The cellular and immunological dynamics of early and transitional human milk.

Human milk is essential for infant nutrition and immunity, providing protection against infections and other immune-mediated diseases during the lactation period and beyond in later childhood. Milk contains a broad range of bioactive factors such as nutrients, hormones, enzymes, immunoglobulins, growth factors, cytokines, and antimicrobial factors, as well as heterogeneous populations of maternal cells. The soluble and cellular components of milk are dynamic over time to meet the needs of the growing infant. In this study, we utilize systems-approaches to define and characterize 62 analytes of the soluble component, including immunoglobulin isotypes, as well as the cellular component of human milk during the first two weeks postpartum from 36 mothers. We identify soluble immune and growth factors that are dynamic over time and could be utilized to classify milk into different phenotypic groups. We identify 24 distinct populations of both epithelial and immune cells by single-cell transcriptome analysis of 128,016 human milk cells. We found that macrophage populations have shifting inflammatory profiles during the first two weeks of lactation. This analysis provides key insights into the soluble and cellular components of human milk and serves as a substantial resource for future studies of human milk.

Preexisting Thyroid Disease in Pregnancy: A Brief Overview.

Maternal thyroid disease, with both an excess or deficiency of thyroid hormone, raises the risk profile of affected pregnancies with regards to preeclampsia, preterm birth, placental problems, thyroid derangement of the fetus and neonate, and neurodevelopment of exposed fetuses later in life. Fortunately, close and tight management of thyroid disease within the fluctuating physiologic milieu of pregnancy offers opportunities to significantly improve perinatal outcomes. However, despite guidelines offered by American College of Obstetrics and Gynecology (ACOG) and American Thyroid Association (ATA), controversy persists regarding interpretation of thyroid labs, screening for disease, surveillance, fetal and placental thyroid physiology, and optimal medication and management strategies. This is a brief overview of what is known and unknown regarding thyroid disease and its impact on maternal, fetal, and pregnancy health.

The effect of race and supplementation on maternal and umbilical cord plasma folates.

OBJECTIVE: The purpose of this study is to test the hypothesis that race and supplementation affect the concentration and correlation of various folate species in maternal and umbilical cord blood. METHODS: This is a single-center, prospective, cross-sectional cohort of cord blood samples obtained from 40 uncomplicated term pregnancies as a pilot study, following a protocol approved by the Institutional Review Board. High performance liquid chromatography mass spectrometry quantitated the following concentrations in extracted plasma samples: 5-methyltetrahydrofolate (5MTHF), 5,10-methenyl-tetrahydrofolate (5,10-MeTHF), tetrahydrofolate (THF), and unmetabolized folic acid. RESULTS: Folate concentrations in the umbilical cord plasma were consistently higher than maternal samples for 5MTHF (p < .001), 5,10-MeTHF (p < .001), and THF (p < .001); cord blood folic acid levels, however, were lower than maternal samples (p < .03). While 5MTHF was the most prevalent folate, ratios comparing cord blood to maternal blood folates suggests a fourfold preponderance of THF in cord blood folate signature, a trend unchanged by supplementation. Prenatal supplementation increased the concentrations of 5MTHF, for both maternal (p < .01) and cord blood samples (p < .005). In comparison to the other two racial groups, African American 5MTHF concentration demonstrated a lower total folate concentration in both maternal samples and cord blood samples, in addition to a relatively blunted response to supplementation. A significantly positive correlation between maternal and cord blood 5MTHF concentration was noted in all three racial groups. Supplementation resulted in a positive correlation between maternal and cord blood 5MTHF concentrations (r = 0.85, p < .0001). CONCLUSIONS: 5MTHF is the most prevalent folate in both cord and maternal plasma, and race and supplementation primarily affect variations in maternal and fetal 5MTHF concentrations and their correlation with each other. However, the greater concentration of THF in cord blood relative to maternal blood offers preliminary insight into the importance of how folate metabolism differs in the specific context of fetal development and physiology, with greater emphasis on DNA synthesis and stability. Furthermore, supplementation appeared to not have as great an impact on African American maternal or cord blood folates, suggesting a variable benefit of current repletion strategies to certain subsets of the population. Future studies that further elucidate these differences and their impact on birth outcomes may help inform supplementation protocols that are more personalized, with greater efficacy in promoting positive perinatal outcomes.

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta.

Preeclampsia (PE) is a serious pregnancy complication, affecting about 5-7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks' gestation and, if left untreated, can lead to serious complications and lifelong disabilities-even death-in both the mother and the infant. As delivery is the only cure for the disease, treatment is primarily focused on the management of blood pressure and other clinical symptoms. The pathogenesis of PE is still not clear. Abnormal spiral artery remodeling, placental ischemia and a resulting increase in the circulating levels of vascular endothelial growth factor receptor-1 (VEGFR-1), also called soluble fms-like tyrosine kinase-1 (sFlt-1), are believed to be among the primary pathologies associated with PE. sFlt-1 is produced mainly in the placenta during pregnancy and acts as a decoy receptor, binding to free VEGF (VEGF-A) and placental growth factor (PlGF), resulting in the decreased bioavailability of each to target cells. Despite the pathogenic effects of increased sFlt-1 on the maternal vasculature, recent studies from our laboratory and others have strongly indicated that the increase in sFlt-1 in PE may fulfill critical protective functions in preeclamptic pregnancies. Thus, further studies on the roles of sFlt-1 in normal and preeclamptic pregnancies are warranted for the development of therapeutic strategies targeting VEGF signaling for the treatment of PE. Another impediment to the treatment of PE is the lack of suitable methods for delivery of cargo to placental cells, as PE is believed to be of placental origin and most available therapies for PE adversely impact both the mother and the fetus. The present review discusses the pathogenesis of PE, the complex role of sFlt-1 in maternal disease and fetal protection, and the recently developed placenta-targeted drug delivery system for the potential treatment of PE with candidate therapeutic agents.

A brief history of fetal echocardiography and its impact on the management of congenital heart disease.

Congenital heart disease (CHD), the most common congenital malformation, is associated with adverse outcome. Development of fetal echocardiography has made prenatal diagnosis of CHD a reality, and in the process revolutionized its management. This historical review briefly narrates this development over the decades focusing on the emergence of the primary modalities of fetal echocardiography comprised of the time-motion mode, two-dimensional B-mode, spectral Doppler, color Doppler, and three- and four-dimensional cardiac imaging. Collaboration between clinicians and engineers has been central to these advances. Also discussed are the accuracy and impact of fetal echocardiography on the management of CHD, and especially its role in the prenatal diagnosis of critical CHD in individualizing the management and improving the outcome. Despite these advances, most cases of CHD are not identified prenatally, emphasizing the continuing need for further technological and educational innovation and improvement.

The Zika virus and pregnancy: evidence, management, and prevention.

OBJECTIVE: To comprehensively review the available evidence and existing consensus reports and guidelines regarding the pregnancy and reproductive implications of the mosquito-transmitted Zika virus (ZIKV) infection. A primary focus was to provide pertinent information to aid clinicians in the management of pregnancies at risk for, exposed to, or with confirmed ZIKV infection. METHOD: An extensive literature review was performed using Pubmed. Practice guidelines and consensus reports were accessed from international, national, and professional organizations' websites. The clinical articles for ZIKV infection testing varied from case reports to small epidemiologic studies. RESULTS: A ZIKV epidemic has been declared in several countries in the Americas. Fifty-two travel-associated ZIKV infection cases have been reported throughout the USA (as of February 10, 2016). The consequences of congenital fetal/newborn ZIKV infection could potentially have devastating consequences including miscarriage, fetal death, and major anomalies such as microcephaly, brain and brain-stem defects, and long-term neurologic sequelae. While not definitive, current evidence suggests the existence of nonvector-borne transmission through sexual activity with an infected male partner. For women at risk for sexual transmission, condom use is advised, especially during pregnancy. CONCLUSION: While ZIKV infection appears to be a mild disease in the general population the potential consequences to the fetus and newborn could be profound. Management guidelines are currently evolving and will be significantly impacted as new evidence develops. It is therefore imperative that obstetric health-care providers keep abreast of this rapidly evolving information landscape that has so far characterized this outbreak.

Male gender significantly increases risk of oxidative stress related congenital anomalies in the non-diabetic population.

OBJECTIVE: Oxidative stress (OS) is an important mechanism of teratogenesis. Recent work suggests increased OS in males. We evaluated whether male gender increased the risk of cyanotic congenital heart defects (CCHD) whose development is linked to OS and other common congenital anomalies (CA) in non-diabetic pregnancies. METHODS: CDC-National Center for Health Statistics data for 19 states in 2006 were reviewed. CCHD, anencephaly, spina bifida, congenial diaphragmatic hernia (CDH), omphalocele, gastroschisis, limb defects, cleft lip with or without cleft palate (CL/P) and isolated cleft palate were evaluated. Adjusted odds ratio (OR) (95% CI) were calculated for CA in males with females as the reference group. RESULTS: Of 1,194, 581, cases analyzed after exclusions, 3037 (0.25%) had major CA. Males had elevated adjusted OR (95% CI) for CCHD: 1.198 (1.027, 1.397), CDH: 1.487 (1.078, 2.051), and CL/P: 1.431 (1.24, 1.651). There was a significant interaction between cigarette use and (male) fetal gender and also with maternal age in the CL/P group. CONCLUSIONS: In non-diabetic pregnancies, male gender appears to be an independent risk factor for some types of CA believed to be associated with OS. Cigarette smoking, a well recognized source of OS only increased the risk of CL/P in males.

Umbilical artery Doppler in the assessment of fetal growth restriction.

Antepartum fetal surveillance with Doppler ultrasound of umbilical artery has shown significant diagnostic efficacy in identifying fetal compromise in pregnancies complicated with fetal growth restriction (FGR). Its effectiveness in decreasing perinatal mortality has been shown by randomized clinical trials (Level I evidence). This test is the only antepartum fetal test that has shown this level of effectiveness and should be the standard of practice in managing FGR (Level A recommendation). The overall management considerations should encompass other standard fetal monitoring tests (Level B and C recommendations).

New horizons in Doppler ultrasound technology: relevance for obstetrical applications.

Technologic advances and clinical research have been extending the scope of Doppler sonography and have resulted in the emergence of new diagnostic tools that show significant promise in clinical applications. This article aims to review some of these developments that are relevant for obstetrical practice. One of the major recent technical developments in ultrasound imaging is the ability to assess tissue deformation. This has led to several clinical applications including functional echocardiography that allows evaluation of myocardial function using Doppler and speckle tracking techniques, and sonoelastography, which is ultrasound evaluation of tissue stiffness. Another relevant innovation is power Doppler imaging of regional perfusion. With further critical investigations, these emerging techniques may evolve into useful clinical tools.

Evidence-based approach to umbilical artery Doppler fetal surveillance in high-risk pregnancies: an update.

Antepartum fetal surveillance with Doppler ultrasound of umbilical artery has shown significant diagnostic efficacy in identifying fetal compromise in pregnancies complicated with fetal growth restriction and preeclampsia. Moreover, randomized clinical trials and their meta-analyses have shown its effectiveness in decreasing perinatal mortality (level I evidence). This is the only antepartum fetal test that has shown this level of effectiveness. There is no evidence that routine Doppler in low-risk pregnancies improves the outcome. It is recommended that umbilical artery Doppler should be the standard of practice in managing high-risk pregnancies complicated with fetal growth restriction and preeclampsia (level A recommendation). However, its use should be integrated with other current fetal monitoring tests (levels B and C recommendation). The overall management should also be guided by additional clinical considerations such as the gestational age, fetal and maternal status, and obstetrical conditions.

Nitration of N-methyl-D-aspartate receptor subunits following in vitro dephosphorylation of cerebral cortical membranes of newborn piglets.

Previous studies have shown that activity of the cerebral N-methyl-D-aspartate (NMDA) receptor is modified by receptor nitration and phosphorylation. Since the sites for tyrosine phosphorylation and nitration are on adjacent carbon atoms, the present study tested the hypothesis that in vitro dephosphorylation of the NR1, NR2A and NR2B subunits of the NMDA receptor increases receptor nitration by peroxynitrite in cortical membranes of newborn piglets. To test this hypothesis, cerebral cortical P(2) membranes were prepared from normoxic and hypoxic newborn piglets and divided into dephosphorylated and non-dephosphorylated control groups. Dephosphorylation was performed in vitro by incubation with protein tyrosine phosphatase 1B and confirmed by immunoprecipitation with antiphosphotyrosine antibody. Dephosphorylated and non-dephosphorylated samples were nitrated with 0.5 mM peroxynitrite. Nitration was measured by immunoprecipitating with agarose-conjugated anti-nitrotyrosine antibody followed by Western blot analysis using specific anti -NR1, -NR2A and -NR2B primary antibodies. The data demonstrate that nitration of the NR1, NR2A and NR2B subunits of the NMDA receptor increases following dephosphorylation in both normoxic and hypoxic animals, however increase is much higher in hypoxic animals. We conclude that dephosphorylation at the site adjacent to the nitration site (ortho-position) on tyrosine residues of the NMDA receptor enhances nitration. Since in vitro nitration of the NMDA receptor increases the affinity of the glutamate recognition site and the receptor ion channel, we speculate that tyrosine dephosphorylation of the NMDA receptor will remove steric hindrance and facilitate nitration of tyrosine residues resulting in increased ion-channel activation in the hypoxic newborn brain.