Ultrasound prediction of Zika virus-associated congenital injury using the profile of fetal growth.

Zika virus (ZIKV) is a mosquito-transmitted flavivirus, recently linked to microcephaly and central nervous system anomalies following infection in pregnancy. Striking findings of disproportionate growth with a smaller than expected head relative to body length have been observed more commonly among fetuses with exposure to ZIKV in utero compared to pregnancies without ZIKV infection regardless of other signs of congenital infection including microcephaly. This study's objective was to determine the diagnostic accuracy of femur-sparing profile of intrauterine growth restriction for the identification of ZIKV-associated congenital injuries on postnatal testing. A retrospective cohort study of pregnant women with possible or confirmed ZIKV infection between January 1, 2016 and December 31, 2017 were included. Subjects were excluded if no prenatal ultrasound was available. A femur-sparing profile of growth restriction determined using INTERGROWTH-21st sonographic standard for head circumference to femur length (HC: FL). Congenital injuries were determined postnatally by imaging, comprehensive eye exam and standard newborn hearing screen. A total of 111 pregnant women diagnosed with ZIKV infection underwent fetal ultrasound and 95 neonates had complete postnatal evaluation. Prenatal microcephaly was detected in 5% of fetuses (6/111). Postnatal testing detected ZIKV-associated congenital injuries in 25% of neonates (24/95). A HC: FL Z-score ≤ -1.3 had a 52% specificity (95% CI 41-63%), 82% negative predictive value (NPV, 95% CI 73-88%) for the detection of ZIKV-associated congenital injuries in the neonatal period. A more stringent threshold with a Z-score ≤ -2 was associated with a 90% specificity (95% CI 81-95%), 81% NPV (95% CI 77-85%). Excluding cases of fetal microcephaly, HC: FL (Z-score ≤ -2) demonstrated a similar specificity (89%, 95% CI 81-95%) with superior NPV (87%, 95% CI 84-90%). The sonographic recognition of a normally proportioned fetus may be useful prenatally to exclude a wider spectrum of ZIKV-associated congenital injuries detected postnatally.

Zika virus and the nonmicrocephalic fetus: why we should still worry.

Zika virus is a mosquito-transmitted flavivirus and was first linked to congenital microcephaly caused by a large outbreak in northeastern Brazil. Although the Zika virus epidemic is now in decline, pregnancies in large parts of the Americas remain at risk because of ongoing transmission and the potential for new outbreaks. This review presents why Zika virus is still a complex and worrisome public health problem with an expanding spectrum of birth defects and how Zika virus and related viruses evade the immune response to injure the fetus. Recent reports indicate that the spectrum of fetal brain and other anomalies associated with Zika virus exposure is broader and more complex than microcephaly alone and includes subtle fetal brain and ocular injuries; thus, the ability to prenatally diagnose fetal injury associated with Zika virus infection remains limited. New studies indicate that Zika virus imparts disproportionate effects on fetal growth with an unusual femur-sparing profile, potentially providing a new approach to identify viral injury to the fetus. Studies to determine the limitations of prenatal and postnatal testing for detection of Zika virus-associated birth defects and long-term neurocognitive deficits are needed to better guide women with a possible infectious exposure. It is also imperative that we investigate why the Zika virus is so adept at infecting the placenta and the fetal brain to better predict other viruses with similar capabilities that may give rise to new epidemics. The efficiency with which the Zika virus evades the early immune response to enable infection of the mother, placenta, and fetus is likely critical for understanding why the infection may either be fulminant or limited. Furthermore, studies suggest that several emerging and related viruses may also cause birth defects, including West Nile virus, which is endemic in many parts of the United States. With mosquito-borne diseases increasing worldwide, there remains an urgent need to better understand the pathogenesis of the Zika virus and related viruses to protect pregnancies and child health.

Components of the antepartum, intrapartum, and postpartum exposome impact on distinct short-term adverse neonatal outcomes of premature infants: A prospective cohort study.

We aimed to test the hypothesis that determinants of the perinatal clinical exposome related to the underlying etiology of premature birth (PTB) impact differently on select neonatal outcomes. We conducted a prospective longitudinal study of 377 singleton preterm neonates [gestational age (GA) at birth: 23-34 weeks] separated into three distinct contemporaneous newborn cohorts: i) spontaneous PTB in the setting of intra-amniotic infection/inflammation (yes-IAI, n = 116); ii) spontaneous PTB in the absence of IAI (no-IAI, n = 130), and iii) iatrogenic PTB for preeclampsia (iPTB-PE, n = 131). Newborns (n = 372) were followed until death or discharge. Amniotic fluid defensins 1&2 and calgranulins A&C were used as biomarkers of IAI. An algorithm considering cord blood interleukin-6 (IL-6) and haptoglobin (Hp switch-on) was used to assess fetal exposure to IAI. Intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), early-onset neonatal (EONS) and late-onset (LOS) sepsis, death. Independent risk factors for adverse outcomes were: i) IVH (n = 53): histologic chorioamnionitis, GA, fetal growth restriction, male sex, Hp switch-on; ii) PVL (n = 11): cord blood IL-6; iii) NEC (n = 25), GA; iv) BPD (n = 53): ventilator support, need for surfactant, GA; v) ROP (n = 79): ventilator support, Hp switch-on, GA; vi) fetal and neonatal death (n = 31): GA, amniotic fluid IL-6; vii) suspect EONS (n = 92): GA, Hp switch-on; viii) LOS (n = 81): GA. Our findings are applicable to pregnancies delivered between 23 and 34 weeks' gestation in the setting of IAI and PE, and suggest that GA and inflammatory intrauterine environment play key roles in occurrence of IVH, PVL, ROP, death, EONS and LOS. Postnatal determinants seem to play major role in NEC and BPD.

Timing of postpartum intrauterine device placement: a cost-effectiveness analysis.

OBJECTIVE: To determine if immediate postpartum (PP) intrauterine device (IUD) placement prevents pregnancy and is cost-effective compared with routine placement. DESIGN: We developed a decision-analysis model to determine the number of pregnancies prevented and the cost-effectiveness of immediate PP IUD placement defined as within the first 10 minutes of placental expulsion compared with routine placement at the PP visit. Associated costs and probability estimates for adherence to PP follow-up, IUD placement, expulsion, and pregnancy were determined from the literature. SETTING: Hospital and outpatient facility. PATIENT(S): Women desiring PP IUDs. INTERVENTION(S): IUD placement. MAIN OUTCOME MEASURE(S): The main outcome measure was the number of pregnancies prevented per 1,000 women. The secondary outcome was an incremental cost-effectiveness ratio (ICER) defined as the marginal cost per quality-adjusted life-year (QALY) gained. An ICER of <$50,000/QALY gained was considered to be cost-effective. RESULT(S): Immediate PP IUD placement prevented 88 unintended pregnancies per 1,000 women over a 2-year time horizon. Immediate PP IUD placement was the dominant strategy. For every 1,000 women who desired a PP IUD, attempted immediate PP placement resulted in a cost savings of $282,540 and a gain of 10 QALYs. The model is most sensitive to the cost of an undesired pregnancy. When the cost of a live birth is <$6,000, immediate placement is no longer cost-saving but remains cost-effective. Monte Carlo simulation demonstrates that immediate PP IUD placement is cost-effective in 99% of simulations. CONCLUSION(S): Immediate PP IUD placement is a dominant strategy that prevents unintended pregnancy.

Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia.

Preeclampsia is a pregnancy-specific disorder of unknown etiology and a leading contributor to maternal and perinatal morbidity and mortality worldwide. Because there is no cure other than delivery, preeclampsia is the leading cause of iatrogenic preterm birth. We show that preeclampsia shares pathophysiologic features with recognized protein misfolding disorders. These features include urine congophilia (affinity for the amyloidophilic dye Congo red), affinity for conformational state-dependent antibodies, and dysregulation of prototype proteolytic enzymes involved in amyloid precursor protein (APP) processing. Assessment of global protein misfolding load in pregnancy based on urine congophilia (Congo red dot test) carries diagnostic and prognostic potential for preeclampsia. We used conformational state-dependent antibodies to demonstrate the presence of generic supramolecular assemblies (prefibrillar oligomers and annular protofibrils), which vary in quantitative and qualitative representation with preeclampsia severity. In the first attempt to characterize the preeclampsia misfoldome, we report that the urine congophilic material includes proteoforms of ceruloplasmin, immunoglobulin free light chains, SERPINA1, albumin, interferon-inducible protein 6-16, and Alzheimer's ß-amyloid. The human placenta abundantly expresses APP along with prototype APP-processing enzymes, of which the α-secretase ADAM10, the ß-secretases BACE1 and BACE2, and the γ-secretase presenilin-1 were all up-regulated in preeclampsia. The presence of ß-amyloid aggregates in placentas of women with preeclampsia and fetal growth restriction further supports the notion that this condition should join the growing list of protein conformational disorders. If these aggregates play a pathophysiologic role, our findings may lead to treatment for preeclampsia.

Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia.

Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient's evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (<2.5 cm) served as controls (n=25). Maternal blood samples of preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting.

Advances in medical diagnosis of intra-amniotic infection.

INTRODUCTION: Intrauterine infection is a global problem and a significant contributor to morbidity and perinatal death. The host response to infection causes an inflammatory state that acts synergistically with microbial insult to induce preterm birth and fetal damage. Prompt and accurate diagnosis of intra-amniotic infection in the asymptomatic stage of the disease is critical for improved maternal and neonatal outcomes. AREAS COVERED: This article provides an overview of the most recent progress, challenges, and opportunities for discovery and clinical implementation of various maternal serum, cervicovaginal, and amniotic fluid biomarkers in pregnancies complicated by intra-amniotic infection. EXPERT OPINION: Clinically relevant biomarkers are critical to the accurate diagnostic of intrauterine infection. Front-end implementation of such biomarkers will also translate in lower incidence of early-onset neonatal sepsis (EONS) which is an important determinant of neonatal morbidity and mortality associated with prematurity. However, of the hundreds of differentially expressed proteins, only few may have clinical utility and thus function as biomarkers. The small number of validation studies along with barriers to implementation of technological innovations in the clinical setting are current limitations.

Antenatal lamivudine to reduce perinatal hepatitis B transmission: a cost-effectiveness analysis.

OBJECTIVES: This study aimed to determine whether administration of lamivudine to pregnant women with chronic hepatitis B in the third trimester is a cost-effective strategy in preventing perinatal transmission. STUDY DESIGN: We developed a decision analysis model to compare the cost-effectiveness of 2 management strategies for chronic hepatitis B in pregnancy: (1) expectant management or (2) lamivudine administration in the third trimester. We assumed that lamivudine reduced perinatal transmission by 62%. RESULTS: Our Markov model demonstrated that lamivudine administration is the dominant strategy. For every 1000 infected pregnant women treated with lamivudine, $337,000 is saved and 314 quality-adjusted life-years are gained. For every 1000 pregnancies with maternal hepatitis B, lamivudine prevents 21 cases of hepatocellular carcinoma and 5 liver transplants in the offspring. The model remained robust in sensitivity analysis. CONCLUSION: Antenatal lamivudine administration to pregnant patients with hepatitis B is cost-effective, and frequently cost-saving, under a wide range of circumstances.

The elevation in circulating anti-angiogenic factors is independent of markers of neutrophil activation in preeclampsia.

BACKGROUND: Severe preeclampsia is associated with increased neutrophil activation and elevated serum soluble endoglin (sEng) and soluble Flt-1 (sFlt-1) in the maternal circulation. To dissect the contribution of systemic inflammation and anti-angiogenic factors in preeclampsia, we investigated the relationships between the circulating markers of neutrophil activation and anti-angiogenic factors in severe preeclampsia or systemic inflammatory state during pregnancy. METHODS AND RESULTS: Serum sEng, sFlt-1, placenta growth factor, interleukin-6 (IL-6), calprotectin, and plasma α-defensins concentrations were measured by ELISA in 88 women of similar gestational age stratified as: severe preeclampsia (sPE, n = 45), maternal systemic inflammatory response (SIR, n = 16) secondary to chorioamnionitis, pyelonephritis or appendicitis; and normotensive controls (CRL, n = 27). Neutrophil activation occurred in sPE and SIR, as α-defensins and calprotectin concentrations were two-fold higher in both groups compared to CRL (P < 0.05 for each). IL-6 concentrations were highest in SIR (P < 0.001), but were higher in sPE than in CRL (P < 0.01). sFlt-1 (P < 0.001) and sEng (P < 0.001) were ≈20-fold higher in sPE compared to CRL, but were not elevated in SIR. In women with sPE, anti-angiogenic factors were not correlated with markers of neutrophil activation (α-defensins, calprotectin) or inflammation (IL-6). CONCLUSIONS: Increased systemic inflammation in sPE and SIR does not correlate with increased anti-angiogenic factors, which were specifically elevated in sPE indicating that excessive systemic inflammation is unlikely to be the main contributor to severe preeclampsia.

Perinatal outcomes in twin pregnancies with discordant Doppler velocimetric findings.

OBJECTIVES: The purpose of this study was to investigate whether poor perinatal outcomes are more common in twins with abnormal umbilical artery Doppler velocimetric findings than in their siblings with normal findings. METHODS: A matched-pair cohort analysis of twin pregnancies with discordant umbilical artery Doppler velocimetric findings (one normal and one abnormal) was performed. Both severely abnormal findings (defined as absent or reversed flow in one twin; n = 23) and mildly abnormal findings (defined as an elevated systolic to diastolic ratio in one twin; n = 28) were included. The matched twins provided a gestational age-and demographically matched comparison group. Outcomes measured included intrauterine fetal death, oligohydramnios, intrauterine growth restriction, and neonatal outcomes (birth weight, Apgar scores, intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis). Associations between abnormal Doppler velocimetric findings and perinatal outcomes were estimated using matched logistic regression analysis. RESULTS: Among this cohort of twin pregnancies with discordant umbilical artery Doppler velocimetric findings, oligohydramnios and intrauterine growth restriction were more frequent in twin fetuses with abnormal findings. Adverse neonatal outcomes were high in both groups (57% among those with normal findings and 49% among those with abnormal findings) because of the overwhelming contribution of preterm delivery (mean gestational age at delivery, 33.3 weeks) but were not significantly different between those fetuses with abnormal findings compared to their cotwins with normal findings. CONCLUSIONS: Our results do not show an association between abnormal umbilical artery Doppler velocimetric findings and short-term adverse neonatal outcomes.

Proteomics mapping of cord blood identifies haptoglobin "switch-on" pattern as biomarker of early-onset neonatal sepsis in preterm newborns.

BACKGROUND: Intra-amniotic infection and/or inflammation (IAI) are important causes of preterm birth and early-onset neonatal sepsis (EONS). A prompt and accurate diagnosis of EONS is critical for improved neonatal outcomes. We sought to explore the cord blood proteome and identify biomarkers and functional protein networks characterizing EONS in preterm newborns. METHODOLOGY/PRINCIPAL FINDINGS: We studied a prospective cohort of 180 premature newborns delivered May 2004-September 2009. A proteomics discovery phase employing two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry identified 19 differentially-expressed proteins in cord blood of newborns with culture-confirmed EONS (n = 3) versus GA-matched controls (n = 3). Ontological classifications of the proteins included transfer/carrier, immunity/defense, protease/extracellular matrix. The 1(st)-level external validation conducted in the remaining 174 samples confirmed elevated haptoglobin and haptoglobin-related protein immunoreactivity (Hp&HpRP) in newborns with EONS (presumed and culture-confirmed) independent of GA at birth and birthweight (P<0.001). Western blot concurred in determining that EONS babies had conspicuous Hp&HpRP bands in cord blood ("switch-on pattern") as opposed to non-EONS newborns who had near-absent "switch-off pattern" (P<0.001). Fetal Hp phenotype independently impacted Hp&HpRP. A bayesian latent-class analysis (LCA) was further used for unbiased classification of all 180 cases based on probability of "antenatal IAI exposure" as latent variable. This was then subjected to 2(nd)-level validation against indicators of adverse short-term neonatal outcome. The optimal LCA algorithm combined Hp&HpRP switch pattern (most input), interleukin-6 and neonatal hematological indices yielding two non-overlapping newborn clusters with low (≤20%) versus high (≥70%) probability of IAI exposure. This approach reclassified ∼30% of clinical EONS diagnoses lowering the number needed to harm and increasing the odds ratios for several adverse outcomes including intra-ventricular hemorrhage. CONCLUSIONS/SIGNIFICANCE: Antenatal exposure to IAI results in precocious switch-on of Hp&HpRP expression. As EONS biomarker, cord blood Hp&HpRP has potential to improve the selection of newborns for prompt and targeted treatment at birth.

Abdominal pain after gastric bypass: labor, uterine rupture, or obstruction and internal hernia.

Background. Although gastric bypass may reduce obesity-related complications of subsequent pregnancies, surgical complications requiring antenatal and postpartum interventions are not uncommon. Case. A 26-year-old G4P1112 status post-Roux-en-Y gastric bypass required multiple urgent antenatal evaluations due to frequent episodes of abdominal pain. At 35 + 4 weeks, she presented with severe abdominal pain; initial evaluation was negative for gastrointestinal pathology. The patient was found to be in preterm labor and underwent a repeat cesarean section. The postoperative course was complicated by bowel obstruction due to internal hernia resulting in an emergent laparotomy and a prolonged hospital course. Conclusion. As more reproductive-aged women opt for surgical treatment of obesity, it is essential that obstetricians recognize complications to be able to counsel and appropriately care for these patients.