Preterm birth associates with increased placental expression of MDR transporters irrespective of prepregnancy BMI

Context Preterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition, however few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected pro-inflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype. Objective To determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and pro-inflammatory cytokine levels are altered by PTB and maternal BMI. Design and Outcomes A cross-sectional study was conducted to assess the effect of PTB (+/- chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin [IL]-6 and 8 expression in 60 preterm and 36 term pregnancies. Results ABCB1 expression was increased in preterm compared to term placentae (p=0.04). P-gp (p=0.008) and BCRP (p=0.01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, p=0.007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (p=0.0005), and PTC associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes. Conclusions PTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6. This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.

At the Borders of the Body Politic: Fetal Citizens, Pregnant Migrants, and Reproductive Injustices in Immigration Detention

To analyze intersecting power relations in reproductive and immigration politics, I examine Garza v. Hargan (an appellate case regarding unaccompanied immigrant minors’ abortion rights) alongside systemic injustices in immigration detention (e.g., exposure to miscarriage risks, coerced sterilization, shackling). These injustices, I argue, emerge from conflicts and compromises over fetal citizenship within the American radical right. Although pro-life and anti-immigrant discourses assume opposing logics of citizenship, respectively interpreting immigrants’ fetuses as “fetal citizens” or “anchor babies,” these contradictions are neutralized by two techniques. Debilitation (systematic degradation of a disposable population) enables the appearance of fetal protection to coexist with de facto exposure to death, injury, and risk. Paralegality (quasi-legal policy making by enforcement agents) allows situational shifts in the meaning of fetal citizenship and adjustments to the pro-life/anti-immigrant compromise. Both obscure culpability for reproductive injustice, reinforce interlocking oppressions, and control women’s bodies in order to control the body politic’s demographic future.

Preterm birth increases placental expression of multidrug resistance (MDR) transporters irrespective of prepregnancy body mass index (BMI)

Context: Preterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition, however few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected pro-inflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype. Objective: To determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and pro-inflammatory cytokine levels are altered by PTB and maternal BMI. Design and Outcomes: A cross-sectional study was conducted to assess the effect of PTB (+/- chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin [IL]-6 and 8 expression in 60 preterm and 36 term pregnancies. Results: ABCB1 expression was increased in preterm compared to term placentae (p=0.04). P-gp (p=0.008) and BCRP (p=0.01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, p=0.007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (p=0.0005), and PTC was associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes. Conclusions: PTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6. This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.

SARS-CoV-2 in Pregnancy: Fitting Into the Existing Viral Repertoire

The risk of viral infection during pregnancy is well-documented; however, the intervention modalities that in practice enable maternal-fetal protection are restricted by limited understanding. This becomes all the more challenging during pandemics. During many different epidemic and pandemic viral outbreaks, worse outcomes (fetal abnormalities, mortality, preterm labor, etc.) seem to affect pregnant women than what has been evident when compared to non-pregnant women. The condition of pregnancy, which is widely understood as “immunosuppressed,” needs to be re-understood in terms of the way the immune system works during such a state. The immune system gets transformed to accommodate and facilitate fetal growth. The interference of such supportive conversion by viral infection and the risk of co-infection lead to adverse fetal outcomes. Hence, it is crucial to understand the risk and impact of potent viral infections likely to be encountered during pregnancy. In the present article, we review the effects imposed by previously established and recently emerging/re-emerging viral infections on maternal and fetal health. Such understanding is important in devising strategies for better preparedness and knowing the treatment options available to mitigate the relevant adverse outcomes.

TLR4-endothelin axis controls syncytiotrophoblast motility and confers fetal protection in placental malaria

Pregnancy associated malaria is often associated with adverse pregnancy outcomes. Placental circulatory impairments are an intriguing and unsolved component of malaria pathophysiology. Here, we uncovered a TLR4-TRIF-endothelin axis that controls trophoblast motility and is linked to fetal protection during Plasmodium infection. In a cohort of 401 pregnancies from Northern Brazil we found that infection during pregnancy reduced expression of endothelin receptor B in syncytiotrophoblasts while endothelin expression was only affected during acute infection. We further show that quantitative expression of placental endothelin and endothelin receptor B proteins are differentially controlled by maternal and fetal TLR4 alleles. Using murine malaria models, we identified placental autonomous responses to malaria infection mediated by fetally encoded TLR4 that not only controlled placental endothelin gene expression but also correlated with fetal viability protection. In vitro assays showed that control of endothelin expression in fetal syncytiotrophoblasts exposed to Plasmodium -infected erythrocytes was dependent on TLR4 via the TRIF pathway but not MyD88 signaling. Time-lapse microscopy in syncytiotrophoblast primary cultures and cell invasion assays demonstrated that ablation of TLR4 or endothelin receptor blockade abrogate trophoblast collective motility and cell migration responses to infected erythrocytes. These results cohesively substantiate the hypothesis that fetal innate immune sensing, namely the TRL4-TRIF pathway exerts a fetal protective role during malaria infection by mediating syncytiotrophoblast vasoregulatory responses that counteract placental insufficiency.

Rhythm of Fetoplacental 11β-Hydroxysteroid Dehydrogenase Type 2 — Fetal Protection From Morning Maternal Glucocorticoids

Context Excess glucocorticoids impact fetal health. Maternal glucocorticoids peak in early morning. Fetoplacental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to cortisone, protecting the fetus from high glucocorticoids. However, time-specific alterations of human fetoplacental 11β-HSD2 have not been studied. Objective We hypothesized that fetoplacental 11β-HSD2 activity shows time-specific alteration and acute affective or anxiety disorders impact fetoplacental 11β-HSD2 activity. Methods In this observational study we investigated 78 pregnant European women undergoing amniocentesis (15.9 ± 0.9 weeks of gestation). Amniotic fluid was collected (8:00 to 16:30 hours) for analysis of fetoplacental 11β-HSD2 activity, using cortisol (F):cortisone (E) ratio in amniotic fluid, E/(E + F). Fetoplacental 11β-HSD2 rhythm and association with “acute affective or anxiety disorder” (patients with at least one of: a major depressive episode, specific phobia, panic disorder, generalized anxiety disorder, mixed anxiety and depressive disorder) and “acute anxiety disorder” (one of: panic disorder, generalized anxiety disorder, mixed anxiety, depressive disorder), assessed using Mini International Neuropsychiatric Interview, were investigated. Results Activity of 11β-HSD2 correlated with time of amniocentesis, peaking in the morning (r = −0.398; P < 0.001) and increased with acute affective or anxiety disorder (mean [M] = 0.70 vs M = 0.74; P = 0.037) and acute anxiety disorder (M = 0.70 vs M = 0.75; P = 0.016). These associations remained significant when controlling for confounders. 11β-HSD2 activity correlated negatively with pre-pregnancy body mass index (r = −0.225; P = 0.047). Conclusion Our study indicates a time-specific alteration of fetoplacental 11β-HSD2 activity with peaking levels in the morning, demonstrating a mechanism of fetal protection from the morning maternal glucocorticoid surge.

A Review on the Effects of Melatonin on Fetal Protection during Pregnancy with Intrauterine Inflammation

Intrauterine inflammation is defined as the inflammation of the chorion, amnion, and placenta. Untreated inflammation increases the risk of fetal inflammatory response syndrome, which may result in multiorgan diseases involving the brain, cardiovascular system, lung, eye, and intestine. Therefore, controlling inflammation is critical in pregnant women to reduce the risk of diseases. However, there are no safe and effective anti-inflammatory drugs for administration during pregnancy. Although the primary function of melatonin is to control circadian rhythms, it has protective effects against cellular insults occurring from hypoxia, oxidative stress, and inflammation. While animal studies support the effective and safe role of melatonin in improving pregnancy-related morbidities, it leaves plenty of opportunities for clinical studies investigating its anti-inflammatory, antioxidant, and protective effects against insults induced by intrauterine inflammation. Therefore, it will be worthwhile to investigate antenatal supplementation of melatonin in pregnant women with intrauterine inflammation to reduce the incidence of associated comorbidities.

Measles-based Zika vaccine induces long-term immunity and requires NS1 antibodies to protect the female reproductive tract.

Zika virus (ZIKV) can cause devastating effects in the unborn fetus of pregnant women. To develop a candidate vaccine that can protect human fetuses, we generated a panel of live measles vaccine (MV) vectors expressing ZIKV-E and -NS1. Our MV-based ZIKV-E vaccine, MV-E2, protected mice from the non-lethal Zika Asian strain (PRVABC59) and the lethal African strain (MR766) challenge. Despite 100% survival of the MV-E2 mice, however, complete viral clearance was not achieved in the brain and reproductive tract of the lethally challenged mice. We then tested a combination of two MV-based vaccines, the MV-E2 and a vaccine expressing NS1 (MV-NS1[2]), and we observed durable plasma cell responses, complete clearance of ZIKV from the female reproductive tract, and complete fetal protection in the lethal African challenge model. Our findings suggest that NS1 antibodies are required to enhance the protection achieved by ZIKV-E antibodies in the female reproductive tract.