Femur-Sparing Pattern of Abnormal Fetal Growth in Pregnant Women from New York City After Maternal Zika Virus Infection

BACKGROUND: Zika virus (ZIKV) is a mosquito-transmitted flavivirus, which can induce fetal brain injury and growth restriction following maternal infection during pregnancy. Prenatal diagnosis of ZIKV-associated fetal injury in the absence of microcephaly is challenging due to an incomplete understanding of how maternal ZIKV infection affects fetal growth and the use of different sonographic reference standards around the world. We hypothesized that skeletal growth is unaffected by ZIKV infection and that the femur length can represent an internal standard to detect growth deceleration of the fetal head and/or abdomen by ultrasound. OBJECTIVE: To determine if maternal ZIKV infection is associated with a femur-sparing pattern of intrauterine growth restriction (IUGR) through analysis of fetal biometric measures and/or body ratios using the INTERGROWTH-21st Project (IG-21) and World Health Organization Fetal Growth Chart (WHO-FGC) sonographic references. STUDY DESIGN: Pregnant women diagnosed with a possible recent ZIKV infection at Columbia University Medical Center after traveling to an endemic area were retrospectively identified and included if a fetal ultrasound was performed. Data was collected regarding ZIKV testing, fetal biometry, pregnancy and neonatal outcomes. The IG-21 and WHO-FGC sonographic standards were applied to obtain Z-scores and/or percentiles for fetal head, abdominal circumference (HC, AC) and femur length (FL) specific for each gestational week. A novel IG-21 standard was also developed to generate Z-scores for fetal body ratios with respect to femur length (HC:FL, AC:FL). Data was then grouped within clinically relevant gestational age strata (34 weeks) to analyze time-dependent effects of ZIKV infection on fetal size. Statistical analysis was performed using Wilcoxon signed-rank test on paired data, comparing either AC or HC to FL. RESULTS: A total of 56 pregnant women were included in the study with laboratory evidence of a confirmed or possible recent ZIKV infection. Based on the CDC definition for microcephaly after congenital ZIKV exposure, microcephaly was diagnosed in 5% (3/56) by both the IG-21 and WHO-FGC standards (HC Z-score ≤ -2 or ≤ 2.3%). Using IG-21, IUGR was diagnosed in 18% of pregnancies (10/56; AC Z-score ≤-1.3, <10%). Analysis of fetal size using the last ultrasound scan for all subjects revealed a significantly abnormal skewing of fetal biometrics with a smaller AC versus FL by either IG-21 or WHO-FGC (p<0.001 for both). A difference in distribution of fetal AC compared to FL was first apparent in the 24-27 6/7 week strata (IG-21, p=0.002; WHO-FGC, p=0.001). A significantly smaller HC compared to FL was also observed by IG-21 as early as the 28-33 6/7 week strata (IG-21, p=0.007). Overall, a femur-sparing pattern of growth restriction was detected in 52% of pregnancies with either an HC:FL or AC:FL fetal body ratio less than the 10th percentile (IG-21 Z-score ≤-1.3). CONCLUSIONS: An unusual femur-sparing pattern of fetal growth restriction was detected in the majority of fetuses with congenital ZIKV exposure. Fetal body ratios may represent a more sensitive ultrasound biomarker to detect viral injury in nonmicrocephalic fetuses that could impart long-term risk for complications of congenital ZIKV infection

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

Phase Change Material for Thermotherapy of Buruli Ulcer: A Prospective Observational Single Centre Proof-of-Principle Trial

Buruli ulcer is an infection of the subcutaneous tissue leading to chronic necrotizing skin ulcers. The causative pathogen, Mycobacterium ulcerans, grows best at 30°C–33°C and not above 37°C, and this property makes the application of heat a treatment option. We achieved a breakthrough in heat treatment of Buruli ulcer by employing the phase change material sodium acetate trihydrate as a heat application system for thermotherapy, which is widely used in commercial pocket heat pads. It is easy to apply, rechargeable in hot water, non-toxic and non-hazardous to the environment. Six laboratory reconfirmed patients with ulcerative Buruli lesions were included in the proof-of-principle study and treated for four to six weeks. In patients with small ulcers, wounds healed completely without further intervention. Patients with large defects had skin grafting after successful heat treatment. Heat treatment was not associated with marked increases in local inflammation or the development of ectopic lymphoid tissue. One and a half years after completion of treatment, all patients are relapse-free. The reusable phase change material–based heat application device appears perfectly suited for use in remote Buruli ulcer–endemic areas of countries with limited resources and infrastructure

Pregnancy, Microchimerism, and the Maternal Grandmother

A WOMAN OF REPRODUCTIVE AGE OFTEN HARBORS A SMALL NUMBER OF FOREIGN CELLS, REFERRED TO AS MICROCHIMERISM: a preexisting population of cells acquired during fetal life from her own mother, and newly acquired populations from her pregnancies. An intriguing question is whether the population of cells from her own mother can influence either maternal health during pregnancy and/or the next generation (grandchildren).Microchimerism from a woman's (i.e. proband's) own mother (mother-of-the-proband, MP) was studied in peripheral blood samples from women followed longitudinally during pregnancy who were confirmed to have uncomplicated obstetric outcomes. Women with preeclampsia were studied at the time of diagnosis and comparison made to women with healthy pregnancies matched for parity and gestational age. Participants and family members were HLA-genotyped for DRB1, DQA1, and DQB1 loci. An HLA polymorphism unique to the woman's mother was identified, and a panel of HLA-specific quantitative PCR assays was employed to identify and quantify microchimerism. Microchimerism from the MP was identified during normal, uncomplicated pregnancy, with a peak concentration in the third trimester. The likelihood of detection increased with advancing gestational age. For each advancing trimester, there was a 12.7-fold increase in the probability of detecting microchimerism relative to the prior trimester, 95% confidence intervals 3.2, 50.3, p<0.001. None of the women with preeclampsia, compared with 30% of matched healthy women, had microchimerism (p = 0.03).These results show that microchimerism from a woman's own mother is detectable in normal pregnancy and diminished in preeclampsia, supporting the previously unexplored hypothesis that MP microchimerism may be a marker reflecting healthy maternal adaptation to pregnancy

The Association between Intrauterine Inflammation and Spontaneous Vaginal Delivery at Term: A Cross-Sectional Study

BACKGROUND:Different factors contribute to the onset of labor at term. In animal models onset of labor is characterized by an inflammatory response. The role of intrauterine inflammation, although implicated in preterm birth, is not yet established in human term labor. We hypothesized that intrauterine inflammation at term is associated with spontaneous onset of labor. METHODS/RESULTS:In two large urban hospitals in the Netherlands, a cross-sectional study of spontaneous onset term vaginal deliveries and elective caesarean sections (CS), without signs of labor, was carried out. Placentas and amniotic fluid samples were collected during labor and/or at delivery. Histological signs of placenta inflammation were determined. Amniotic fluid proinflammatory cytokine concentrations were measured using ELISA. A total of 375 women were included. In term vaginal deliveries, more signs of intrauterine inflammation were found than in elective CS: the prevalence of chorioamnionitis was higher (18 vs 4%, p = 0.02) and amniotic fluid concentration of IL-6 was higher (3.1 vs 0.37 ng/mL, p<0.001). Similar results were obtained for IL-8 (10.93 vs 0.96 ng/mL, p<0.001) and percentage of detectable TNF-alpha (50 vs 4%, p<0.001). CONCLUSIONS:This large cross-sectional study shows that spontaneous term delivery is characterized by histopathological signs of placenta inflammation and increased amniotic fluid proinflammatory cytokines

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