1. Zika in Pregnancy: Maternal and Fetal Complications Anna Powell, MD Department of Obstetrics and Gynecology, Reproductive Infectious Disease Anna Powell, MD Department of Obstetrics and Gynecology, Reproductive Infectious Disease

2. Zika in Pregnancy  Retrospective analysis of French Polynesia outbreak: microcephaly affected 1% of women affected by ZIKV in first trimester by mathematical modeling  Substantial increase in reported cases of microcephaly in Brazil in 2015  Prelim report from Brazil: fetal abnormalities by US present in 29% of women with ZIKV during pregnancy  Infection can occur in ANY trimester; greatest risk for microcephaly in first trimester.  Evidence of perinatal transmission at time of delivery  Retrospective analysis of French Polynesia outbreak: microcephaly affected 1% of women affected by ZIKV in first trimester by mathematical modeling  Substantial increase in reported cases of microcephaly in Brazil in 2015  Prelim report from Brazil: fetal abnormalities by US present in 29% of women with ZIKV during pregnancy  Infection can occur in ANY trimester; greatest risk for microcephaly in first trimester.  Evidence of perinatal transmission at time of delivery

4. Clinical Features of ZIKV Infection

5. ZIKV in Pregnant Women in Rio de Janiero (Brasil P, et al. NEJM 2016)  Methods : prospective clinical trial of pregnant women with rash in previous 5 days. Urine and blood specimens tested by RT-PCR, patients followed for clinical and US data  Results : 88 women Sept 2015- Feb 2016  72 (82%) tested positive for ZIKV in blood, urine or both  5-38 weeks gestation  Clinical features: pruritic/descending maculopapular rash, conjunctival involvement, lymphadenopathy.  Fetal US performed in 42 ZIKV + women and all ZIKV – (16 total)  Fetal abnormalities detected in 12/42 ZIKV + (29%) and 0/16 of ZIKV –  Adverse findings include: fetal death (2), IUGR with or without microcephaly (5), ventricular calcifications or other CNS lesion (7), abnormal AFI or cerebral or umbilical artery flow (7)  Methods : prospective clinical trial of pregnant women with rash in previous 5 days. Urine and blood specimens tested by RT-PCR, patients followed for clinical and US data  Results : 88 women Sept 2015- Feb 2016  72 (82%) tested positive for ZIKV in blood, urine or both  5-38 weeks gestation  Clinical features: pruritic/descending maculopapular rash, conjunctival involvement, lymphadenopathy.  Fetal US performed in 42 ZIKV + women and all ZIKV – (16 total)  Fetal abnormalities detected in 12/42 ZIKV + (29%) and 0/16 of ZIKV –  Adverse findings include: fetal death (2), IUGR with or without microcephaly (5), ventricular calcifications or other CNS lesion (7), abnormal AFI or cerebral or umbilical artery flow (7)

6. ZIKV in Pregnant Women in Rio de Janiero (Brasil P, et al. NEJM 2016)  ZIKV infected versus non-infected more likely to have:  Pruritic/descending maculopapular rash (44% vs 12%, p= 0.02)  Conjunctival involvement (58% vs 13%, p=0.002)  Lymphadenopathy (40% vs 7%, p=0.02)  Other findings:  Arthralgia (65% vs 41%, p=0.16)  Fever not prominent  ZIKV infected versus non-infected more likely to have:  Pruritic/descending maculopapular rash (44% vs 12%, p= 0.02)  Conjunctival involvement (58% vs 13%, p=0.002)  Lymphadenopathy (40% vs 7%, p=0.02)  Other findings:  Arthralgia (65% vs 41%, p=0.16)  Fever not prominent

7. Week of Gestation at time of ZIKV infection and abnormal US/Doppler findings

8. ZIKV in Pregnant Women in Rio de Janiero (Brasil P, et al. NEJM 2016)  Study findings are concerning  Present study identified a 4.8% fetal death rate and serious fetal developmental problems  Prior study of 662 pregnancies in HIV-infected women followed for 9 years in Rio showed stillbirth rate 2.5% and 2% mild to moderate infant malformations  Study findings are concerning  Present study identified a 4.8% fetal death rate and serious fetal developmental problems  Prior study of 662 pregnancies in HIV-infected women followed for 9 years in Rio showed stillbirth rate 2.5% and 2% mild to moderate infant malformations

9. Microcephaly  Occipitofrontal circumference (OFC) >2 SD below the mean for a given age, sex, or gestation (< 3 rd percentile).  Severe microcephaly defined as OFC ≥ 5 SD below mean.  2 major mechanisms:  abnormal or absent brain development related to developmental insult during sensitive time of induction/cellular migration  Injury or insult to a previously normal brain (reduced number of dendritic processes and synaptic connections)  DDx includes: TORCH, genetic syndromes, vascular disruption during brain development, nutritional deficiencies, toxin exposure  ZIKV associated microcephaly: Fetal brain disruption sequence, ophthalmic abnormalities  Occipitofrontal circumference (OFC) >2 SD below the mean for a given age, sex, or gestation (< 3 rd percentile).  Severe microcephaly defined as OFC ≥ 5 SD below mean.  2 major mechanisms:  abnormal or absent brain development related to developmental insult during sensitive time of induction/cellular migration  Injury or insult to a previously normal brain (reduced number of dendritic processes and synaptic connections)  DDx includes: TORCH, genetic syndromes, vascular disruption during brain development, nutritional deficiencies, toxin exposure  ZIKV associated microcephaly: Fetal brain disruption sequence, ophthalmic abnormalities

10. Evidence Suggesting Causality  Findings of ZIKV RNA in amniotic fluid of fetuses with microcephaly, in brain tissue of fetuses and infants with microcephaly  High rates of microcephaly among infants born to mothers with proven antecedent acute ZIKV infection  Meets 3 of Shepard’s 7 criteria for proof of teratogenicity in humans (Rasmussen SA et al. Zika Virus and Birth Defects– Reviewing the Evidence for Causality. NEJM 2016.)  Findings of ZIKV RNA in amniotic fluid of fetuses with microcephaly, in brain tissue of fetuses and infants with microcephaly  High rates of microcephaly among infants born to mothers with proven antecedent acute ZIKV infection  Meets 3 of Shepard’s 7 criteria for proof of teratogenicity in humans (Rasmussen SA et al. Zika Virus and Birth Defects– Reviewing the Evidence for Causality. NEJM 2016.)

11. ZIKV Exposure in Pregnancy (Inactive Area)

12. Pregnant Women in ZIKV Active Area  Take home :  Test for Zika  Perform fetal ultrasonography  Consider serial fetal ultrasounds in setting of suspected abnormalities  Take home :  Test for Zika  Perform fetal ultrasonography  Consider serial fetal ultrasounds in setting of suspected abnormalities

14. ZIKV Pregnancy Registry  CDC collecting prospective data on ZIKV in pregnancy via US Zika Pregnancy Registry and Zika Active Pregnancy Surveillance System in Puerto Rico  In US and DC: Pregnant women with any laboratory evidence of possible Zika virus infection: 195 as of 5/26/2016  In US Territories: Pregnant women with any lab evidence of possible Zika virus infection: 146 as of 5/26/2016  As of 06/01/2016, no locally acquired ZIKV cases in continental US  CDC collecting prospective data on ZIKV in pregnancy via US Zika Pregnancy Registry and Zika Active Pregnancy Surveillance System in Puerto Rico  In US and DC: Pregnant women with any laboratory evidence of possible Zika virus infection: 195 as of 5/26/2016  In US Territories: Pregnant women with any lab evidence of possible Zika virus infection: 146 as of 5/26/2016  As of 06/01/2016, no locally acquired ZIKV cases in continental US

15. UZPR and ZAPSS Combined Data Simeone RM et al. MMWR Morb Mortal WklyRep 2016;65. US +DC (N=157)US Territories (N=122) Symptomatic rate 73 (49%)80 (66%) Rash 64 (88%)29 (36%) Arthralgia 36 (49%)60 (75%) Fever 37 (51%)27 (34%) Conjunctivitis 17 (23%)15 (19%)

16. 4/26-5/12: US and DC

17. 4/26-5/12: US Territories

19. Zika Q&A from CDC to help guide counseling  1. Is there a vaccine to prevent Zika?  2. I am pregnant, should I travel to a country where Zika has been reported?  3. I am pregnant. How will Zika affect me or my unborn baby?  4. Is it safe to use insect repellent if I am pregnant or nursing?  5. Is it safe to get pregnant after traveling to a country with Zika?  1. Is there a vaccine to prevent Zika?  2. I am pregnant, should I travel to a country where Zika has been reported?  3. I am pregnant. How will Zika affect me or my unborn baby?  4. Is it safe to use insect repellent if I am pregnant or nursing?  5. Is it safe to get pregnant after traveling to a country with Zika?

20. Zika Q&A from CDC to help guide counseling  Is there a vaccine to prevent Zika?  No; any strain of ZIKV used to develop the vaccine should protective against all strains 2’ high conservation among different strains of virus (<12% divergence at nucleotide level)  2. I am pregnant, should I travel to a country where Zika has been reported?  CDC travel advisory recommends against travel to endemic areas if possible  3. I am pregnant. How will Zika affect me or my unborn baby?  Most exposures asymptomatic- testing is recommended based on personal travel or partner exposure history  4. Is it safe to use insect repellent if I am pregnant or nursing?  Yes– take measures to avoid mosquito bites  5. Is it safe to get pregnant after traveling to a country with Zika?  CDC recommends avoiding pregnancy for 8 weeks after symptoms or ZIKV exposure  Men with ZIKV should wait at least 6 months after symptom onset to attempt conception  Is there a vaccine to prevent Zika?  No; any strain of ZIKV used to develop the vaccine should protective against all strains 2’ high conservation among different strains of virus (<12% divergence at nucleotide level)  2. I am pregnant, should I travel to a country where Zika has been reported?  CDC travel advisory recommends against travel to endemic areas if possible  3. I am pregnant. How will Zika affect me or my unborn baby?  Most exposures asymptomatic- testing is recommended based on personal travel or partner exposure history  4. Is it safe to use insect repellent if I am pregnant or nursing?  Yes– take measures to avoid mosquito bites  5. Is it safe to get pregnant after traveling to a country with Zika?  CDC recommends avoiding pregnancy for 8 weeks after symptoms or ZIKV exposure  Men with ZIKV should wait at least 6 months after symptom onset to attempt conception

21. In Summary:  Causal linkage between ZIKV and microcephaly  Pregnant women should avoid unnecessary travel to ZIKV active areas and take necessary precautions against mosquito bites  ZIKV associated microcephaly and fetal brain disruption sequence may have serious future implications  No evidence to support testing for local transmission  Many unanswered questions about exact infectivity rate and asymptomatic carrier rate  Providers should keep up to date on recommendations for pregnant women, their partners, and patients planning pregnancy in the near future  Causal linkage between ZIKV and microcephaly  Pregnant women should avoid unnecessary travel to ZIKV active areas and take necessary precautions against mosquito bites  ZIKV associated microcephaly and fetal brain disruption sequence may have serious future implications  No evidence to support testing for local transmission  Many unanswered questions about exact infectivity rate and asymptomatic carrier rate  Providers should keep up to date on recommendations for pregnant women, their partners, and patients planning pregnancy in the near future

22. Thank you!  Questions?