A Case Report to Assess Passive Immunity in a COVID Positive Pregnant Patient.

INTRODUCTION: Data regarding transplacental passage of maternal coronavirus disease 2019 (COVID-19) antibodies and potential immunity in the newborn is limited. CASE REPORT: We present a 25-year-old multigravida with known red blood cell isoimmunization, who was found to be COVID-19 positive at 27 weeks of gestation while undergoing serial periumbilical blood sampling and intrauterine transfusions. Maternal COVID-19 antibody was detected 2 weeks after positive molecular testing. Antibodies were never detected on cord blood samples from two intrauterine fetal cord blood samples as well as neonatal cord blood at the time of delivery. CONCLUSION: This case demonstrates a lack of passive immunity of COVID-19 antibodies from a positive pregnant woman to her fetus, neither in utero nor at the time of birth. Further studies are needed to understand if passage of antibodies can occur and if that can confer passive immunity in the newborn. KEY POINTS: · Passive immunity should not be assumed in COVID-19 infection in pregnancy.. · Isoimmunization may impair passive immunity of certain antibodies.. · Vaccination to or maternal infection of COVID-19 may not be protective for the fetus..

Group B Streptococcus and the Vaginal Microbiota.

Background: Streptococcus agalactiae (group B Streptococcus [GBS]) is an important neonatal pathogen and emerging cause of disease in adults. The major risk factor for neonatal disease is maternal vaginal colonization. However, little is known about the relationship between GBS and vaginal microbiota. Methods: Vaginal lavage samples from nonpregnant women were tested for GBS, and amplicon-based sequencing targeting the 16S ribosomal RNA V3-V4 region was performed. Results: Four hundred twenty-eight of 432 samples met the high-quality read threshold. There was no relationship between GBS carriage and demographic characteristics, α-diversity, or overall vaginal microbiota community state type (CST). Within the non-Lactobacillus-dominant CST IV, GBS positive status was significantly more prevalent in CST IV-A than CST IV-B. Significant clustering by GBS status was noted on principal coordinates analysis, and 18 individual taxa were found to be significantly associated with GBS carriage by linear discriminant analysis. After adjusting for race/ethnicity, 4 taxa were positively associated with GBS, and 6 were negatively associated. Conclusions: Vaginal microbiota CST and α-diversity are not related to GBS status. However, specific microbial taxa are associated with colonization of this important human pathogen, highlighting a potential role for the microbiota in promotion or inhibition of GBS colonization.

Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency.

Defective placentation and subsequent placental insufficiency lead to maternal and fetal adverse pregnancy outcome, but their pathologic mechanisms are unclear, and treatment remains elusive. The mildly hypertensive BPH/5 mouse recapitulates many features of human adverse pregnancy outcome, with pregnancies characterized by fetal loss, growth restriction, abnormal placental development, and defects in maternal decidual arteries. Using this model, we show that recruitment of neutrophils triggered by complement activation at the maternal/fetal interface leads to elevation in local TNF-α levels, reduction of the essential angiogenic factor vascular endothelial growth factor, and, ultimately, abnormal placentation and fetal death. Blockade of complement with inhibitors specifically targeted to sites of complement activation, depletion of neutrophils, or blockade of TNF-α improves spiral artery remodeling and rescues pregnancies. These data underscore the importance of innate immune system activation in the pathogenesis of placental insufficiency and identify novel methods for treatment of pregnancy loss mediated by abnormal placentation.

Prenatal screening for microcephaly: an update after three decades.

BACKGROUND: Due to the recent outbreak of Zika virus, there has been a newfound interest in fetal and neonatal microcephaly. In 1984, Chervenak et al. proposed criteria for the prenatal ultrasound diagnosis of microcephaly as ≤3 standard deviations (SD) from the mean. Despite improvements in medicine these criteria have not been reevaluated in 30 years. OBJECTIVE: To examine how the original 1984 Chervenak et al. criteria for the diagnosis of fetal microcephaly apply to a current population utilizing modern ultrasound equipment and techniques. STUDY DESIGN: Retrospective database review of 27,697 ultrasound exams between 18 and 40 weeks' gestation. Mean and SDs were calculated for each week of gestation from 18 to 40 completed weeks and these were compared to the 1984 data. RESULTS: There is no statistically significant difference in gestational age-specific mean head circumference (HC) between the two studied populations. Because the current dataset is larger the SD differ. CONCLUSIONS: The 1984 ultrasound criteria for microcephaly remain valid. Physicians today have two alternatives: either use the 3SD cutoff as recommended by Chervenak et al. and endorsed by the Society for Maternal-Fetal Medicine (SMFM) or develop a new dataset for one's population with statistical validation.

Single center experience in selective feticide in high-order multiple pregnancy: clinical and ethical issues.

OBJECTIVE: This paper describes the 20-year experience with selective feticide (SF) of high-order multiple quadruplet and higher pregnancies in a single center. METHODS: The paper describes protocols, procedures, management, outcomes, and ethical issues. RESULTS: SF was performed in 49 pregnancies with 244 fetuses, with median gestational age of 12+2 weeks. The initial number was nine (one case), eight (one case), seven (three cases), six (11 cases), five (eight cases), and four (27 cases). Nuchal translucency was utilized prior to the procedure starting in 1996. The technique was transabdominal ultrasound-guided and intrathoracic injection of potassium chloride. One pregnancy (with seven fetuses) was reduced to three, 42 to two, and four (starting with four fetuses) to singletons. There were ten pregnancy losses (20.4%). A decreasing trend in losses was evident over the 20-year time period: 7/23 (30.4%) from 1994 to 2004 down to 3/26 (11.5%) for 2004-2014. No chromosomal abnormalities were present in any of the survivors. The ethical issues focus on the justification of SF in high-order multifetal pregnancies. CONCLUSION: In this series, pregnancy loss decreased with operator experience. Excellent outcomes can be achieved with the ethically justified use of feticide in high-order multiple pregnancies.

Ethical Dimensions of Counseling about the Clinical Management of Gestational Diabetes.

Gestational diabetes is associated with both short- and long-term adverse outcomes for the mother and the child. Glycemic control to improve perinatal outcomes is consistent with the best available evidence and should be recommended. The evidence for interventions to improve long-term outcomes is less robust. Therefore, patients need to be informed of the data, have the limitations explained, and be supported in decision-making. Theoretical risks do not need to be revealed to patients. Enthusiasm for interventions not supported by evidence should not be promoted. This article provides an ethical framework for counseling patients about the management of gestational diabetes.

Fetal tissue research: an ongoing story of professionally responsible success.

Therapies derived from fetal tissue research are some of the greatest success stories in medicine. Research using fetal tissue has allowed for development of vaccines for numerous diseases including polio, rubella, and measles. These vaccines have saved countless lives, improved quality of life, and decreased the need for induced abortion secondary to congenital infection. Research using cell lines derived from fetal tissue has assisted in better understanding disease pathogenesis and has served to produce human proteins as research reagents and therapies. Ongoing research points to the potential for fetal tissue to be used to cure debilitating diseases such as Parkinson disease. These scientific and medical advances are dependent on the use of fetal tissue from aborted fetuses. While the practice of induced abortion despite societal benefit may be theologically objectionable to some, these practices are professionally responsible. Federal regulations exist to discourage patients from being influenced by the societal benefit of fetal research in arriving at the decision to terminate as well as to prevent researchers from influencing a patient's decision. After a patient has chosen termination of pregnancy, it is consistent with professional responsibility to allow her to choose the disposition of the cadaveric fetal tissue. While some may view induced abortion and societal benefit from this practice as an ethical burden, the principle of justice makes it ethically obligatory to bear this ethical burden. The success story of cadaveric fetal tissue research and treatment should continue unhindered, to fulfill professional responsibility to current and future patients.

Group B Streptococcus ß-hemolysin/cytolysin breaches maternal-fetal barriers to cause preterm birth and intrauterine fetal demise in vivo.

BACKGROUND: Maternal vaginal colonization with Streptococcus agalactiae (Group B Streptococcus [GBS]) is a precursor to chorioamnionitis, fetal infection, and neonatal sepsis, but the understanding of specific factors in the pathogenesis of ascending infection remains limited. METHODS: We used a new murine model to evaluate the contribution of the pore-forming GBS ß-hemolysin/cytolysin (ßH/C) to vaginal colonization, ascension, and fetal infection. RESULTS: Competition assays demonstrated a marked advantage to ßH/C-expressing GBS during colonization. Intrauterine fetal demise and/or preterm birth were observed in 54% of pregnant mice colonized with wild-type (WT) GBS and 0% of those colonized with the toxin-deficient cylE knockout strain, despite efficient colonization and ascension by both strains. Robust placental inflammation, disruption of maternal-fetal barriers, and fetal infection were more frequent in animals colonized with WT bacteria. Histopathologic examination revealed bacterial tropism for fetal lung and liver. CONCLUSIONS: Preterm birth and fetal demise are likely the direct result of toxin-induced damage and inflammation rather than differences in efficiency of ascension into the upper genital tract. These data demonstrate a distinct contribution of ßH/C to GBS chorioamnionitis and subsequent fetal infection in vivo and showcase a model for this most proximal step in GBS pathogenesis.

Pregnancy-specific association of vitamin D deficiency and bacterial vaginosis.

OBJECTIVE: Recent data suggest vitamin D deficiency (VDD) is associated with bacterial vaginosis (BV) during pregnancy. We hypothesized that VDD is a risk factor for BV in nonpregnant women. STUDY DESIGN: Using National Health and Nutrition Examination Survey data, we conducted multivariable logistic regression analyses stratified by pregnancy. RESULTS: VDD was associated with BV only in pregnant women (adjusted odds ratio [AOR], 2.87; 95% confidence interval [CI], 1.13-7.28). Among nonpregnant women, douching (AOR, 1.72; 95% CI, 1.25-2.37), smoking (AOR, 1.66; 95% CI, 1.23-2.24), and black race (AOR, 2.41; 95% CI, 1.67-3.47) were associated with BV; oral contraceptive use was inversely associated with BV (AOR, 0.60; 95% CI, 0.40-0.90). VDD moderated the association between smoking and BV in nonpregnant women. CONCLUSION: Risk factors for BV differ by pregnancy status. VDD was a modifiable risk factor for BV among pregnant women; evaluation of vitamin D supplementation for prevention or adjunct therapy of BV in pregnancy is warranted.

The recommendation for bed rest in the setting of arrested preterm labor and premature rupture of membranes.

OBJECTIVE: The objective of the study was to estimate practice patterns regarding bed rest in women with preterm premature rupture of membranes (PPROM) and arrested preterm labor. STUDY DESIGN: This was a mail-based survey of all Society for Maternal-Fetal Medicine members in the United States asking whether they would recommend bed rest in the setting of arrested preterm labor or PPROM at 26 weeks. Bed rest was defined as no more than 1-2 hours per day out of bed, with permitted activities including bathroom use, bathing, and brief ambulation inside the home/hospital. RESULTS: Seventy-one percent and 87% would recommend bed rest for women with cervical dilation and arrested preterm labor and women with PPROM, respectively, even though the majority believed bed rest was associated with minimal or no benefit. Female sex, nonacademic practice, and practice location in the South or West were independently associated with the recommendation for bed rest. CONCLUSION: Despite the belief that bed rest is associated with minimal or no benefit, most maternal-fetal medicine specialists recommend bed rest for arrested preterm labor and PPROM. Randomized, prospective trials are needed to evaluate the efficacy of bed rest in these settings.

Inappropriate use of vancomycin for preventing perinatal group B streptococcal (GBS) disease in laboring patients.

OBJECTIVE: The 2002 CDC guidelines for the prevention of perinatal group B streptococcus (GBS) stipulate that vancomycin is reserved for penicillin-allergic women at high risk for beta-lactam anaphylaxis with resistance to clindamycin or erythromycin. Our objective was to evaluate practitioner adherence to these guidelines. METHODS: This is a retrospective chart review of patients admitted to labor and delivery who received vancomycin for GBS prophylaxis from January 1st, 2005 to June 1st, 2007. Identification and documentation of allergic reactions to beta lactams and performance of GBS sensitivities at the time of screening were recorded. RESULTS: Eighty-seven patients reporting a penicillin allergy received vancomycin during labor. In 71 patients screened at 35-37 weeks, sensitivities were not performed for 55 patients, of which 10 reported an anaphylactic-like reaction to penicillin. Of 15 patients who had sensitivities performed at the time of screening and were resistant to clindamycin and/or erythromycin, only two patients, however, described an anaphylactic-like reaction to penicillin. Fourteen patients received vancomycin due to an unknown GBS status at <35 weeks of gestation and only three patients from this group reported an anaphylactic-like reaction to penicillin. There were deviations from the CDC protocol in 82 (94%) of 87 patients who received intrapartum vancomycin there were deviations in the CDC protocol. CONCLUSION: Most patients receiving intrapartum vancomycin for perinatal GBS prophylaxis either did not have a culture with sensitivities performed at the time of GBS screening due to a history of anaphylactic-like reactions to penicillin or received vancomycin for a mild or unknown allergy. Physician adherence to the CDC guidelines with regards to the use of vancomycin is far from optimal.

Increased circulating levels of Epidermal Growth Factor-like Domain 7 in pregnant women affected by preeclampsia.

Proper placental development is crucial to establish a successful pregnancy. Defective placentation is the major cause of several pregnancy complications, including preeclampsia (PE). We have previously demonstrated that the secreted factor Epidermal Growth Factor-like Domain 7 (EGFL7) is expressed in trophoblast cells of the human placenta and that it regulates trophoblast migration and invasion, suggesting a role in placental development. In the present study, we demonstrate that circulating levels of EGFL7 are undetectable in nonpregnant women, increase during pregnancy and decline toward term. Close to term, circulating levels of EGFL7 are significantly higher in patients affected by PE when compared to normal pregnancies. Consistent with these results, villus explant cultures obtained from placentas affected by PE display increased release of EGFL7 in the culture medium when compared to those from normal placentas. Our results suggest that increased release of placenta-derived EGFL7 and increased circulating levels of EGFL7 are associated with the clinical manifestation of PE.

Functional and phylogenetic characterization of Vaginolysin, the human-specific cytolysin from Gardnerella vaginalis.

Pore-forming toxins are essential to the virulence of a wide variety of pathogenic bacteria. Gardnerella vaginalis is a bacterial species associated with bacterial vaginosis (BV) and its significant adverse sequelae, including preterm birth and acquisition of human immunodeficiency virus. G. vaginalis makes a protein toxin that generates host immune responses and has been hypothesized to be involved in the pathogenesis of BV. We demonstrate that G. vaginalis produces a toxin (vaginolysin [VLY]) that is a member of the cholesterol-dependent cytolysin (CDC) family, most closely related to intermedilysin from Streptococcus intermedius. Consistent with this predicted relationship, VLY lyses target cells in a species-specific manner, dependent upon the complement regulatory molecule CD59. In addition to causing erythrocyte lysis, VLY activates the conserved epithelial p38 mitogen-activated protein kinase pathway and induces interleukin-8 production by human epithelial cells. Transfection of human CD59 into nonsusceptible cells renders them sensitive to VLY-mediated lysis. In addition, a single amino acid substitution in the VLY undecapeptide [VLY(P480W)] generates a toxoid that does not form pores, and introduction of the analogous proline residue into another CDC, pneumolysin, significantly decreases its cytolytic activity. Further investigation of the mechanism of action of VLY may improve understanding of the functions of the CDC family as well as diagnosis and therapy for BV.

Contemporary practice patterns and beliefs regarding tocolysis among u.s. Maternal-fetal medicine specialists.

OBJECTIVE: To estimate maternal-fetal medicine specialists' practice patterns and perceived risks and benefits to tocolysis. METHODS: We performed a mail-based survey of all Society for Maternal-Fetal Medicine (SMFM) members in the United States. Subjects were asked whether they would recommend tocolysis and what would be their first-line tocolytic in five scenarios: 1) acute preterm labor; 2) maintenance tocolysis after arrested preterm labor; 3) repeat acute preterm labor; 4) preterm premature rupture of membranes (PROM) without contractions; and 5) preterm PROM with contractions. RESULTS: A total of 827 (46%) SMFM members responded. Ninety-six percent, 56%, 56%, 32%, and 29% would recommend tocolysis for acute preterm labor, repeat acute preterm labor, preterm PROM with contractions, preterm PROM without contractions, and maintenance tocolysis, respectively. The most common first-line tocolytic was magnesium for acute preterm labor (45%) and repeat acute preterm labor (41%); nifedipine was the most common maintenance tocolysis (79%). Eighty percent believed tocolysis was associated with moderate or significant benefit in the setting of acute preterm labor; however, fewer than 50% responded similarly for the other four scenarios. In all five scenarios, more than 50% of respondents indicated there was minimal or no risk associated with tocolysis. Having a nonacademic practice was independently associated with the recommendation for tocolysis. CONCLUSION: Almost all maternal-fetal medicine specialists recommend tocolysis in the setting of acute preterm labor, and many recommend tocolysis for other indications. Magnesium and nifedipine are the most commonly prescribed first-line tocolytics. LEVEL OF EVIDENCE: III.

Antibodies to the 70 kDa heat shock protein in midtrimester amniotic fluid and intraamniotic immunity.

OBJECTIVE: Antibodies to the 70 kDa heat shock protein (hsp70) immunoglobulin (Ig) G are markers for exposure to adverse or nonphysiological stimuli. In addition, these antibodies cross-link hsp-70 microbial antigen complexes and enhance development of antimicrobial immunity. The association between intraamniotic hsp70 IgG concentrations and intraamniotic immune responses were evaluated. STUDY DESIGN: Midtrimester amniotic fluids from 90 women undergoing an amniocentesis were tested for hsp70 IgG, hsp70 antigen, tumor necrosis factor (TNF)-alpha, secretory leukocyte protease inhibitor (SLPI), and interferon (IFN)-alpha by enzyme-linked immunosorbent assay. Clinical outcomes were obtained after completion of all testing. Associations were analyzed by nonparametric statistics. RESULTS: Intraamniotic hsp70 IgG concentrations, but not hsp70 antigen levels, were positively associated with levels of TNF-alpha (P < .0001), IFN-alpha (P = .0001), and SLPI (P = .0038). There were no associations between hsp70 IgG and maternal age or parity, race/ethnicity or pregnancy outcome. CONCLUSION: The hsp70 IgG levels correlate with intraamniotic concentrations of antimicrobial immune mediators. This antibody may potentiate antimicrobial immunity during fetal development.

Pregnant women's attitudes about topical microbicides for the prevention and treatment of bacterial vaginosis during pregnancy.

We sought to understand pregnant women's product preference and likelihood of use of topical microbicides for bacterial vaginosis (BV) prevention and treatment. Pregnant women (N = 196) in a obstetrics clinic completed a survey between June 2014 and January 2015 about vaginal product use for BV. This cross-sectional study explored product preferences, likelihood of product use for BV management and father of the baby (FOB) involvement. Most participants were under 30 (68%) and underrepresented minorities (47% Hispanic, 21% African-American). Most women preferred the gel (69%). Only 30% were likely to use either product for prevention of BV; 76% if high risk for BV; 83% treatment of BV. Anticipated FOB involvement in decision-making included that 46% would ask his opinion, 38% would inform him of the decision and 7% would need approval. Most (87%) would ask the FOB for reminders and 66% for insertion help. Those under 30 were more likely to agree to ask the FOB for reminders (p < 0.01) and insertion help (p = 0.05). African-American women were less likely to have their FOB help with insertion (p < 0.01). Product preferences may be less critical than risk perception. Involvement of the FOB in decision-making may be vital.

Variation in vaginal immune parameters and microbial hydrolytic enzymes in bacterial vaginosis positive pregnant women with and without Mobiluncus species.

OBJECTIVE: This study was undertaken to assess if levels of interleukin-1beta (IL-1beta), IL-8, sialidase, prolidase and immunoglobulin A against Gardenerella vaginalis hemolysin (anti-Gvh IgA) in vaginal secretions differ between BV+ women with (M+) and without (M-) Mobiluncus spp. STUDY DESIGN: Vaginal secretions were obtained from 265 women at their first prenatal care visit and assessed for all study parameters. Gram stain evaluation using Nugent criteria was performed and coinfection with sexually transmitted infections determined. Differences between BV+/M+ and BV+/M- women were evaluated using the chi2 statistic or Mann-Whitney test. RESULTS: Of the 265 BV+ women, 43% (n = 113) were M+ of which 97% (n = 110) had Nugent scores of 9 or 10 . BV+/M+ women had elevated levels of sialidase (median value: 4.11 nmol vs 1.91 nmol of converted substrate; P = .003) but no difference in prolidase, anti-Gvh IgA, IL-1beta, IL-8, levels were found between the two groups. BV+/M- women had significantly higher rates of coinfection with Trichomonas vaginalis. CONCLUSION: BV+/M+ women have higher vaginal concentrations of sialidase and lower rates of T. vaginalis compared with BV+/M- women. Further research is needed to assess the association of this, and other, microbiologic profiles to risk of adverse pregnancy outcome.

ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice.

OBJECTIVE: Pregnancies in women with the antiphospholipid syndrome (APS) are frequently complicated by fetal loss and intrauterine growth restriction (IUGR). How circulating antiphospholipid antibodies (aPL) cause pregnancy complications in APS is poorly understood. We sought to determine whether the low-density lipoprotein receptor family member apolipoprotein E receptor 2 (ApoER2) mediates trophoblast dysfunction and pregnancy complications induced by aPL. METHODS: Placental and trophoblast ApoER2 expression was evaluated by immunohistochemistry and immunoblotting. Normal human IgG and aPL were purified from healthy individuals and APS patients, respectively. The role of ApoER2 in aPL-induced changes in trophoblast proliferation and migration and in kinase activation was assessed using RNA interference in HTR-8/SVneo cells. The participation of ApoER2 in aPL-induced pregnancy loss and IUGR was evaluated in pregnant ApoER2(+/+) and ApoER2(-/-) mice injected with aPL or normal human IgG. RESULTS: We found that ApoER2 is abundant in human and mouse placental trophoblasts and in multiple trophoblast-derived cell lines, including HTR-8/SVneo cells. ApoER2 and its interaction with the cell surface protein ß2 -glycoprotein I were required for aPL-induced inhibition of cultured trophoblast proliferation and migration. In parallel, aPL antagonism of Akt kinase activation by epidermal growth factor in trophoblasts was mediated by ApoER2. Furthermore, in a murine passive-transfer model of pregnancy complications of APS, ApoER2(-/-) mice were protected from both aPL-induced fetal loss and aPL-induced IUGR. CONCLUSION: ApoER2 plays a major role in the attenuation of trophoblast function by aPL, and the receptor mediates aPL-induced pregnancy complications in vivo in mice. ApoER2-directed interventions can now potentially be developed to combat the pregnancy complications associated with APS.