cattle. BVDV infection at different stages of gestation may lead to a spectrum of adverse pregnancy outcomes, including pregnancy loss and neurologic manifestations (including deformations such as hydrocephalus and microcephaly) in the offspring. Similar to hepatitis C, which is a virus of Hepacivirus genus, BVDV is capable of persistent infection, meaning that virus may stay in mother and future generations of calves may be infected as well, which may, in turn, result in persistence of infection in offspring. Would this be a case with Zika virus? Along with mother-to-fetus transmission, sexual transmission is a concerning implication for Zika virus. Would woman become a persistent career or male be able to persistently carry virus with its sperm is yet unknown; yet, there is a concern for the reservoir of infection. Animal models of the disease are urgently needed not only to demonstrate the mother-to-fetus transmission and confirm the fetal neurologic manifestations but also to address the effects of virus on life-long host’s immunity and reproductive health. Along those lines, women desiring pregnancies who are identified to travel, have a partner traveling to, or living in the areas of Zika infections should be encouraged to have a preconception consultation with maternal-fetal medicine. © 2016 Springer Science+Business Media New York


News Article | February 21, 2017
Site: www.eurekalert.org

Johns Hopkins researchers say that in early pregnancy in mice with complete immune systems, Zika virus can cross the placenta -- intended to protect the developing fetus -- and appears to lead to a high percentage of miscarriages and to babies born with thin brain tissue and inflammation in brain cells. By administering Zika virus directly into the reproductive tract of pregnant mice that have an intact immune system, the researchers found that the Zika virus appears to create disorganization in the cellular layers of the placenta that keep toxins, bacteria and viruses from crossing. This disorganization could be how the virus penetrates the placenta to infect the fetus. The researchers also discovered a mechanism by which Zika may be keeping antiviral proteins in the body from doing their job of protecting cells from the virus. These findings, published Feb. 21 in Nature Communications, put scientists one step closer to developing targets for vaccines or other treatments for Zika. Currently there is no cure or treatment for the virus, which has been linked to serious neurological problems in infants whose mothers were exposed in early pregnancy. For much of 2016, Zika was considered a public health emergency by the World Health Organization. "We need to find a way to stop transmission of Zika through the placenta into the fetus, because that is where the damage is being done," says study co-leader Sabra L. Klein, PhD, an immunologist and microbiologist at the Johns Hopkins Bloomberg School of Public Health. "In the placentas of our mice, we're seeing a defense against Zika being mounted, but falling short, especially in early pregnancy, a time that corresponds to the first trimester in humans." Study co-leader Irina Burd, MD, PhD, a maternal/fetal medicine physician at Johns Hopkins Medicine, is hopeful that this is an important step toward halting the transmission of Zika from mother to child. "If we can determine what is happening, we may be able to find ways to minimize or even eliminate what can be devastating consequences for children of infected mothers," she says. For their research, the scientists developed a new mouse model that they say is uniquely capable of helping them to understand the mechanisms behind Zika transmission to the fetus. Unlike other mice used to study the virus, the Hopkins mice have completely intact immune systems more similar to humans, which enable researchers to see all that is involved in mounting an immune response. They intend to continue to follow up on their initial findings using the same model. To conduct this study, the researchers injected Zika virus directly into the reproductive tract of the pregnant mice during what would be the equivalent of the first trimester in a human. Since different species of animals may clear infections in different ways, they wanted to make sure the virus was getting to the most relevant tissues of the pregnant mice. The researchers used several different strains of the virus, using older strains - one from an outbreak in Nigeria in 1968 and another from Cambodia in 2010 - and contemporary ones from Brazil and Puerto Rico from the most recent epidemics. Nearly 94 percent of all pregnancies remained viable when a mock infection was introduced during the first trimester, while the viability of fetuses after Zika infection was reduced, regardless of which strain was used. Viability ranged from 56 percent from infection with the Brazil strain to 71 percent following infection with the Nigeria strain. That means anywhere from 29 to 44 percent of pregnancies were lost following infection. Since miscarriages can be caused by a multitude of factors, this Zika connection was not previously known. When the researchers infected the mice in the equivalent of the late second trimester instead, however, many fewer miscarriages occurred, suggesting that there is less vulnerability to Zika later in pregnancy. The researchers also could see the activation of antiviral defenses in the placentas of pregnant mice infected with virus. To cause an infection, viruses work like a lock and key, attaching to specific receptors on cells to take hold and spread. The researchers identified receptors on cells in the placenta that the virus may use to cross into the fetus. These anti-viral pathways could be potential targets for treatments that could stop transmission, the researchers say. The placenta is the key organ to a healthy pregnancy. It is typically organized into discrete layers of tissue. Under a microscope, the researchers found that the layers of tissue in the placentas of the mice infected with Zika virus were no longer organized well and might be how the virus could penetrate the fetus. "This could be why the fetuses in the Zika-infected mice were so vulnerable to either miscarriage or brain damage," Burd says. While the virus appeared to cross into the placenta fairly easily during the first trimester, the same was not true in the second trimester. As in humans, the direct effects on the pregnancy were much less pronounced if the infection occurred later in pregnancy. Those mouse pups born after an early infection were likely to have thinner cortexes and have inflammatory cells in the brain, while those born to mothers who had a later infection were much less likely to suffer those effects. In humans, Burd says, some babies born to mothers infected later are still showing some ill-effects, though it is unclear why. Since still so little is known about the long-term consequences of the Zika virus, in future experiments the researchers say they want to see if the siblings of the babies born during Zika infection will also suffer neurological effects. "We don't know if the effects persist in future pregnancies," Klein says. "We're just dealing with the here and now. We have no idea what the long-term consequences are for the mother." "Intrauterine Zika virus infection of pregnancy immunocompetent mice models transplacental transmission and adverse perinatal outcomes" was written by Meghan S. Vermillion; Jun Lei; Yahya Shabi; Victoria K. Baxter; Nathan P. Crilly; Michael McLane; Diane E. Griffin; Andrew Pekosz; Sabra L. Klein and Irina Burd. The research was supported by the Center for Emerging and Infectious Diseases at the Johns Hopkins Bloomberg School of Public Health; Medtronics Award from the Society for Women's Health Research; the Integrated Research Center for Fetal Medicine, the Sheikh Abdullah Bugshan Fund, the Merial Veterinary Scholars Fund and the National Institutes of Health's Training Veterinarians for Careers in Biomedical Research fund (T32 OD011089).


News Article | February 22, 2017
Site: www.futurity.org

Zika virus can penetrate the placenta in early pregnancy, causing miscarriages, studies with mice suggest. In addition, the virus—already known to cause a birth defect involving smaller-than-normal heads and brains—can also lead to babies born with thin brain tissue and inflammation in brain cells. The virus that causes the mosquito-borne disease appears to create disorganization in cellular layers of the placenta, layers meant to keep toxins, bacteria, and viruses from crossing from the mother to the fetus, researchers say. “We need to find a way to stop transmission of Zika through the placenta into the fetus, because that is where the damage is being done,” says study co-leader Sabra L. Klein, an immunologist and microbiologist at John Hopkins University’s Bloomberg School of Public Health. “In the placentas of our mice, we’re seeing a defense against Zika being mounted, but falling short, especially in early pregnancy, a time that corresponds to the first trimester in humans.” There is currently no cure or treatment for Zika, which causes relatively mild symptoms in most adults but potentially devastating consequences for developing fetuses whose mothers are infected. For much of 2016, Zika was considered a public health emergency by the World Health Organization, with outbreaks in South America and the Caribbean. Co-leader Irina Burd, a maternal/fetal medicine physician, is hopeful that the study, published in Nature Communications, is a step toward halting transmission of Zika from mother to child. “If we can determine what is happening, we may be able to find ways to minimize or even eliminate what can be devastating consequences for children of infected mothers.” Scientists developed a new mouse model they say is uniquely capable of helping them understand the mechanisms behind Zika transmission to the fetus. Unlike other mice used to study the virus, these have completely intact immune systems similar to that of humans, which allows researchers to see all that is involved in mounting an immune response. Researchers injected Zika virus directly into the reproductive tract of pregnant mice during the equivalent of the first trimester in a human. They used several strains of the virus, both older strains—one from an outbreak in Nigeria in 1968 and another from Cambodia in 2010—and strains from recent epidemics in Brazil and Puerto Rico. Nearly 94 percent of all pregnancies remained viable when a mock infection was introduced during the first trimester, but miscarriages rose significantly after Zika infection, no matter which strain was used. Viability ranged from 56 percent after infection with the Brazil strain to 71 percent with the Nigeria strain. That means anywhere from 29 to 44 percent of pregnancies were lost following infection. Since miscarriages have many causes, this Zika connection was not previously known. When the researchers infected the mice in the equivalent of the late second trimester, many fewer miscarriages occurred, suggesting that there is less vulnerability to Zika later in pregnancy. The placenta is the key organ to a healthy pregnancy. It is typically organized into discrete layers of tissue. Under a microscope, the researchers found that the placentas of the mice infected with Zika virus were no longer organized well. “This could be why the fetuses in the Zika-infected mice were so vulnerable to either miscarriage or brain damage,” Burd says. Those mouse pups who did not miscarry and were born after an early infection were likely to have thinner cortexes and have inflammatory cells in the brain, while those born to mothers who had a later infection were much less likely to suffer those effects. Support for the research came from the Center for Emerging and Infectious Diseases at the Johns Hopkins Bloomberg School of Public Health, the Society for Women’s Health Research, the Integrated Research Center for Fetal Medicine, the Sheikh Abdullah Bugshan Fund, the Merial Veterinary Scholars Fund, and the National Institutes of Health.


Burd I.,Integrated Research Center for Fetal Medicine | Zhang F.,Wilmer Eye Institute | Dada T.,Integrated Research Center for Fetal Medicine | Mishra M.K.,Wilmer Eye Institute | And 5 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2014

Intrauterine inflammation is associated with preterm birth and can lead to fetal neuroinflammation and neurobehavioral disorders in newborns. Dendrimers can intrinsically target and deliver drugs for the treatment of neuroinflammation. We explore whether hydroxyl polyamidoamine (PAMAM) dendrimer (G4-OH)-based nanomedicines can be delivered to the fetus by intra-amniotic administration, in a mouse model of intrauterine inflammation. The time-dependent accumulation of G4-OH-fluorophore conjugate was quantified by fluorescence. These studies suggest that, after intra-amniotic administration, there is significant accumulation of dendrimer in the fetus gut and brain. In addition, there is some fetal-maternal transport of the dendrimer. Confocal microscopy confirmed the presence of G4-OH in the fetal brain, with a large accumulation in the brain blood vessels and the brain parenchyma, and some microglial uptake. We believe that intra-amniotic administration of G4-OH-drug nanomedicines may enable the treatment of diseases related to intrauterine inflammation and fetal neuroinflammation. From the Clinical Editor: Using a mouse model of intrauterin inflammation leading to neuroinflammation in the fetus, these investigators demonstrate that intra-amniotic delivery of hydroxyl polyamidoamine (PAMAM) dendrimer (G4-OH)-based nanomedicines may provide an effective method in preventing this complication. © 2014 Elsevier Inc.

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