Martha Rac

Primary Human Placental Trophoblasts are Permissive for Zika Virus (ZIKV) Replication

Zika virus (ZIKV) is an emerging mosquito-borne (Aedes genus) arbovirus of the Flaviviridae family. Although ZIKV has been predominately associated with a mild or asymptomatic dengue-like disease, its appearance in the Americas has been accompanied by a multi-fold increase in reported incidence of fetal microcephaly and brain malformations. The source and mode of vertical transmission from mother to fetus is presumptively transplacental, although a causal link explaining the interval delay between maternal symptoms and observed fetal malformations following infection has been missing. In this study, we show that primary human placental trophoblasts from non-exposed donors (n = 20) can be infected by primary passage ZIKV-FLR isolate, and uniquely allowed for ZIKV viral RNA replication when compared to dengue virus (DENV). Consistent with their being permissive for ZIKV infection, primary trophoblasts expressed multiple putative ZIKV cell entry receptors, and cellular function and differentiation were preserved. These findings suggest that ZIKV-FLR strain can replicate in human placental trophoblasts without host cell destruction, thereby serving as a likely permissive reservoir and portal of fetal transmission with risk of latent microcephaly and malformations.

Testing for Zika virus infection in pregnancy: key concepts to deal with an emerging epidemic

&NA; Zika virus is an emerging mosquito‐borne (Aedes genus) arbovirus of the Flaviviridae family. Following epidemics in Micronesia and French Polynesia during the past decade, more recent Zika virus infection outbreaks were first reported in South America as early as May 2013 and spread to now 50 countries throughout the Americas. Although no other flavivirus has previously been known to cause major fetal malformations following perinatal infection, reports of a causal link between Zika virus and microcephaly, brain and ocular malformations, and fetal loss emerged from hard‐hit regions of Brazil by October 2015. Among the minority of infected women with symptoms, clinical manifestations of Zika virus infection may include fever, headache, arthralgia, myalgia, and maculopapular rash; however, only 1 of every 4–5 people who are infected have any symptoms. Thus, clinical symptom reporting is an ineffective screening tool for the relative risk assessment of Zika virus infection in the majority of patients. As previously occurred with other largely asymptomatic viral infections posing perinatal transmission risk (such as HIV or cytomegalovirus), we must develop and implement rapid, sensitive, and specific screening and diagnostic testing for both viral detection and estimation of timing of exposure. Unfortunately, despite an unprecedented surge in attempts to rapidly advance perinatal clinical testing for a previously obscure arbovirus, there are several ongoing hindrances to molecular‐ and sonographic‐based screening and diagnosis of congenital Zika virus infection. These include the following: (1) difficulty in estimating the timing of exposure for women living in endemic areas and thus limited interpretability of immunoglobulin M serologies; (2) cross‐reaction of immunoglobulin serologies with other endemic flaviruses, such as dengue; (3) persistent viremia and viruria in pregnancy weeks to months after primary exposure; and (4) fetal brain malformations and anomalies preceding the sonographic detection of microcephaly. In this commentary, we discuss screening and diagnostic considerations that are grounded not only in the realities of current obstetrical practice in a largely global population but also in basic immunology and virology. We review recent epidemiological data pertaining to the risk of congenital Zika virus malformations based on trimester of exposure and consider side by side with emerging data demonstrating replication of Zika virus in placental and fetal tissue throughout gestation. We discuss limitations to ultrasound based strategies that rely largely or solely on the detection of microcephaly and provide alternative neurosonographic approaches for the detection of malformations that may precede or occur independent of a small head circumference. This expert review provides information that is of value for the following: (1) obstetrician, maternal‐fetal medicine specialist, midwife, patient, and family in cases of suspected Zika virus infection; (2) review of the methodology for laboratory testing to explore the presence of the virus and the immune response; (3) ultrasound‐based assessment of the fetus suspected to be exposed to Zika virus with particular emphasis on the central nervous system; and (4) identification of areas ready for development.

Multidisciplinary team learning in the management of the morbidly adherent placenta: outcome improvements over time

BACKGROUND: Morbidly adherent placenta (MAP) is a serious obstetric complication causing mortality and morbidity. OBJECTIVE: To evaluate whether outcomes of patients with MAP improve with increasing experience within a well‐established multidisciplinary team at a single referral center. STUDY DESIGN: All singleton pregnancies with pathology‐confirmed MAP (including placenta accreta, increta, or percreta) managed by a multidisciplinary team between January 2011 and August 2016 were included in this retrospective study. Turnover of team members was minimal, and cases were divided into 2 time periods so as to compare 2 similarly sized groups: T1 = January 2011 to April 2014 and T2 = May 2014 to August 2016. Outcome variables were estimated blood loss, units of red blood cell transfused, volume of crystalloid transfused, massive transfusion protocol activation, ureter and bowel injury, and neonatal birth weight. Comparisons and adjustments were made by use of the Student t test, Mann‐Whitney U test, χ2 test, analysis of covariance, and multinomial logistic regression. RESULTS: A total of 118 singleton pregnancies, 59 in T1 and 59 in T2, were managed during the study period. Baseline patient characteristics were not statistically significant. Forty‐eight of 59 (81.4%) patients in T1 and 42 of 59 (71.2%) patients in T2 were diagnosed with placenta increta/percreta. The median [interquartile range] estimated blood loss (T1: 2000 [1475‐3000] vs T2: 1500 [1000‐2700], P = .04), median red blood cell transfusion units (T1: 2.5 [0‐7] vs T2: 1 [0‐4], P = .02), and median crystalloid transfusion volume (T1: 4200 [3600‐5000] vs T2: 3400 [3000‐4000], P < .01) were significantly less in T2. Also, a massive transfusion protocol was instituted more frequently in T1: 15/59 (25.4%) vs 3/59 (5.1%); P < .01. Neonatal outcomes and surgical complications were similar between the 2 groups. CONCLUSION: Our study shows that patient outcomes are improved over time with increasing experience within a well‐established multidisciplinary team performing 2−3 cases per month. This suggests that small, collective changes in team dynamics lead to continuous improvement of clinical outcomes. These findings support the development of centers of excellence for MAP staffed by stable, core multidisciplinary teams, which should perform a significant number of these procedures on an ongoing basis.

Sonographic Findings of Morbidly Adherent Placenta in the First Trimester

The purpose of this study was to evaluate the association between first‐trimester sonographic findings and morbidly adherent placenta at delivery.

Progression of ultrasound findings of fetal syphilis after maternal treatment

OBJECTIVE The purpose of this study was to evaluate ultrasound findings of fetal syphilis and to describe their progression after maternal treatment. STUDY DESIGN This was a retrospective cohort study from September 1981 to June 2011 of seropositive women after 18 weeks of gestation who had an ultrasound before treatment to evaluate for fetal syphilis. Only those women who received treatment after the initial ultrasound scan, but before delivery, were included. If the initial ultrasound scan was abnormal, serial sonography was performed until resolution of the abnormality or delivery. Patient demographics, ultrasound findings, stage of syphilis, delivery, and infant outcomes were recorded. Standard statistical analyses were performed. Kaplan-Meier estimates were constructed to estimate time to resolution. RESULTS Two hundred thirty-five women met the inclusion criteria; 73 of them (30%) had evidence of fetal syphilis on initial ultrasound scan. Abnormalities included hepatomegaly (79%), placentomegaly (27%), polyhydramnios (12%), ascites (10%) and abnormal middle cerebral arterial Doppler assessment (33%). After treatment, middle cerebral arterial Doppler assessment abnormalities, ascites, and polyhydramnios resolved first, followed by placentomegaly and finally hepatomegaly. Infant outcomes were available for 173 deliveries; of these, 32 infants (18%) were diagnosed with congenital syphilis. Congenital syphilis was more common when antenatal ultrasound abnormalities were present (39% vs 12%; P < .001). Infant examination findings at delivery were similar between women with and without an abnormal pretreatment ultrasound scan. However, in those infants with congenital syphilis, hepatomegaly was the most frequent abnormality found, regardless of antenatal ultrasound findings. CONCLUSION Sonographic signs of fetal syphilis confer a higher risk of congenital syphilis at delivery for all maternal stages. Hepatomegaly develops early and resolves last after antepartum treatment.

Placenta accreta and vaginal bleeding according to gestational age at delivery.

OBJECTIVE: To evaluate the incidence of vaginal bleeding in women with placenta accreta according to gestational age at delivery. METHODS: This is a retrospective cohort study of women with prior cesarean delivery and persistent placenta previa delivered at our institution between December 1997 and December 2011. Diagnosis of invasion was based on hysterectomy performed for an abnormally adherent placenta with histologic confirmation. Suspicion for invasion was based on the impression of the attending physician at the time of ultrasonography. Records were reviewed to identify indication for delivery and estimated blood loss. Statistical analyses were performed using Students t test, &khgr;2 test, and Mantel-Haenszel and Jonckheere-Terpstra tests for trend. RESULTS: Of 216 women with prior cesarean delivery and persistent previa, 65 (30%) required cesarean hysterectomy and had histologic confirmation of invasion. Urgent delivery for bleeding was performed in 20% of these pregnancies (13/65). Delivery for bleeding decreased significantly with advancing gestation (P=.001). In our series, 71% with accreta were delivered at 36 weeks of gestation or greater with delivery for bleeding in five (11%), and estimated blood loss was not increased in these pregnancies. Of 79 women with ultrasonographic suspicion for accreta, the incidence of vaginal bleeding prompting urgent delivery also decreased with advancing gestation (P<.001). CONCLUSION: Likelihood of vaginal bleeding necessitating delivery declined with advancing gestation in pregnancies with placenta accreta as did blood loss. Most were delivered at 36 weeks of gestation or greater, nearly 90% in the absence of bleeding complications. Thus, although preterm delivery is an important consideration when placenta accreta is suspected, our findings support individualizing delivery planning. LEVEL OF EVIDENCE: II

Prevention and Management of Viral Hepatitis in Pregnancy

Of the 5 types of viral hepatitis (HAV-HEV), HBV and HCV are by far the most common causes of chronic hepatitis in both pregnant and nonpregnant populations, causing more than 50% of cirrhosis cases and 78% of cases of primary liver cancer. Infection during pregnancy can have adverse effects on both the mother and her fetus. For all 5 viral hepatitis syndromes, early identification allows appropriate measures to be taken to optimize pregnancy outcomes and minimize the risk of perinatal transmission. This article reviews the prevention and management of all 5 viral hepatitis syndromes during pregnancy.

Syphilis during pregnancy: a preventable threat to maternal-fetal health

Syphilis remains the most common congenital infection worldwide and has tremendous consequences for the mother and her developing fetus if left untreated. Recently, there has been an increase in the number of congenital syphilis cases in the United States. Thus, recognition and appropriate treatment of reproductive-age women must be a priority. Testing should be performed at initiation of prenatal care and twice during the third trimester in high-risk patients. There are 2 diagnostic algorithms available and physicians should be aware of which algorithm is utilized by their testing laboratory. Women testing positive for syphilis should undergo a history and physical exam as well as testing for other sexually transmitted infections, including HIV. Serofast syphilis can occur in patients with previous adequate treatment but persistent low nontreponemal titers (<1:8). Syphilis can infect the fetus in all stages of the disease regardless of trimester and can sometimes be detected with ultrasound >20 weeks. The most common findings include hepatomegaly and placentomegaly, but also elevated peak systolic velocity in the middle cerebral artery (indicative of fetal anemia), ascites, and hydrops fetalis. Pregnancies with ultrasound abnormalities are at higher risk of compromise during syphilotherapy as well as fetal treatment failure. Thus, we recommend a pretreatment ultrasound in viable pregnancies when feasible. The only recommended treatment during pregnancy is benzathine penicillin G and it should be administered according to maternal stage of infection per Centers for Disease Control and Prevention guidelines. Women with a penicillin allergy should be desensitized and then treated with penicillin appropriate for their stage of syphilis. The Jarisch-Herxheimer reaction occurs in up to 44% of gravidas and can cause contractions, fetal heart rate abnormalities, and even stillbirth in the most severely affected pregnancies. We recommend all viable pregnancies receive the first dose of benzathine penicillin G in a labor and delivery department under continuous fetal monitoring for at least 24 hours. Thereafter, the remaining benzathine penicillin G doses can be given in an outpatient setting. The rate of maternal titer decline is not tied to pregnancy outcomes. Therefore, after adequate syphilotherapy, maternal titers should be checked monthly to ensure they are not increasing four-fold, as this may indicate reinfection or treatment failure.

Extensive thrombosis and first-trimester pregnancy loss caused by sticky platelet syndrome.

BACKGROUND: Sticky platelet syndrome is an autosomal-dominant thrombophilia characterized by platelet hyperaggregability in the presence of adenosine diphosphate or epinephrine. The result clinically can be widespread thromboses, often arterial, in patients without apparent risk factors for thrombotic disease. Limited data exist regarding its role in adverse pregnancy outcomes. CASE: A gravid woman with two previous first-trimester miscarriages presented at 11 weeks of gestation with a deep venous thrombosis. Despite anticoagulation, she developed extensive and progressive arterial and venous thromboses and suffered a fetal demise. A thrombophilia panel was unremarkable, but platelet aggregometry demonstrated hyperactive platelets in the presence of adenosine diphosphate and epinephrine consistent with sticky platelet syndrome. CONCLUSION: Sticky platelet syndrome causes arterial thromboses and may be an underappreciated etiology for adverse pregnancy outcomes.

Jarisch-Herxheimer reaction triggered by group B streptococcus intrapartum antibiotic prophylaxis.

BACKGROUND: The Jarisch-Herxheimer reaction is an acute systemic event that can occur during the treatment of spirochetal infections. During pregnancy, it can cause signs and symptoms in both the mother and fetus, including fever, tachycardia, uterine contractions, and fetal heart rate pattern changes. CASE: A pregnant woman with limited prenatal care presented at 34 weeks of gestation in preterm labor with possible genital herpes. She received ampicillin for group B Streptococcus prophylaxis. Subsequently, she experienced subjective fever and late fetal heart rate decelerations prompting repeat cesarean delivery. Postpartum, her genital lesions were diagnosed as secondary syphilis, and her newborn had congenital syphilis. CONCLUSION: Beta-lactam antibiotics for group B Streptococcus intrapartum prophylaxis can trigger the Jarisch-Herxhemer reaction in patients with undiagnosed syphilis resulting in unanticipated changes in maternal and fetal well-being.