Fetal Outcomes with Detoxification from Opioid Drugs during Pregnancy: A Systematic Review.

OBJECTIVE: This study aimed to perform a systematic review of all studies reporting fetal outcomes following detoxification or tapering of opioid drugs during pregnancy. STUDY DESIGN: PubMed, Scopus, Medline, and Google Scholar were searched, and only manuscripts clearly reporting pregnancy/fetal outcomes involving tapering or detoxification from opioid drugs were included. Only pregnancies managed after 1980 were included (when antenatal fetal surveillance became more routine). Collected data included study design, location, years patients were managed, number of patients who were tapered or detoxified, method of tapering, and pregnancy outcome. RESULTS: A total of 14 publications met the criteria for review after evaluating more than 2,000 abstracts and 153 published manuscripts. In 1,097 pregnancies, based on mortality rate analyses and forest plots, no increased fetal risks due to tapering or detoxification from opioid drugs were identified. No increased risk of preterm delivery was found. CONCLUSION: Pregnant women with opioid use disorder who are stable in a medication-assisted treatment program with behavioral health can be informed that tapering or full detoxification from opioid drugs does not increase the fetal risk of poor pregnancy outcome. Future research needs to answer the questions on maternal and long-term newborn consequences of tapering or detoxification versus long-term newborn consequences of continued chronic in utero opioid exposure.

Use of naltrexone in treating opioid use disorder in pregnancy.

BACKGROUND: The mainstay of the management of opioid use disorder in pregnancy is with methadone or buprenorphine medication-assisted treatment. Methadone and buprenorphine are opioid agonist drugs. Naltrexone, an opioid antagonist, is also a medication-assisted treatment option; however, to date, only a few retrospective studies have reported its use in pregnancy. OBJECTIVE: Our study objective was to evaluate prospectively obstetric and newborn outcomes and the maternal/fetal effects of the use of naltrexone as a medication-assisted treatment in pregnant patients with opioid use disorder. STUDY DESIGN: We performed a prospective cohort study collecting data on all pregnant women who were treated with naltrexone medication-assisted treatment compared with pregnant women who were treated with methadone or buprenorphine medication-assisted treatment. Based on a sample size calculation, it was determined that for a power of 90, a minimum of 160 study participants (80 in each group) was needed with an alpha of .01 and an expected 60% rate of newborn infants who were treated for neonatal abstinence syndrome in the methadone or buprenorphine medication-assisted treatment group compared with a 30% rate in the naltrexone medication-assisted treatment group. In a random subset of 20 maternal/newborn dyads, blood levels for naltrexone and 6-beta-naltrexol (an active metabolite) were analyzed at delivery. RESULTS: A total of 230 patients were studied: 121 patients with naltrexone medication-assisted treatment compared with 109 patients with methadone or buprenorphine medication-assisted treatment. No differences between groups were seen regarding demographics, the use of comedications/drugs, or obstetric outcomes. For newborn outcomes, the rate of neonatal abstinence syndrome in neonates >34 weeks gestation was significantly lower in the naltrexone medication-assisted treatment group (10/119 [8.4%] vs 79/105 [75.2%]; P<.0001). Multivariate analysis demonstrated that the only significant factor for the rate of neonatal abstinence syndrome was the form of medication-assisted treatment. Of 87 patients who received naltrexone up to delivery, no neonates experienced symptoms of neonatal abstinence syndrome. No maternal relapses occurred in the 7-day no-treatment window before the initiation of naltrexone therapy. No cases of spontaneous abortion or stillbirth occurred in either group. In 64 patients who started naltrexone therapy at ≥24 weeks gestation, no changes were seen in the fetal heart monitor tracing with drug initiation. The incidence of birth anomalies was no different between the groups. Umbilical cord blood and maternal levels for naltrexone and 6-beta-naltrexol matched; no levels were elevated, and values were undetected if naltrexone was discontinued >60 hours before delivery. CONCLUSION: These study data demonstrate that, in pregnant women who choose to completely detoxify off opioid drugs during gestation, naltrexone, as a continued form of medication-assisted treatment, is a viable option for some pregnant patients who experience opioid use disorder. Naltrexone crosses the placenta, and maternal and fetal levels are concordant. Because naltrexone clears quickly from the maternal circulation, this rapid clearance needs to be addressed with patients. This is important because maternal relapse could occur in a short time-period if the oral drug is discontinued without the knowledge of their healthcare providers. Nonetheless, the drug is well-tolerated by both mother and fetus, and newborn infants do not experience symptoms of neonatal abstinence syndrome if naltrexone medication-assisted treatment is maintained to delivery.

Psychosocial Background History of Pregnant Women with Opioid Use Disorder: A Prospective Cohort Study.

OBJECTIVE: This study aimed to evaluate the psychosocial background history and confounding social factors in pregnant women with opioid use disorder (OUD). STUDY DESIGN: We performed a prospective observational cohort study of pregnant women from a dedicated obstetrical OUD clinic. Data collection came from extensive interview sessions regarding psychosocial background events and other social factors that might impact prenatal care. RESULTS: From February 1, 2017, through September 30, 2018, 411 pregnant women were evaluated and 294 (72%, 95% confidence interval [CI]: 67-76%) reported abuse of which 217 (53%, 95% CI: 48-58%) involved sexual abuse (prior to the age of 13 years in 54% of cases) and 209 (51%, 95% CI: 46-56%) involved cases of other physical abuse. Only 10% reported habitual opioid use for managing chronic pain. Only 9% had a valid driver's license with access to a car making transportation to office visits difficult. CONCLUSION: A history of abuse (mainly sexual and/or physical) appears to be the main precipitating event leading to OUD in our pregnant population. Transportation was the primary social factor limiting access to prenatal care. For primary prevention to be successful in our region, early identification of young women who have experienced abuse needs to occur followed by psychotherapy health care intervention before opioid drugs are used.

Neonatal Head Circumference in Newborns With Neonatal Abstinence Syndrome.

OBJECTIVES: To compare head circumference (HC) in neonates treated for neonatal abstinence syndrome (NAS) with control neonates without antenatal opioid exposure. METHODS: Our prospective cohort study ran from April 1, 2014, through December 31, 2016. Newborns treated for NAS delivered from well-dated pregnancies ≥34 weeks' gestation were compared with newborns who were nonopioid exposed and matched for race, parity, mode of delivery, and gestational age. All mothers underwent serial antenatal urine drug testing. A minimum of 754 study participants were needed (377 in each group) to demonstrate an increase in the proportion of newborns with HCs less than or equal to the 10th percentile from 10% in controls to a minimum of 20% in NAS newborns with 90% power. RESULTS: A total of 858 neonates were enrolled (429 NAS cases and 429 controls). Mean HC for cases was 33.04 cm (±1.9 cm) compared with 33.99 cm (±2.0 cm) for controls (P < .0001). Among the 429 NAS cases, the mothers of 372 (87%) were on opioid medication-assisted treatment. For NAS cases, 30.1% (95% confidence interval: 25.8%-34.7%) had an HC less than or equal to the 10th percentile (129 of 429 neonates), and 8.2% (95% confidence interval: 5.8%-11.2%) had an HC less than or equal to the third percentile (35 of 429 neonates). Multivariate analysis was used and determined that only chronic opioid use during gestation resulting in a neonate who was NAS treated was a significant risk factor for the observed smaller HC. CONCLUSIONS: Chronic opioid use during pregnancy sufficient to cause NAS was associated with smaller HCs at birth. Most mothers were on opioid agonist medication-assisted treatment, which is currently the recommended treatment option during pregnancy.

Extremely preterm fetal sheep lung responses to antenatal steroids and inflammation.

BACKGROUND: The efficacy of antenatal steroids for fetal lung maturation in the periviable period is not fully understood. OBJECTIVE: We sought to determine the lung maturational effects of antenatal steroids and inflammation in early gestation sheep fetuses, similar to the periviable period in human beings. STUDY DESIGN: Date-mated ewes with singleton fetuses were randomly assigned to 1 of 4 treatment groups (n = 8/group): (1) maternal intramuscular injection of betamethasone; (2) intraamniotic lipopolysaccharide; (3) betamethasone + lipopolysaccharide; and (4) intraamniotic + intramuscular saline (controls). Fetuses were delivered surgically 48 hours later at 94 days' gestation (63% term gestation) for comprehensive evaluations of lung maturation, and lung and systemic inflammation. RESULTS: Relative to controls, first, betamethasone increased the fetal lung air space to mesenchymal area ratio by 47% but did not increase the messenger RNAs for the surfactant proteins-B and -C that are important for surfactant function or increase the expression of pro-surfactant protein-C in the alveolar type II cells. Second, betamethasone increased expression of 1 of the 4 genes in surfactant lipid synthetic pathways. Third, betamethasone increased genes involved in epithelium sodium channel transport, but not sodium-potassium adenosine triphosphatase or Aquaporin 5. Fourth, lipopolysaccharide increased proinflammatory genes in the lung but did not effectively recruit activated inflammatory cells. Last, betamethasone incompletely suppressed lipopolysaccharide-induced lung inflammation. In the liver, betamethasone when given alone increased the expression of serum amyloid A3 and C-reactive protein messenger RNAs. CONCLUSION: Compared the more mature 125-day gestation sheep, antenatal steroids do not induce pulmonary surfactants during the periviable period, indicating a different response.

Contemporary practice patterns in the use of amniocentesis for fetal lung maturity.

PURPOSE: Fetal lung maturity (FLM) testing has been performed to help direct delivery timing in complex obstetrical conditions. We explored current practice patterns of FLM testing attempting to identify factors affecting its use. MATERIALS AND METHODS: We distributed a 31-question survey to obstetricians and perinatologists that examined practice characteristics potentially affecting FLM usage. Logistic regression measured associations between these factors and test utilization. Weighted averages were calculated for conditions in which respondents considered FLM testing helpful. RESULTS: Three hundred four surveys were completed. The response rate for respondents actively practicing obstetrics was 52%. The majority of respondents utilize FLM testing; however, 80% reported a decline in use over the past five years with 64% citing "published guidelines" as the reason. Respondents found FLM testing most applicable for poorly dated pregnancies. After an immature FLM test, 44% of respondents administer antenatal corticosteroids in the late-preterm period. None of the factors surveyed were significantly associated with FLM testing use. CONCLUSION: The majority of respondents use FLM testing although significant factors contributing to its use were not identified. We discover a high frequency of antenatal corticosteroid administration beyond 34 weeks gestational age in response to immature FLM indices that may be an area for future study.

Fetal Heart Monitor Tracing in a Pregnancy Complicated by a Ruptured Fetal Vessel on the Placenta: A Case Report.

Background: This report describes the fetal heart rate (FHR) tracing in a pregnancy complicated by antenatal spontaneous rupture of fetal vessels on the placental surface that resulted in a live birth. Case: 36-year-old woman, G2P1001, was being followed with weekly antenatal testing for gestational diabetes type A2 on insulin with possible intrauterine growth restriction. She presented for an office visit at 37.5 weeks' gestation with a complaint of decreased fetal movement. The FHR pattern demonstrated minimal baseline variability with an occasional spontaneous deceleration not associated with a contraction, an absence of recurrent decelerations, and no accelerations. The antenatal evaluation is discussed, and portions of the FHR tracing and the placental findings at delivery are provided. Conclusion: The FHR pattern did not fit with what is usually depicted with uteroplacental insufficiency or umbilical cord entrapment. In addition, even though the fetus is anemic, the process may occur too quickly for a sinusoidal pattern to develop.

Blood Contaminated Amniotic Fluid and the Lamellar Body Count Fetal Lung Maturity Test.

OBJECTIVE: To determine if maternal blood contamination falsely elevates the lamellar body count fetal lung maturity test. STUDY DESIGN: Fifty mothers undergoing amniocentesis for fetal lung maturity consented to participation in the study. For each participant a blood-contaminated sample using the patient's own blood was run in tandem with the noncontaminated sample used for clinical practice. RESULTS: Of the 50 study patient samples the lamellar body count decreased by ≥ 3,000/µL in 33 (66%) and remained unchanged in 16 (32%). In only 1 case did the value increase--the actual result of 37,000/µL increased to 44,000/µL, both of which exceeded the mature level in our institution. CONCLUSION: Maternal blood contamination of amniotic fluid does not falsely increase the lamellar body count in 98% of cases. The result was falsely lowered in 2 out of 3 cases. Therefore, a mature lamellar body count test result in a blood-contaminated sample is reliable

Chronic opiate use in pregnancy and newborn head circumference.

OBJECTIVE: The aim of the study is to evaluate whether chronic opiate use in pregnancy affects newborn head circumference (HC). STUDY DESIGN: All newborns from January 1, 2010, to June 30, 2012, admitted to the neonatal intensive care unit for treatment of neonatal abstinence syndrome were prospectively collected. The demographic, obstetrical, neonatal, and perinatal ultrasound data were retrospectively obtained. A gestational age-matched control was used for comparison purposes. RESULTS: Of 332 neonates admitted for the treatment of neonatal abstinence syndrome, 98 (29.5%) had a HC ≤ 10th percentile for gestational age that was significantly increased when compared with controls (p < 0.001). Of these 98, 25 had a HC ≤ 3rd percentile. Of the case population, 141 had an ultrasound in the perinatal unit within 10 days of birth. A HC < 5th percentile was found in 38.3% of cases of which 74% were ≤ 10th percentile postdelivery. The ultrasound femur and humerus length measurements were also < 5th percentile in 36.2 and 28.9%, respectively. CONCLUSION: Chronic opiate use in pregnancy appears to increase the risk for a HC ≤ 10th percentile and ≤ 3rd percentile when compared with controls. From ultrasound findings, femur and humerus lengths also appear to be shortened suggesting a possible effect on bone growth.

Pathogenic IgG antibodies against desmoglein 3 in pemphigus vulgaris are regulated by HLA-DRB1*04:02-restricted T cells.

Pemphigus vulgaris (PV) is considered as a model for an autoantibody-mediated organ-specific autoimmune disorder. IgG autoantibodies directed against the desmosomal cadherin desmoglein 3 (Dsg3), the major autoantigen in PV, cause loss of epidermal keratinocyte adhesion, resulting in blisters and erosions of the skin and mucous membranes. The association of human autoimmune diseases with distinct HLA alleles is a well-known phenomenon, such as the association with HLA-DRB1*04:02 in PV. However, direct evidence that HLA-DRB1*04:02-restricted autoreactive CD4(+) T cells recognizing immunodominant epitopes of Dsg3 initiate the production of Dsg3-reactive IgG autoantibodies is still missing. In this study, we show in a humanized HLA-DRB1*04:02-transgenic mouse model that HLA-DRB1*04:02-restricted T cell recognition of human Dsg3 epitopes leads to the induction of pathogenic IgG Abs that induce loss of epidermal adhesion, a hallmark in the immune pathogenesis of PV. Activation of Dsg3-reactive CD4(+) T cells by distinct human Dsg3 peptides that bind to HLA-DRß1*04:02 is tightly regulated by the HLA-DRB1*04:02 allele and leads, via CD40-CD40L-dependent T cell-B cell interaction, to the production of IgG Abs that recognize both N- and COOH-terminal epitopes of the human Dsg3 ectodomain. These findings demonstrate key cellular and humoral immune events in the autoimmune cascade of PV in a humanized HLA-transgenic mouse model. We show that CD4(+) T cells recognizing immunodominant Dsg3 epitopes in the context of the PV-associated HLA-DRB1*04:02 induce the secretion of Dsg3-specific IgG in vivo. Finally, these results identify Dsg3-reactive CD4(+) T cells as potential therapeutic targets in the future.

hCG in ectopic pregnancy.

Ectopic pregnancies remain an important cause of morbidity and mortality in women of reproductive age. Management of these pregnancies has changed dramatically over the years. Human chorionic gonadotropin (hCG) is a glycoprotein hormone composed of 2 dissimilar subunits, alpha and beta, joined non-covalently. The free beta-subunit is the principal immuno-reactive agent in pregnancy serum samples. Improved diagnostic methods using hCG levels in combination with transvaginal ultrasound have lead to earlier detection rates, subsequent treatment and a reduction in mortality resulting from ectopic pregnancies. This chapter will describe current trends in ectopic pregnancy diagnosis based on hCG levels.

The response of mycobacterium tuberculosis to reactive oxygen and nitrogen species.

The bacteriostatic and bactericidal effects and the transcriptional response of Mycobacterium tuberculosis to representative oxidative and nitrosative stresses were investigated by growth and survival studies and whole genome expression analysis. The M. tuberculosis reaction to a range of hydrogen peroxide (H(2)O(2)) concentrations fell into three distinct categories: (1) low level exposure resulted in induction of a few highly sensitive H(2)O(2)-responsive genes, (2) intermediate exposure resulted in massive transcriptional changes without an effect on growth or survival, and (3) high exposure resulted in a muted transcriptional response and eventual death. M. tuberculosis appears highly resistant to DNA damage-dependent, mode-one killing caused by low millimolar levels of H(2)O(2) and only succumbs to overwhelming levels of oxidative stress observed in mode-two killing. Nitric oxide (NO) exposure initiated much the same transcriptional response as H(2)O(2). However, unlike H(2)O(2) exposure, NO exposure induced dormancy-related genes and caused dose-dependent bacteriostatic activity without killing. Included in the large shared response to H(2)O(2) and NO was the induction of genes encoding iron-sulfur cluster repair functions including iron acquisition. Stress regulons controlled by IdeR, Sigma H, Sigma E, and FurA comprised a large portion of the response to both stresses. Expression of several oxidative stress defense genes was constitutive, or increased moderately from an already elevated constitutive level, suggesting that bacilli are continually primed for oxidative stress defense.

Ancestral antibiotic resistance in Mycobacterium tuberculosis.

Chemotherapeutic options to treat tuberculosis are severely restricted by the intrinsic resistance of Mycobacterium tuberculosis to the majority of clinically applied antibiotics. Such resistance is partially provided by the low permeability of their unique cell envelope. Here we describe a complementary system that coordinates resistance to drugs that have penetrated the envelope, allowing mycobacteria to tolerate diverse classes of antibiotics that inhibit cytoplasmic targets. This system depends on whiB7, a gene that pathogenic Mycobacterium shares with Streptomyces, a phylogenetically related genus known as the source of diverse antibiotics. In M. tuberculosis, whiB7 is induced by subinhibitory concentrations of antibiotics (erythromycin, tetracycline, and streptomycin) and whiB7 null mutants (Streptomyces and Mycobacterium) are hypersusceptible to antibiotics in vitro. M. tuberculosis is also antibiotic sensitive within a monocyte model system. In addition to antibiotics, whiB7 is induced by exposure to fatty acids that pathogenic Mycobacterium species may accumulate internally or encounter within eukaryotic hosts during infection. Gene expression profiling analyses demonstrate that whiB7 transcription determines drug resistance by activating expression of a regulon including genes involved in ribosomal protection and antibiotic efflux. Components of the whiB7 system may serve as attractive targets for the identification of inhibitors that render M. tuberculosis or multidrug-resistant derivatives more antibiotic-sensitive.

Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program.

An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis.

Cytokines elicited by T cell epitopes from a synovial autoantigen: altered peptide ligands can reduce interferon-gamma and interleukin-10 production.

OBJECTIVE: To explore the cytokine responses associated with T cell epitopes from human cartilage glycoprotein 39 (HC gp-39) and the potential for modifying cytokine secretion using altered peptide ligands (APLs). METHODS: Draining lymph node cells were harvested from HLA-DR*0401 transgenic mice that had been immunized with HC gp-39. Cytokine responses to 5 previously identified HLA-DR*0401-restricted HC gp-39 T cell epitopes were studied in vitro. The anchor and T cell receptor (TCR) contact residues of peptide 322-337 were identified, and this information was used to design alanine-substituted APLs. T cells were primed in vivo with wild-type peptide 322-337, restimulated with wild-type peptide or APLs, and the cytokine profiles were compared. RESULTS: Restimulation with individual peptides elicited distinct cytokine profiles. HC gp-39 (peptide 322-337) elicited a dominant interferon-gamma (IFNgamma) response. Residues within the core (positions P1-P9) 322-337 peptide sequence were critical for T cell recognition. Surprisingly, the N-terminal flanking region was also important for recognition by 6 of 10 specific T cell hybridomas. Substitutions of charged TCR contact residues in the 322-337 core epitope (E332A and K335A) were associated with a significant reduction in the IFNgamma and interleukin-10 (IL-10) stimulation indices. Restimulation with peptides W325A and V326A was also associated with a trend toward reduced IFNgamma and IL-10 secretion. In contrast, restimulation with peptide D330N elicited cytokine profiles more comparable with those resulting from restimulation with wild-type peptide. CONCLUSION: This study indicates that APLs of a proinflammatory HC gp-39 T cell epitope may be used to alter the cytokine response from a memory T cell population.

Humanized mice as a model for rheumatoid arthritis.

Genetic susceptibility to rheumatoid arthritis (RA), a common autoimmune disease, is associated with certain HLA-DR4 alleles. Treatments are rarely curative and are often tied to major side effects. We describe the development of a humanized mouse model wherein new, less toxic, vaccine-like treatments for RA might be pretested. This model includes four separate transgenes: HLA-DR*0401 and human CD4 molecules, a RA-related human autoantigenic protein (HCgp-39), and a T-cell receptor (TCRalphabeta) transgene specific for an important HCgp-39 epitope, eliciting strong Th1 responses in the context of HLA-DR*0401.

Relationship between kinetic stability and immunogenicity of HLA-DR4/peptide complexes.

Immunodominant T cell epitopes from the autoantigen human cartilage glycoprotein 39 have previously been mapped in the context of HLA-DR*0401 and *0402, using mice expressing HLA-DR4 transgenes. We measured the dissociation rates of these epitopes from soluble recombinant DR*0401 and DR*0402 to assess the relationship between peptide/HLA-DR4 kinetic stability and immunogenicity. Experiments were performed at endosomal pH (5.5) and at cell surface pH (7), in the absence and presence of soluble recombinant HLA-DM (sDM). All (4/4) immunodominant peptide/HLA-DR complexes exhibit dissociation half-times of 1h to several days. In contrast, most (3/4) non-immunodominant complexes dissociate with half-times <30 min under at least one of these conditions. Interestingly, a complex which is stable except in the presence of HLA-DM at pH 5.5 is immunogenic only following peptide immunization, while a complex which is stable at acidic but not at neutral pH, is non-immunogenic following either whole protein or peptide immunization. These data indicate that kinetic stability of peptide/MHC complexes in vivo is a key determinant of immunogenicity.