Zika & Microcephaly Study In Rio de Janeiro Brazil NEJM

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ORIGINAL ARTICLE

Zika Virus Infection in Pregnant Women in Rio de Janeiro — Preliminary Report

http://www.nejm.org/doi/full/10.1056/NEJMoa1602412

 

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Patrícia Brasil, M.D., Jose P. Pereira, Jr., M.D., Claudia Raja Gabaglia, M.D., Luana Damasceno, M.S., Mayumi Wakimoto, Ph.D., Rita M. Ribeiro Nogueira, M.D., Patrícia Carvalho de Sequeira, Ph.D., André Machado Siqueira, M.D., Liege M. Abreu de Carvalho, M.D., Denise Cotrim da Cunha, M.D., Guilherme A. Calvet, M.D., Elizabeth S. Neves, M.D., Maria E. Moreira, M.D., Ana E. Rodrigues Baião, M.D., Paulo R. Nassar de Carvalho, M.D., Carla Janzen, M.D., Stephanie G. Valderramos, M.D., James D. Cherry, M.D., Ana M. Bispo de Filippis, Ph.D., and Karin Nielsen-Saines, M.D.

March 4, 2016DOI: 10.1056/NEJMoa1602412

 

OURCE INFORMATION

From Fundação Oswaldo Cruz, Rio de Janeiro (P.B., J.P.P.J., L.D., M.W., R.M.R.N., P.C.S., A.M.S., L.M.A.C., D.C.C., G.A.C., E.S.N., M.E.M., A.E.R.B., P.R.N.C., A.M.B.F.); Biomedical Research Institute of Southern California, Oceanside (C.R.G.); and David Geffen UCLA School of Medicine, Los Angeles (C.J., S.G.V., J.D.C., K.N.-S.).

Address reprint requests to Dr. Nielsen-Saines at the Division of Pediatric Infectious Diseases, David Geffen School of Medicine at UCLA, MDCC 22-442, 10833 LeConte Ave., Los Angeles, CA 90095, or at [email protected].

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BACKGROUND

Zika virus (ZIKV) has been linked to neonatal microcephaly. To characterize the spectrum of ZIKV disease in pregnancy, we followed patients in Rio de Janeiro to describe clinical manifestations in mothers and repercussions of acute ZIKV infection in fetuses.

Full Text of Background...

 

METHODS

We enrolled pregnant women in whom a rash had developed within the previous 5 days and tested blood and urine specimens for ZIKV by reverse-transcriptase–polymerase-chain-reaction assays. We followed the women prospectively and collected clinical and ultrasonographic data.

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RESULTS

A total of 88 women were enrolled from September 2015 through February 2016; of these 88 women, 72 (82%) tested positive for ZIKV in blood, urine, or both. The timing of acute ZIKV infection ranged from 5 to 38 weeks of gestation. Predominant clinical features included pruritic descending macular or maculopapular rash, arthralgias, conjunctival injection, and headache; 28% had fever (short-term and low-grade). Women who were positive for ZIKV were more likely than those who were negative for the virus to have maculopapular rash (44% vs. 12%, P=0.02), conjunctival involvement (58% vs. 13%, P=0.002), and lymphadenopathy (40% vs. 7%, P=0.02). Fetal ultrasonography was performed in 42 ZIKV-positive women (58%) and in all ZIKV-negative women. Fetal abnormalities were detected by Doppler ultrasonography in 12 of the 42 ZIKV-positive women (29%) and in none of the 16 ZIKV-negative women. Adverse findings included fetal deaths at 36 and 38 weeks of gestation (2 fetuses), in utero growth restriction with or without microcephaly (5 fetuses), ventricular calcifications or other central nervous system (CNS) lesions (7 fetuses), and abnormal amniotic fluid volume or cerebral or umbilical artery flow (7 fetuses). To date, 8 of the 42 women in whom fetal ultrasonography was performed have delivered their babies, and the ultrasonographic findings have been confirmed.

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CONCLUSIONS

Despite mild clinical symptoms, ZIKV infection during pregnancy appears to be associated with grave outcomes, including fetal death, placental insufficiency, fetal growth restriction, and CNS injury.

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Zika virus (ZIKV) was first identified in Brazil in 2015 by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays of serum specimens from patients from the state of Bahia who presented with a denguelike illness that was characterized by rash, fever, myalgias, arthralgias, and conjunctivitis.1 Soon thereafter, local transmission of ZIKV was reported,2 and a link for transmission of ZIKV between French Polynesia and Brazil was described.3 In September 2015, researchers reported a substantial increase in the number of cases of neonatal microcephaly among women giving birth in northeastern Brazil,4,5 and a subsequent increase was reported in southeast Brazil.6 ZIKV has been isolated from the amniotic fluid of women who are pregnant with infants who have confirmed microcephaly4,6,7 and from the brain of a fetus with central nervous system (CNS) abnormalities.8

We have been conducting active surveillance for dengue infection in the general population of Rio de Janeiro since 2007. In 2012, we established a prospective cohort for dengue surveillance in mother–infant pairs within the Manguinhos Rio de Janeiro area. In 2015, we noted an increase in cases of a denguelike illness that was characterized by a descending rash, generally without fever; this increase coincided with a surge in the number of cases in northeastern Brazil of illness characterized by a pruriginous rash. In early 2015, most cases were originally reported to surveillance systems as dengue; however, ZIKV was eventually identified.9 To identify ZIKV cases in our population, we modified our pregnancy cohort study and enrolled women at any week of gestation who presented with a rash. Here we report demographic, clinical, laboratory, and gestational ultrasonographic findings in the cohort of pregnant women enrolled in our ZIKV study to date.

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METHODS

Study Population

In this cohort study, pregnant women at any week of gestation who presented to the acute febrile illness clinic at the Oswaldo Cruz Foundation with a rash that had developed within the previous 5 days were offered enrollment and were included in the study after providing informed consent. After the women were enrolled, detailed demographic, medical, and prenatal history information, as well as clinical findings, were entered into case-report forms. Information in prenatal records regarding rubella, cytomegalovirus, and Venereal Disease Research Laboratory serologic testing was reviewed. Serum and urine specimens were obtained at study entry. Women had weekly follow-ups by telephone, and a second visit was scheduled within 30 days after enrollment for clinical and laboratory follow-up. Women were referred for fetal ultrasonography before 20 weeks of gestation, between 20 and 30 weeks of gestation, and after 30 weeks of gestation. No women had had diagnoses of fetal malformations in the current pregnancy before enrollment. The study population was generally healthy; the women reported no coexisting conditions or medication use. Infants born to ZIKV-positive mothers will be followed prospectively.

Study Oversight

The study protocol was approved by the institutional review boards at Fundação Oswaldo Cruz (Fiocruz) and the University of California, Los Angeles. Participants provided written informed consent. The authors vouch for the accuracy and completeness of the data and the analyses and for the fidelity of the study to the protocol.

Laboratory Testing

Real-time RT-PCR assays for ZIKV were performed with the QuantiTect Probe RT-PCR kit (Qiagen), as described previously,10 with the same primers and cycle times, at the Fiocruz Flavivirus Laboratory; assays were performed on blood specimens, urine specimens, or both that were obtained at the entry visit. The Fiocruz Flavivirus Laboratory is a reference laboratory for flavivirus infections in the region. Serologic testing for IgG antibodies to dengue (Abcam) was performed on the serum specimens obtained at the entry visit.

Fetal Ultrasonography

All abdominal scanning was performed with a 4-to-8-mHz probe (Voluson 730 Expert/Voluson E6, GE) by perinatologists who were certified by the Brazilian College of Radiology and the Brazilian Federation of Societies of Gynecology and Obstetrics (Febrasgo). The variables that were measured are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org. For Doppler studies, the pulsatility index of the umbilical artery and of the middle cerebral artery were used.11 Abnormalities such as cerebral calcifications and microcephaly were noted. Measured fetal ultrasonographic variables were plotted by gestational age according to the nomograms published on www.perinatology.com. Intrauterine growth restriction was defined as fetal weight estimated according to the Hadlock formula that was below the 10th percentile.12Microcephaly in fetal imaging was defined as fetal head measurements (e.g., head circumference) that were two standard deviations below the mean expected at a particular gestational age or below the third percentile.13

Statistical Analysis

We compared the demographic and clinical variables of pregnant women who were positive for ZIKV on PCR with those who were negative for ZIKV on PCR, using Fisher’s exact test (two-sided); P values of less than or equal to 0.05 were considered to indicate statistical significance. For comparison of medians, an independent-samples median test was used.

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RESULTS

Characteristics of Participants

During the period from September 2015 through February 2016, we enrolled 88 pregnant women and tested blood specimens, urine specimens, or both for ZIKV by qualitative RT-PCR. Of these 88 women, 72 (82%) had positive results for ZIKV on PCR in blood, urine, or both: 60 women had positive PCR results in serum specimens, 46 had positive PCR results in urine samples, and 34 had positive PCR results in both specimens; 12 women had positive results in urine specimens only, and 26 had positive results in blood specimens only (median number of PCR cycles for serum specimens, 33.0; interquartile range, 30.0 to 34.0; range, 24.0 to 37.0; and median number of PCR cycles for urine specimens, 29.0; interquartile range, 26.0 to 31.8; range, 22.0 to 37.0). Demographic and clinical characteristics are described in Table 1TABLE 1Baseline Demographic and Clinical Characteristics of Women in the Pregnancy Cohort.. Among ZIKV-positive women, more than half reported similar illnesses in other family members, and 21% reported that their partner had been ill. ZIKV infection was present in women of all socioeconomic strata. More than half the women presented with acute infection in the second trimester of pregnancy. There were no significant differences in demographic characteristics or medical history between women who were positive for ZIKV and those who were negative for ZIKV. ZIKV-positive women resided across multiple neighborhoods and municipalities within the larger metropolitan Rio de Janeiro area (Fig. S1 in the Supplementary Appendix).

Clinical Presentation

All pregnant women had rash as part of their clinical presentation, since rash was an inclusion criterion. A descending macular or maculopapular rash was the most common type of exanthem noted in ZIKV-positive women (Figure 1FIGURE 1Clinical features of Zika Virus Infection in Pregnant Women.). The maculopapular rash was seen far more frequently in ZIKV-positive women than in ZIKV-negative women (P=0.02). The other prevalent finding was pruritus, which was seen in 94% of the women in our study. The next most common finding was arthralgia, which was reported in 65% of ZIKV-positive women and in 41% of ZIKV-negative women (P=0.16). Conjunctival injection was present in 58% of ZIKV-positive women, and in a far smaller percentage (19%) of ZIKV-negative women (P=0.002), which suggests that this symptom is a specific clinical feature of ZIKV infection. Lymphadenopathy (isolated or generalized) was found more prominently in women with acute ZIKV infection than in ZIKV-negative women (41% vs. 6%, P=0.02). Fever was not a highly prominent finding, occurring in less than a third of women with acute ZIKV-infection. When fever was present, it was generally short-term and low grade (37.5 to 38.0oC). Nausea or vomiting was reported in 21% of ZIKV-positive women and was more common (38%) in ZIKV-negative women (P=0.20). Findings consistent with bleeding (primarily gingival) were present in less than 21% of all women. Respiratory findings were rare (7%) in ZIKV-positive women.

Outcomes of Pregnancies

Two ZIKV-positive women miscarried during the first trimester. Of the 70 remaining women with ZIKV infection, 42 (60%) had prenatal ultrasonographic examinations, with a total of 56 studies performed; 28 women declined imaging studies either because the obstetrical facility was too far away or because of fear of possible fetal abnormalities related to ZIKV infection. ZIKV-negative women had undergone fetal ultrasonography as part of regular prenatal care, and the results were reported as normal. All the women in the cohort had received prenatal care; immunity to rubella and cytomegalovirus was documented, and none of the women had syphilis; 88% of the women had positive results for dengue-specific IgG antibodies at study entry.

As seen in Figure 2FIGURE 2Week of Gestation at the Time of ZIKV Infection and Abnormal Ultrasonographic and Doppler Findings. and Table 2TABLE 2Ultrasonographic Features of Fetuses and Findings at Birth., the timing of acute ZIKV infection ranged from 6 to 35 weeks of gestation among the 42 women in whom fetal ultrasonography was performed. Abnormal results on ultrasonography or Doppler studies were seen in 12 cases (29%). Five of the 12 fetuses had intrauterine growth restriction, as determined by ultrasonography, with or without accompanying microcephaly. Cerebral calcifications were noted in 4 fetuses and other CNS alterations in 2 fetuses. Abnormal arterial flow in the cerebral or umbilical arteries was seen in 4 fetuses. Oligohydramnios and anhydramnios were seen in two cases. There were two fetal deaths after 30 weeks of gestation, which were detected by ultrasonography performed in one woman who had been infected at 25 weeks of gestation and in a second woman who had been infected at 32 weeks of gestation. One fetus was found to have additional malformations, including agenesis of the vermis, Blake’s pouch cyst, and potentially a club foot, in addition to cerebral calcifications, intrauterine growth restriction, and microcephaly (genetic findings have been negative). The mothers of this fetus and of another fetus with intrauterine growth restriction and accompanying cerebral calcifications were infected in the first trimester of pregnancy. Cerebral calcifications were also seen in fetuses of women infected as late as 27 weeks, and intrauterine growth restriction was present in fetuses of women infected within a wide range of infant gestational age. (For ultrasonographic findings and clinical features of infants born to date and for an ultrasound of a fetus with cerebral calcifications, see Table S1 and Figure S2 in the Supplementary Appendix.) Figure 3FIGURE 3Fetal Biometric Variables as Measured on Ultrasonography. shows plots of ultrasonographic measures for fetuses of ZIKV-positive pregnant women (also see Fig. S3 in the Supplementary Appendix).

At the time of this preliminary report, six live births and two stillbirths have occurred (Infants 2, 3, 10, 12, 19, 23, 36, and 53) (Table 2 and Table S1 in the Supplementary Appendix). Two infants with normal ultrasonographic results had normal measures and a normal physical examination at birth (Infants 2 and 3). Two infants with an ultrasonographic diagnosis of fetal death were delivered stillborn (Infants 10 and 53). Infant 19 was born at term with severe microcephaly; computed tomography of the brain confirmed ultrasonographic findings of cerebral calcifications and global cerebral atrophy. Funduscopic exam showed macular hypoplasia of the left eye and macular scarring on the right eye. Infant 12 was delivered prematurely by cesarean section because of severe intrauterine growth restriction, oligohydramnios, and placental insufficiency and was found to be small for gestational age, with a head circumference below the 5th percentile for gestational age. Funduscopic examination showed macular hypoplasia. Infant 23 was delivered on an emergency basis owing to anhydramnios and was found to have normal growth measures despite the suggestion of intrauterine growth restriction on ultrasonography performed at 40 weeks. This infant was found to be lethargic with poor sucking reflexes at birth; electroencephalography during the infant’s stay in the neonatal intensive care unit (NICU) showed nonspecific findings, but the infant has done well. Infant 36 had intrauterine growth restriction on ultrasonography and was small for gestational age at the time of birth. The head circumference was proportional to the small body size. This infant is currently in the NICU.

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DISCUSSION

ZIKV is a flavivirus that was recently introduced into Brazil. Its rapid expansion into a population that is probably fully susceptible is due to the effectiveness of its vector, the Aedes aegyptimosquito. Diagnosis of ZIKV infection in Brazil has been complicated by the cross-reactivity between flavivirus antibodies and by the fact that dengue has been endemic in Brazil for more than 30 years. Serosurveillance studies have found evidence of dengue antibodies in more than 90% of the population of Recife.14 In our cohort, dengue IgG antibodies were present in 88% of the women. The diagnosis of ZIKV in Brazil relies on identification of the virus through RT-PCR during the acute period of infection. The virus is detectable in blood during the period of acute viremia and initial symptoms and subsequently is shed in the urine, generally for 3 to 14 days.15 Because RT-PCR assays for ZIKV are generally not available, most cases of ZIKV infection in Brazil are diagnosed clinically, without laboratory confirmation. In our cohort, all 72 women who were positive for ZIKV had acute infection with virus that was detected in blood, urine, or both. As compared with women who tested negative for acute ZIKV infection, women who tested positive for the virus had distinctive clinical features of ZIKV infection that included conjunctival injection, lymphadenopathy, and absence of respiratory symptoms. These clinical features, in addition to a macular or maculopapular rash with pruritus, should raise the suspicion for ZIKV infection. Low-grade fever was found in only 28% of the women; therefore a case definition that is based on the presence of fever would miss more than 70% of cases.16

Whether sexual transmission of ZIKV played a role in transmission to pregnant women in our cohort is difficult to assess, since couples usually cohabitate and would presumably have the same type of vector exposure. ZIKV-positive women more frequently had a history of a symptomatic partner than did ZIKV-negative women; however, this could also be due to less exposure to the vector among uninfected couples.

Links between the current ZIKV epidemic in Brazil and the rise in the number of observed cases of neonatal microcephaly have been discussed in both the scientific literature and the lay press and have generated considerable debate about whether the observed phenomenon is real, and, if so, whether microcephaly is a direct effect of ZIKV or whether it could be due to potential environmental exposure of pregnant women to teratogenic agents.17 Ultrasonographic findings in our cohort showed serious and frequent problems in fetal and central nervous system development, affecting 29% of the 42 women whose fetuses were evaluated by ultrasonography. Abnormalities were noted in the fetuses of women who were infected at any week of gestation. Fetuses infected in the first trimester had findings suggestive of pathologic change during embryogenesis, but CNS abnormalities were also seen in fetuses infected as late as 27 weeks of gestation. Findings suggestive of placental insufficiency were identified in fetuses with intrauterine growth restriction and infections occurring at later gestational ages. There were two cases of late fetal death. Microcephaly as detected by ultrasonography and confirmed at birth was noted, but in only one case was it an isolated finding that was not present in conjunction with intrauterine growth restriction. Microcephaly in our cohort was mainly part of an overall composite of restricted fetal growth and not an asymmetric, isolated finding. Although microcephaly has been widely discussed in relation to ZIKV infection in Brazil, it is important to note that other findings such as cerebral calcifications and intrauterine growth restriction were frequently present.

Our findings are worrisome because 29% of ultrasonograms showed abnormalities, including intrauterine growth restriction, CNS findings, and fetal death, in fetuses of women with PCR-positive ZIKV infection. These were all healthy women with no other risk factors for adverse pregnancy outcomes. In a prior study of 662 pregnancies in HIV-infected women who were followed for 9 years in Rio de Janeiro, we noted a stillbirth rate of 2.5% and 13 mild-to-moderate infant malformations (2%), none of which occurred more than once.18 In the present scenario, over a period of a few months, we identified a fetal death rate of 4.8% — nearly twice the rate in an HIV-infected pregnant cohort followed for a decade — in addition to the serious fetal developmental problems.

To date six live births have occurred: two infants with normal ultrasonographic results had normal measures and normal examinations at birth; one infant had severe microcephaly and global cerebral atrophy as identified prenatally; two infants with growth restriction in utero were found to be small for gestational age at delivery with proportionally small heads, and one infant with anhydramnios was found to have normal measures at birth.

Our findings point to a link between ZIKV and abnormal fetal and placental development or placental insufficiency in a subgroup of ZIKV-positive women in whom fetal ultrasonography was performed. None of the 16 women who tested negative for acute ZIKV infection had abnormal results on fetal ultrasonography. Although the size of our control group was small and the ZIKV-negative women presumably had alternative processes for their rash, these women lived in the same geographic area as ZIKV-positive women and are likely to have had environmental exposures that were similar to those of ZIKV-positive women.

Our observations suggest that many aspects of ZIKV infection are similar to those of rubella, particularly rash, arthralgias, pruritus, and lymphadenopathy in the mother without high fever. About 85% of babies with congenital rubella in the U.S. pandemic of 1959–1965 had intrauterine growth restriction.19 In congenital rubella, specific organs are small because they have a subnormal number of cells, but the cytoplasmic mass of individual cells is within normal limits 19,20; in contrast, in intrauterine growth restriction due to maternal malnutrition, for example, the number of cells is normal but the cells contain less cytoplasm. A major difference of concern between ZIKV infections in Brazil in 2015–2016 and rubella virus infections in the U.S. pandemic of 1959–1965 is the level of population immunity. In Brazil in 2015–2016, none of the population has antibodies to ZIKV. In contrast, in the United States during the rubella epidemic, there were 20,000 cases of the congenital rubella syndrome, but in 1959 only 17.5% of women of childbearing age lacked rubella antibodies.21

In summary, we believe that our findings provide further support for a link between maternal ZIKV infection and fetal and placental abnormalities that is not unlike that of other viruses that are known to cause congenital infections characterized by intrauterine growth restriction and placental insufficiency. Women with suspected or confirmed ZIKV infection should be monitored closely, with serial ultrasonography to evaluate for signs of placental insufficiency, given the risks of fetal death and intrauterine growth restriction. The establishment of a scientifically credible link between ZIKV and abnormal congenital findings is of utmost importance for the effective and successful management of this epidemic in Brazil and worldwide.

 

 

This study was not supported by any research funds.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on March 4, 2016, at NEJM.org.

We thank the women who enrolled in this study, Mr. Marcelo dos Santos for assistance with the graphics of one of our figures, Dr. Yvonne Bryson for her ongoing support of our study, and Drs. Celina Boga and Eliane Chaves Vianna of the Centro de Saúde Escola Germano Sinval Faria–ENSP/FIOCRUZ for their continued support of our pregnancy cohort study.

SOURCE INFORMATION

From Fundação Oswaldo Cruz, Rio de Janeiro (P.B., J.P.P.J., L.D., M.W., R.M.R.N., P.C.S., A.M.S., L.M.A.C., D.C.C., G.A.C., E.S.N., M.E.M., A.E.R.B., P.R.N.C., A.M.B.F.); Biomedical Research Institute of Southern California, Oceanside (C.R.G.); and David Geffen UCLA School of Medicine, Los Angeles (C.J., S.G.V., J.D.C., K.N.-S.).

Address reprint requests to Dr. Nielsen-Saines at the Division of Pediatric Infectious Diseases, David Geffen School of Medicine at UCLA, MDCC 22-442, 10833 LeConte Ave., Los Angeles, CA 90095, or at [email protected].

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Study Finds Multiple Problems In Fetuses Exposed To Zika Virus

Updated March 4, 20164:53 PM ETPublished March 4, 20164:33 PM ET

ROB STEIN

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Audio for this story from All Things Considered will be available at approximately 7:00 p.m. ET.

i

Scientists are trying to figure out how Zika virus may be affecting fetuses.

Felipe Dana/AP

The Zika virus has sparked international alarm largely because of fears that the pathogen is causing microcephaly, a condition in which babies are born with unusually small heads and damaged brains.

But the preliminary results of a study released Friday suggest Zika can also cause other potentially grave complications among fetuses being carried by women who get infected when they are pregnant.

"There seems to be a whole spectrum of conditions that are related to this — not only microcephaly," says Karin Nielsen-Saines, a professor of clinical pediatrics at the David Geffen School of Medicine at UCLA who led the study.

The analysis, based on the first 42 women in a larger ongoing study, found that Zika appears to increase the risk for miscarriages, poorly developed placentas, low or no amniotic fluid, severe growth problems, other kinds of brain damage, blindness and deafness, according to a preliminary report published in the New England Journal of Medicine.

The results "make a very strong case for Zika virus being the cause of all these pregnancy outcomes that are not very good," Nielsen-Saines says.

She cautions, however, that the study is still small and needs to be confirmed by following many more women for longer periods of time.

The link between Zika and microcephaly remains largely circumstantial. It's based on the observation that the number of cases of microcephaly appear to have increased in Brazil after the virus became epidemic in that country. Researchers have also found evidence of Zika in the brains of a handful of babies with microcephaly who died shortly after birth.

Concern about a possible link sparked a rush of studies to test the possibility, as well as explore whether the virus is causing other problems.

The new results mark the first from a prospective study, which involves tracking the health of women who are infected with Zika and comparing them to very similar people who are not infected.

"The take-home message is that this is another important addition to the growing evidence that seems to now be quite compelling of the relationship between infection of a pregnant women and the development of congenital abnormalities," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.

For the study, Nielsen-Saines and colleagues from Brazil identified 88 women in the Rio de Janeiro area who had symptoms of Zika when they were pregnant. Seventy-two of the women had their Zika infection confirmed by polymerase-chain reaction (PCR) testing, which can identify genetic material from the virus.

Forty-two of those women, as well as 16 women who did not test positive for Zika, underwent ultrasounds to examine their fetuses. The ultrasounds of 12 of the infected women — 29 percent — found abnormalities. None of the Zika-negative women's ultrasounds found any problems.

Five of the fetuses being carried by the Zika-infected women were not growing normally; seven had central nervous system abnormalities; and seven had abnormalities in amniotic fluid volume or blood flow. In some cases, placentas didn't seem to be developing normally.

The problems observed on the ultrasounds are being explored and confirmed as the babies are being born. For example, two of the children have lesions in their retinas, Nielsen-Saines says, which means they might be blind. And she said that some may be deaf. Two were born extremely small, which means they could experience complications of low birth weight. One baby was born with microcephaly.

And some of the babies are not making it to birth. There were two miscarriages early in the pregnancies, and two stillbirths just a few weeks before the babies were due, Nielsen-Saines says.

Other experts say the results are alarming, given the scope of the Zika outbreak.

"Millions are being affected as the epidemic has spread throughout the Americas," says Albert Ko, a professor of epidemiology at the Yale School of Public Health, who is studying Zika in Brazil. So, yes, I think this is very disturbing."

http://www.npr.org/sections/health-shots/2016/03/04/469179452/study-finds-multiple-problems-in-fetuses-exposed-to-zika-virus

 

[niman]

Study provides 'strongest evidence yet' linking Zika, birth defects

 Liz Szabo, USA TODAY5:04 p.m. EST March 4, 2016

(Photo: Andre Penner, AP)

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A new study provides the strongest evidence yet that the Zika virus is the cause of devastating birth defects seen in Brazil, home to the largest outbreak of the disease.

Authors of the new study have followed 88 pregnant women in Brazil to see whether being infected with Zika, which is spread by mosquitoes, increases the rate of birth defects. Seventy-two of the women tested positive for the virus. The women's blood and urine were tested five days or less after they developed an itchy rash, a tell-tale symptom of Zika. Other symptoms of Zika infection included fever, pink eye, swollen lymph nodes and joint pain. Most people with Zika have no symptoms.

Ultrasounds found major abnormalities in 29% of the fetuses from women who tested positive for Zika, but none of the women without Zika infections, according to the study, published online Friday in The New England Journal of Medicine. Women were exposed to the Zika virus between the sixth and 35th week of pregnancy. A typical pregnancy lasts 40 weeks.

Those abnormalities included microcephaly, in which babies are born with unusually small skulls, which typically signifies incomplete brain development; restricted growth in the womb; poor development of brain structures; calcifications in the brain, which signal places where tissue has died; abnormal amniotic fluid levels; or abnormal blood flow in the fetal brain, umbilical cord or placenta, according to the study.

"Even if the fetus isn’t affected, the virus appears to damage the placenta, which can lead to fetal death," said study senior author Karin Nielsen,  a professor of clinical pediatrics in the division of pediatric infectious diseases at the David Geffen School of Medicine at UCLA.

Two women with Zika infections miscarried early in pregnancy, according to the study, led by doctors at the UCLA and Fiocruz, also known as the Oswaldo Cruz Foundation, a large biomedical institute in Rio de Janeiro. Two of the babies were stillborn, dying at 36 weeks and 38 weeks, according to the study.

Six women have given birth so far. Doctors plan to follow the remaining women through the end of their pregnancies and beyond, Nielsen said.

Two of the babies were born small for their gestational age. One was born with severe microcephaly and eye lesions that could indicate blindness, according to the study.

Doctors delivered one baby by emergency C-section because there was no amniotic fluid left in the uterus, a potentially life-threatening problem. The baby, a boy, recovered and appears to be healthy. His mother was infected with Zika in her 35th week of pregnancy.

Two infants of mothers with normal ultrasound results appear to be healthy, according to the study.

Ultrasound results were shown to be accurate for the two stillbirths and the six babies born alive, according to the study.

"We're seeing a spectrum of abnormalities," said Nielsen, who referred to the baby's conditions as Zika Virus Congenital Syndrome. "It's not all just microcephaly."

All of the mothers in the study were healthy, with no other risk factors for pregnancy complications.

Babies will need hearing and vision tests, Nielsen said.

http://www.usatoday.com/story/news/2016/03/04/study-provides-strongest-evidence-yet-linking-zika-birth-defects/81318418/

 

[niman]

Breakthrough Study Shows Strong Link Between Zika Virus, Severe Birth Defects

 

 

By: Beth Galvin

•  

POSTED:MAR 04 2016 05:30PM EST

UPDATED:MAR 04 2016 05:30PM EST

ATLANTA, Ga. -

There is still no direct confirmation Zika virus, spread by infected mosquitoes, is to blame more than 5,600 Brazilian babies born with abnormally small heads.  But the CDC and other health organizations say the evidence of a link between Zika and microcephaly is growing.

The Atlanta-based agency is warning pregnant women to avoid more than 30 areas where the Zika virus is actively spreading.

Now a chilling new study, conducted by  both American and Brazilian researchers, is driving home that warning.

The team followed 88 woman at a clinic in Rio de Janeiro.  The researchers found when a pregnant women is infected and becomes symptomatic, there is a good chance the virus could do serious damage to her unborn baby.

The study found 29% percent of pregnant women given ultrasounds after testing positive for Zika virus had fetuses that suffered "grave outcomes," including fetal death and nerve damage that can lead to blindness.

And the virus may pose a threat not just in the first trimester, but throughout a woman’s pregnancy. 

Two women in the Brazil study, infected at 25 and 32 weeks gestation, lost their pregnancies, even though their previous ultrasounds prior to their infections were normal. 

The study was published in the online version of The New England Journal of Medicine.

In another research study, published in the journal Cell Stem Cell, researchers say they may have a better understanding of how the virus may damage the developing brain.

They found Zika virus may directly target fetal brain cells, disrupting normal brain development.

Working quickly, they say, the virus infects the cells and causes them to die off.  Then, it uses those damaged brain cells to reproduce itself and infect more cells.

http://www.fox5atlanta.com/health/fox-medical-team/100654678-story

 

[niman]

 

ZIKA VIRUS OUTBREAK

MAR 4 2016, 6:38 PM ET

Study Finds Zika Damages Babies at All Stages of Pregnancy

by MAGGIE FOX

 

Gleyse Kelly holds her daugther Maria Geovana, in Recife, Brazil UESLEI MARCELINO / Reuters

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The babies of women infected with Zika virus while they are pregnant can suffer the effects at any stage of gestation, researchers reported Friday in a troubling look at how Zika affects unborn children.

Two babies died just before they should have been born after their mothers became infected, the international team found. They also found the virus causes a range of birth defects beyond microcephaly.

They suggest a name for these effects: Zika virus congenital syndrome. Babies have been born with a range of brain and eye defects and some have also been abnormally small.

The findings, together with other studies, support what most experts already believe: that Zika is causing an epidemic of birth defects.

Earlier Friday, a different team reported that tests in lab dishes show that Zika goes straight into developing brain cells and turns them into virus factories before killing them.

And the findings strongly support the idea that Zika, a once-obscure virus believed to cause little more than a headache and a rash, can be a killer.

"Despite mild clinical symptoms, Zika virus infection during pregnancy appears to be associated with grave outcomes, including fetal death, placental insufficiency, fetal growth restriction and central nervous system injury," they wrote in their report, published in the New England Journal of Medicine.

"THERE'S MORE THAN MICROCEPHALY. THERE IS A SPECTRUM OF DISEASE."

"We saw problems with the fetus or the pregnancy at eight weeks, 22 weeks, 25 weeks, and we saw problems at 35 weeks," said Dr. Karin Nielsen, professor of clinical pediatrics at the David Geffen School of Medicine at the University of California Los Angeles, who helped organize the study.

"Even if the fetus isn't affected the virus appears to damage the placenta, which can lead to fetal death," Nielsen said. Two babies died just days before they were due.

Related: Zika Can Cause Eye Defects

"Any woman with Zika virus should be handled as a high-risk pregnancy," Nielsen told NBC News.

"There's more than microcephaly. There is a spectrum of disease. There are parts of the brain that are not formed. There are calcifications in the brain. There is in-utero growth restriction."

Many of the symptoms are similar to what's been seen when women get rubella while pregnant, including microcephaly, marked by a smaller than normal brain and head. Children who survive birth with microcephaly can grow up with often profound physical and mental disabilities.

Calcifications are hardened remnants of dead tissue. Other studies have shown that Zika in the brains of some babies miscarried or aborted after a mother was infected.

Related: Two Cases Link Zika to Paralyzing Condition

Nielsen was working with Dr. Patricia Brasil and colleagues at the Oswaldo Cruz Foundation in Rio de Janeiro. They were already running a study of dengue virus, asking pregnant women to come in and be tested if they showed symptoms of dengue, such as a rash.

Dengue is related to Zika and it's spread by the same mosquitoes, the Aedes aegypti mosquitoes that spread Zika. And like Zika, dengue is spreading fast across Brazil and other Latin American countries.

So Nielsen's team was up and running when Zika started causing alarm. They tested blood and urine from 88 women between September and February. More than 80 percent of the women with symptoms such as fever and rash tested positive for Zika in the blood, urine or both.

The women were at various stages of pregnancy. Nielsen's team was able to follow them in real time to see what happened to their pregnancies. They found 29 percent of the fetuses had some sort of problem, from brain damage to damage to the placenta.

"ONE IMPORTANT FINDING WAS THAT THERE WERE PROBLEMS WITH PREGNANCY IN THE THIRD TRIMESTER AS WELL, WHICH WAS SURPRISING TO US."

Nielsen's study is the first to show what happens from the time a woman becomes infected. That can answer one big question: when the most dangerous time of pregnancy is.

"We know when the infection is taking place," she said. "We can associate that with weeks of gestation, so we can know if there are any malformations, what time they happened — we can associate them with a first trimester, second trimester and third trimester infection."

The answers are not reassuring. The experts have predicted that the first trimester would be the most dangerous time for a fetus if a woman became infected. But Nielsen's team found babies were hurt even late in pregnancy.

"One important finding was that there were problems with pregnancy in the third trimester as well, which was surprising to us," she said.

Some had looked normal on ultrasound, even, before they died in the womb. "It is not normal to find two fetal deaths that late in pregnancy in that small a group of women," she said.

Related: CDC Confirms 9 Zika Pregnancies in U.S.

The team is studying the babies to see if they can find out why they died. And they're watching the rest of the pregnant women to see what happens.

World Health Organization and Brazilian health officials are worried. They've seen more than 4,000 cases of microcephaly in recent months, and more than a million people have been infected. Colombia, the second Latin American country to get hit with Zika, has started to report Zika-linked cases of microcephaly.

"This virus hit in a perfect storm," Nielsen said. "You are talking about a very large population in Brazil. When you have a lot of people infected, you are going to see problems." 

http://www.nbcnews.com/storyline/zika-virus-outbreak/study-finds-zika-damages-babies-all-stages-pregnancy-n532086

 

[niman]

Zika 'guilty until proven innocent,' new studies show

The mosquito-borne virus may cause microcephaly and other negative outcomes during all stages of pregnancy.

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UESLEI MARCELINO / REUTERS

A study in Brazil showed a higher-than-usual rate of abnormalities in ultrasounds of pregnant women. Of 42 women who had the exam, 29 per cent had abnormal results. The norm is 1 or 2 per cent.

By: Jennifer Yang Global health reporter, Published on Fri Mar 04 2016

Two new studies provide “frightening and sobering” evidence that the Zika virus may be causing not just microcephaly but other negative outcomes during all stages of pregnancy, from fetal death to potential blindness caused by damage to the central nervous system.

The papers, published by the New England Journal of Medicineand Cell Stem Cell, were both published online Friday, hours after the World Health Organization announced an emergency committee meeting next week to review “accumulating evidence” linking Zika with serious neurological disorders.

It will be the second such meeting since the WHO first declared a public health emergency over Zika’s worrying link to the autoimmune disorder Guillain-Barré syndrome and microcephaly, a birth defect associated with abnormally small brains and developmental delays.

Zika’s culpability has yet to be definitively proven —proof is probably months or years away — but these latest studies lend further support to the WHO’s position that Zika is “guilty until proven innocent.”

“The evidence has now become very compelling and I think it’s urgent to continue to study this very aggressively,” said Dr. Mark Schleiss, director of pediatric infectious diseases and immunology at the University of Minnesota Medical School, who was not involved with either study.

Schleiss said study reported in Cell Stem Cell is a “very, very important paper,” demonstrating that Zika can kill brain cells while offering a framework for understanding how the virus might be causing microcephaly.

The NEJM research, which followed 88 pregnant women in Brazil, provided “a rather frightening and sobering” perspective, showing that out of 42 women who had an ultrasound exam, 29 per cent had abnormal results.

“The risk is really probably much higher, as reported in this paper, than what any of us would’ve predicted,” Schleiss said. “So we may just now be seeing the beginning of an increasing epidemic with even more cases. It is very sobering.”

In the Cell Stem Cell paper, U.S. researchers used lab-grown human stem cells to show that Zika can infect cells that form the brain’s cortex. Infected cells were then more likely to die and less likely to divide normally.“We’re literally the first people in the world to know this, to know that this virus can infect these very important cells and interfere with their function,” said lead author,Hengli Tang, a virologist with Florida State University.

The NEJM paper, on the other hand, is the first “prospective cohort study” of Zika and newborn malformations — meaning U.S. and Brazilian researchers enrolled a group of women and followed them over the course of their pregnancies.

The 88 pregnant women included in the study all developed a rash within five days of being treated by a clinic with the Oswaldo Cruz Foundation in Rio de Janeiro. Seventy-two had blood or urine samples that tested positive for Zika virus between September 2015 and mid-February.

Of the 42 women who consented to ultrasound exams, 29 per cent had abnormal results, according to senior author Dr. Karin Nielsen, a professor and infectious pediatric disease expert with UCLA’s David Geffen School of Medicine. “In a healthy population, it’s usually around 1 per cent or 2 per cent at most,” she said.

By comparison, all 16 women who were not infected by Zika had normal ultrasounds.

The abnormal results included not just microcephaly but also “intrauterine growth restrictions” and brain malformations. Of the eight babies born so far, two were stillborn and three have microcephaly or brain calcifications, according to Nielsen. Two also suffer from retinal impairment, indicating they will probably suffer from vision problems.

Nielsen was surprised that even women infected during their third trimester experienced serious outcomes, including stillbirths and one baby at 40 weeks who had no amniotic fluid.

“Zika seems to be a problem when there is an infection in women in any trimester of pregnancy,” she said. “They’re not out of the woods just because the first trimester is over.”

Nielsen said Brazil is now suffering a “perfect storm” because this surge in microcephaly is converging with a struggling economy and failure to control the mosquito that spreads Zika. “This will be a big burden on the country,” she said. “Children with brain disorders are very expensive to follow and to maintain, and need a lot of services.”

According to the WHO, only two countries have reported an increase in microcephaly cases during a Zika outbreak so far: Brazil and French Polynesia, which suffered an outbreak in 2013 and 2014.

But this week news reports indicated that Colombian scientists have confirmed their first cases of birth defects associated with Zika. A large prospective study involving roughly 5,000 pregnant women, mostly in Colombia, is still underway, however, and final results probably won’t be available until June, according to WHO.

http://www.thestar.com/news/world/2016/03/04/zika-guilty-until-proven-innocent-new-studies-show.html

 

[niman]

Zika has spread to more than 50 countries and territories, but so far officials have said that only one country has experienced a spike of the birth defect microcephaly linked to Zika. (AP Photo)

 

 

WHO reticent to confirm Zika-birth defect link

 

By ROBERT KING • 3/5/16 12:01 AM

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Evidence is mounting that the Zika virus causes a debilitating birth defect, but the World Health Organization is not prepared to confirm such a link.

Zika has spread to more than 50 countries and territories, but so far officials have said that only one country has experienced a spike of the birth defect microcephaly linked to Zika. That country is Brazil, which was the first to be affected by the outbreak that started last spring.

The World Health Organization said Friday that it will be "some months" before a link can be proven between Zika and microcephaly, which causes babies to be born with abnormally small heads and brain damage.

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"Microcephaly is a pregnancy outcome, probably associated most with first trimester exposure [to Zika] if indeed that relationship is causal," Bruce Aylward, executive director for Outbreaks and Health Emergencies at the WHO, said during a Friday press conference.

A recent small study is the latest to find evidence of a link between Zika and microcephaly.

The New England Journal of Medicine published a study Friday that followed 88 women from September 2015 to February 2016, about 72 of whom tested positive for Zika. The women got infected between five-38 weeks of pregnancy.

Researchers performed an ultrasound on 42 Zika-positive women and in all Zika-negative women. The ultrasounds were taken at different parts of the pregnancy, including between 20-30 weeks and after 30 weeks.

Fetal abnormalities were found in 12 of the 42 Zika-positive women and none of the other women. Eight of the 42 women have delivered their babies, and the ultrasound findings were confirmed, the study said.

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Abnormalities included not just microcephaly, but other defects such as far too much fluid in the brain and fetuses that were very small.

The researchers behind the study said women with suspected or confirmed Zika infection need to be monitored very closely and have frequent ultrasounds.

"The establishment of a scientifically credible link between [Zika] and abnormal congenital findings is of utmost importance for the effective and successful management of this epidemic in Brazil and worldwide," the study said.

The study was released on the same day as another finding that scientists discovered a potential link in how Zika affects pregnancies.

But so far the WHO said that Zika-linked cases of microcephaly were found only in Brazil and French Polynesia, which experienced an outbreak back in 2013-14. The spike in that country was found after the outbreak subsided.

http://www.washingtonexaminer.com/who-reticent-to-confirm-zika-birth-defect-link/article/2585008?custom_click=rss

 

[niman]

Study Finds Multiple Problems In Fetuses Exposed To Zika Virus

Updated March 4, 20164:53 PM ETPublished March 4, 20164:33 PM ET

ROB STEIN

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Audio for this story from All Things Considered will be available at approximately 7:00 p.m. ET.

i

Scientists are trying to figure out how Zika virus may be affecting fetuses.

Felipe Dana/AP

The Zika virus has sparked international alarm largely because of fears that the pathogen is causing microcephaly, a condition in which babies are born with unusually small heads and damaged brains.

But the preliminary results of a study released Friday suggest Zika can also cause other potentially grave complications among fetuses being carried by women who get infected when they are pregnant.

"There seems to be a whole spectrum of conditions that are related to this — not only microcephaly," says Karin Nielsen-Saines, a professor of clinical pediatrics at the David Geffen School of Medicine at UCLA who led the study.

The analysis, based on the first 42 women in a larger ongoing study, found that Zika appears to increase the risk for miscarriages, poorly developed placentas, low or no amniotic fluid, severe growth problems, other kinds of brain damage, blindness and deafness, according to a preliminary report published in the New England Journal of Medicine.

The results "make a very strong case for Zika virus being the cause of all these pregnancy outcomes that are not very good," Nielsen-Saines says.

She cautions, however, that the study is still small and needs to be confirmed by following many more women for longer periods of time.

The link between Zika and microcephaly remains largely circumstantial. It's based on the observation that the number of cases of microcephaly appear to have increased in Brazil after the virus became epidemic in that country. Researchers have also found evidence of Zika in the brains of a handful of babies with microcephaly who died shortly after birth.

Concern about a possible link sparked a rush of studies to test the possibility, as well as explore whether the virus is causing other problems.

The new results mark the first from a prospective study, which involves tracking the health of women who are infected with Zika and comparing them to very similar people who are not infected.

"The take-home message is that this is another important addition to the growing evidence that seems to now be quite compelling of the relationship between infection of a pregnant women and the development of congenital abnormalities," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.

For the study, Nielsen-Saines and colleagues from Brazil identified 88 women in the Rio de Janeiro area who had symptoms of Zika when they were pregnant. Seventy-two of the women had their Zika infection confirmed by polymerase-chain reaction (PCR) testing, which can identify genetic material from the virus.

Forty-two of those women, as well as 16 women who did not test positive for Zika, underwent ultrasounds to examine their fetuses. The ultrasounds of 12 of the infected women — 29 percent — found abnormalities. None of the Zika-negative women's ultrasounds found any problems.

Five of the fetuses being carried by the Zika-infected women were not growing normally; seven had central nervous system abnormalities; and seven had abnormalities in amniotic fluid volume or blood flow. In some cases, placentas didn't seem to be developing normally.

The problems observed on the ultrasounds are being explored and confirmed as the babies are being born. For example, two of the children have lesions in their retinas, Nielsen-Saines says, which means they might be blind. And she said that some may be deaf. Two were born extremely small, which means they could experience complications of low birth weight. One baby was born with microcephaly.

And some of the babies are not making it to birth. There were two miscarriages early in the pregnancies, and two stillbirths just a few weeks before the babies were due, Nielsen-Saines says.

Other experts say the results are alarming, given the scope of the Zika outbreak.

"Millions are being affected as the epidemic has spread throughout the Americas," says Albert Ko, a professor of epidemiology at the Yale School of Public Health, who is studying Zika in Brazil. So, yes, I think this is very disturbing."

http://www.npr.org/sections/health-shots/2016/03/04/469179452/study-finds-multiple-problems-in-fetuses-exposed-to-zika-virus

 

Audio

http://www.npr.org/player/v2/mediaPlayer.html?action=1&t=1&islist=false&id=469179452&m=469233742&live=1

Edited March 5, 2016 by niman

[niman]

Colombia has first cases of microcephaly related zika 

Researchers predict that in two or three months, the country will live a wave of babies born with the virus linked problems

 

By: AFP

03/04/2016 - 19:28 | Updated on 04/03/2016 - 19:32

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Photo: GUGA MATOS / JC IMAGE / Estadão Content

Researchers diagnosed the first cases of birth defects related to zika babies in Colombia. According to a report published in Nature, these are indications that in two or three months the country will have a wave of children born with problems related to the virus. According to the magazine, a newborn had diagnosis of microcephaly and two abnormalities in the brain. The three had positive tests for zika.

Read also: Rio Grande do Sul has 97 suspected cases of zika virus research suggests that mosquito can transmit zika

 

Alfonso Rodriguez-Morales, president of the Colombian Collaborative League in zika who made the diagnoses, says the group is investigating other cases. For the researcher, the risk posed by zika can much lower than that of other diseases that are known to cause microcephaly, such as toxoplasmosis, rubella, but this is a preliminary estimate. 

The virus reached the neighboring country in September 2015 and now Colombia is the second country in number of infected, behind Brazil. Here, the first cases of zika began to be recorded in May 2015, but before that had infection reports in the Northeast. 

In August, neurologists Pernambuco realized the increasing number of cases of microcephaly. In November the Ministry of Health confirmed that the increase in cases of microcephaly was related to the virus. On Tuesday, the Ministry of Health report has confirmed 641 cases of microcephaly. Of these, 82 had a positive laboratory tests for infection zika. 

http://zh.clicrbs.com.br/rs/vida-e-estilo/vida/noticia/2016/03/colombia-tem-primeiros-casos-de-microcefalia-relacionados-ao-zika-4990487.html

 

[niman]

Zika infection in pregnancy is linked to range of fetal abnormalities, data indicate

BMJ 2016; 352 doi: http://dx.doi.org/10.1136/bmj.i1362 (Published 07 March 2016)Cite this as: BMJ 2016;352:i1362

 

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1. Susan Mayor

1. Author affiliations

Infection with Zika virus in pregnancy is associated with a range of fetal abnormalities, including fetal death and growth restriction in addition to neonatal microcephaly, shows a preliminary report on data from Brazil,1 announced at a World Health Organization report last week.2

Researchers tested blood and urine specimens in pregnant women who had developed a rash in the previous five days and who were cared for at centres in Rio de Janeiro. The researchers tested for Zika virus before following the women prospectively, collecting clinical and ultrasound scan data.

A total of 88 women were enrolled in the study from September 2015 to February 2016. More than three quarters (72 of 88) of them tested positive for Zika virus in blood, urine, or both. The timing of infection ranged from five to 38 weeks of gestation.

Fetal abnormalities were detected in 12 of 42 women testing positive for Zika virus who underwent Doppler ultrasonography (29%) but in none of the 16 women who tested negative.

Death of the fetus occurred in two of the women infected with Zika, at 36 and 38 weeks of gestation. Other adverse events included in utero growth restriction with or without microcephaly (five fetuses) and ventricular calcifications or other central nervous system lesions (seven fetuses). Abnormal amniotic fluid content or cerebral, umbilical, or placental artery abnormalities were seen in seven fetuses.

So far eight of the 42 women with Zika infection who underwent ultrasonography in pregnancy have delivered their babies, and the researchers said that the ultrasonographic findings were confirmed.

Footnotes

• For The BMJ’s latest articles on the Zika virus epidemic go to bmj.co/zika.

References

1. ↵
   Brasil P, Pereira JP Jr, , Raja Gabaglia C, et al. Zika virus infection in pregnant women in Rio de Janeiro: preliminary report. N Engl J Med 2016;4. doi:10.1056/NEJMoa1602412. .26943629.

    
2. ↵
   Gulland A. Zika virus may be linked to several birth defects, expert warns.BMJ 2016;352:i1322.26940642.
3. http://www.bmj.com/content/352/bmj.i1362
4.  

[niman]

Zika and Birth Defects: The Evidence Mounts

Posted on March 15, 2016 by Dr. Francis Collins

Caption: Human neural progenitor cells (gray) infected with Zika virus (green) increased the enzyme caspase-3 (red), suggesting increased cell death.
Credit: Sarah C. Ogden, Florida State University, Tallahassee

Recently, public health officials have raised major concerns over the disturbing spread of the mosquito-borne Zika virus among people living in and traveling to many parts of Central and South America [1]. While the symptoms of Zika infection are typically mild, grave concerns have arisen about its potential impact during pregnancy. The concerns stem from the unusual number of births of children with microcephaly, a very serious condition characterized by a small head and damaged brain, coinciding with the spread of Zika virus. Now, two new studies strengthen the connection between Zika and an array of birth defects, including, but not limited to, microcephaly.

In the first study, NIH-funded laboratory researchers show that Zika virus can infect and kill human neural progenitor cells [2]. Those progenitor cells give rise to the cerebral cortex, a portion of the brain often affected in children with microcephaly. The second study, involving a small cohort of women diagnosed with Zika virus during their pregnancies in Rio de Janeiro, Brazil, suggests that the attack rate is disturbingly high, and microcephaly is just one of many risks to the developing fetus. [3]

The NIH-supported study, described in a recent issue of Cell Stem Cell, was led by Guo-li Ming and Hongjun Song of Johns Hopkins University School of Medicine, Baltimore, and Hengli Tang of Florida State University, Tallahassee. Their research teams turned to human induced pluripotent stem (iPS) cells, derived from skin biopsies, to produce human neural progenitor cells (hNPCs). These cells are readily found in the developing brain and are capable of becoming neurons in the cerebral cortex.

The researchers found that Zika virus could readily infect those neural progenitors in lab dishes. In fact, within three days of inoculation, the virus had infected 65 to 90 percent of the cells. The infection also led to a 30 percent reduction in viable hNPCs, as some cells died and others grew more slowly. In another important experiment, the group discovered that, once infected, a neural progenitor cell turns into “a virus factory.” In other words, the virus exploits the cell’s own machinery to produce and release more Zika to infect more cells.

While these findings will need to be confirmed in clinical studies, they suggest for the first time that Zika virus can directly target these essential neural cells. They also help to explain how Zika infection could cause harm to the developing brain, providing a possible link to microcephaly.

Unfortunately, it now appears that microcephaly isn’t the only cause for worry about children exposed to Zika virus in the womb. In the second study, reported recently inThe New England Journal of Medicine, a team of U.S. and Brazilian researchers enrolled 88 healthy pregnant Brazilian women who within the past five days had developed a red skin rash, one of the symptoms associated with Zika infection. Seventy-two of these women were later confirmed by blood and/or urine tests to have Zika virus, and 42 of those agreed to undergo an abdominal ultrasound.

Of the Zika-infected women, almost a third had developing babies that showed signs of very serious abnormalities by ultrasound. Five babies showed growth restrictions with or without microcephaly. Seven had other abnormalities of the central nervous system. Seven babies showed abnormally low levels of amniotic fluid or blood flow to the brain or umbilical cord. Doctors delivered one of the babies by emergency C-section due to a dangerous lack of amniotic fluid. Two babies in the study were stillborn just weeks before their due dates. None of the 16 Zika-uninfected women had pregnancies with fetal abnormalities.

These preliminary findings suggest that exposure to Zika virus is risky at any stage of pregnancy—even for developing babies that don’t appear to have microcephaly or other malformations. Further research is urgently needed, and these researchers have now enrolled a total of 280 Brazilian women into their ongoing study. They’ll also continue to follow the outcomes for these women and their children over the coming months.

Taken together, these studies strengthen the case that the Zika virus may well be behind the deeply troubling rise in microcephaly in Brazil. These new developments raise the question of why the ability of Zika virus to cause birth defects wasn’t previously known—after all, this virus has been around for a long time (it was originally described in 1947 in the Zika forest in Uganda). One possibility is that in endemic areas nearly all individuals are infected as children, have a mild illness, and then develop lifelong immunity. Only in the situation where a previously unexposed population encounters the virus in adulthood is the risk of active infection in pregnancy, and subsequent birth defects in the offspring, possible. (Scholars of virology will recognize this phenomenon as having similarities to rubella, or “German measles.”) The NIH is now working aggressively to develop a vaccine. But there are still many steps in development and testing before a vaccine could be made available to vulnerable populations. Meanwhile, CDC recommendations for travelers should be scrutinized by everyone.

References:

[1] Zika virus disease in the United States, 2015-2016. Centers for Disease Control and Prevention. 2016 Mar 9.

[2] Zika virus infects human cortical neural progenitors and attenuates their growth. Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, Yao B, Shin J, Zhang F, Lee EM, Christian KM, Didier RA, Jin P, Song H, Ming G. Cell Stem Cell. 2016 Mar 4. [Epub ahead of print]

[3] Zika Virus Infection in Pregnant Women in Rio de Janeiro – Preliminary Report. Brasil P, Pereira JP Jr, Raja Gabaglia C, Damasceno L, Wakimoto M, Ribeiro Nogueira RM, Carvalho de Sequeira P, Machado Siqueira A, Abreu de Carvalho LM, Cotrim da Cunha D, Calvet GA, Neves ES, Moreira ME, Rodrigues Baião AE, Nassar de Carvalho PR, Janzen C, Valderramos SG, Cherry JD, Bispo de Filippis AM, Nielsen-Saines K. N Engl J Med. 2016 Mar 4. [Epub ahead of print]

Links:

Zika Virus (National Institute of Allergy and Infectious Diseases/NIH)

Microcephaly Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Hongjun Song (Johns Hopkins University, Baltimore)

Hengli Tang (Florida State University, Tallahassee)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of Neurological Disorders and Stroke

http://directorsblog.nih.gov/2016/03/15/zika-and-birth-defects-the-evidence-mounts/