Update: Interim Guidance for Health Care Providers Caring for Pregnant Women with Possible Zika Virus Exposure — United States, July 2016

Introduction

Zika virus continues to spread worldwide, and as of July 21, 2016, 50 countries and territories reported active Zika virus transmission (locations with mosquitoes transmitting Zika virus to persons in the area).^¶ Although most persons with Zika virus infection are asymptomatic or have mild clinical disease, infection during pregnancy can cause congenital microcephaly and other brain defects (1). Zika virus has also been linked to other adverse pregnancy outcomes, including miscarriage and stillbirth (1,2). The U.S. Zika Pregnancy Registry (USZPR)** and the Puerto Rico Zika Active Pregnancy Surveillance System (ZAPPS)^†† were established in collaboration with state, tribal, local, and territorial health departments to monitor pregnant women with confirmed or possible Zika virus infection to determine the risk for Zika virus infection during pregnancy and the spectrum of conditions associated with congenital Zika virus infection (3). As of July 14, 2016, a total of 400 women in the 50 U.S. states and the District of Columbia, and 378 women in all U.S. territories (aggregated territories’ data from the USZPR and ZAPSS) were determined to have laboratory evidence of confirmed or possible Zika virus infection during pregnancy.^§§

Data from the USZPR and published case reports indicate that Zika virus RNA can persist in serum of some pregnant women longer than had been previously reported; the longest documented duration of Zika virus RNA detection in serum is 10 weeks after symptom onset (4–7). In addition, recent data indicate that Zika virus RNA might be detected in the serum or urine of some asymptomatic pregnant women (7). The frequency of this finding is unknown, but the detection of Zika virus RNA in serum or urine provides a definitive diagnosis of Zika virus infection. Preliminary data suggest that plaque reduction neutralization testing (PRNT) might not discriminate between Zika virus and other flavivirus infections, particularly in persons with previous flavivirus exposure (8), which complicates interpretation of serologic testing (IgM antibody test and PRNT). Given these challenges, expanded rRT-PCR testing might provide a definitive diagnosis for more pregnant women who are infected with Zika virus.

CDC has revised its interim guidance for U.S. health care providers caring for pregnant women with possible Zika virus exposure. The revised testing recommendations extend the timeframe for rRT-PCR testing of serum and include rRT-PCR testing for some asymptomatic pregnant women. CDC continues to evaluate all available evidence and will update recommendations as new information becomes available.

Updated Recommendations for Evaluating and Testing of Pregnant Women with Possible Zika Virus Exposure

All pregnant women in the United States and U.S. territories should be assessed for possible Zika virus exposure at each prenatal care visit. CDC recommends that pregnant women not travel to an area with active Zika virus transmission (9,10). Pregnant women who must travel to one of these areas should strictly follow steps to prevent mosquito bites during the trip.^¶¶ In addition, it is recommended that pregnant women with a sex partner who has traveled to or lives in an area with active Zika virus transmission use condoms or other barrier methods to prevent infection or abstain from sex for the duration of the pregnancy (11).

Symptomatic pregnant women. Pregnant women who report signs or symptoms consistent with Zika virus disease (acute onset of fever, rash, arthralgia, conjunctivitis) should be tested for Zika virus infection (Figure). The testing recommendations for symptomatic pregnant women are the same regardless of the circumstances of possible exposure; however, the type of testing recommended varies depending on the time of evaluation relative to symptom onset. Testing of serum and urine by rRT-PCR is recommended for pregnant women who seek care <2 weeks after symptom onset. This recommendation extends the previous recommendation for testing of serum from <1 week after symptom onset to <2 weeks (Figure). A positive rRT-PCR result confirms the diagnosis of recent maternal Zika virus infection. Symptomatic pregnant women with negative rRT-PCR results should receive both Zika virus IgM and dengue virus IgM antibody testing. If Zika virus rRT-PCR testing is requested from laboratories that do not have IgM antibody testing capacity or a process to forward specimens to another testing laboratory, storing of additional serum samples is recommended for IgM antibody testing in the event of a negative rRT-PCR result (12). If either the Zika virus or dengue virus IgM antibody test yields positive or equivocal results, PRNT should be performed on the same IgM-tested sample or a subsequently collected sample to rule out false-positive results (8).

Symptomatic pregnant women who seek care 2–12 weeks after symptom onset should first receive Zika virus and dengue virus IgM antibody testing (Figure). If the Zika virus IgM antibody testing yields positive or equivocal results, reflex rRT-PCR testing should be automatically performed on the same serum sample to determine whether Zika virus RNA is present. A positive rRT-PCR result confirms the diagnosis of recent maternal Zika virus infection. However, if the rRT-PCR result is negative, a positive or equivocal Zika virus IgM antibody test result should be followed by PRNT. Positive or equivocal dengue IgM antibody test results with a negative Zika virus IgM antibody test result should also be confirmed by PRNT. Interpretation of serologic results has been described (8).

Asymptomatic pregnant women. Testing recommendations for asymptomatic pregnant women with possible Zika virus exposure differ based on the circumstances of possible exposure (i.e., ongoing versus limited exposure) and the elapsed interval since the last possible Zika virus exposure (Figure). Asymptomatic pregnant women living in areas without active Zika virus transmission who are evaluated <2 weeks after possible Zika virus exposure should be offered serum and urine rRT-PCR testing (Figure). A positive rRT-PCR result confirms the diagnosis of recent maternal Zika virus infection. However, because viral RNA in serum and urine declines over time and depends on multiple factors, asymptomatic pregnant women with a negative rRT-PCR result require additional testing to exclude infection. These women should return 2–12 weeks after possible Zika virus exposure for Zika virus IgM antibody testing. A positive or equivocal IgM antibody test result should be confirmed by PRNT.

Asymptomatic pregnant women living in an area without active Zika virus transmission, who seek care 2–12 weeks after possible Zika virus exposure, should be offered Zika virus IgM antibody testing (Figure). If the Zika virus IgM antibody test yields positive or equivocal results, reflex rRT-PCR testing should be performed on the same sample. If the rRT-PCR result is negative, PRNT should be performed.

As recommended in previous guidance (9,13), IgM antibody testing is recommended as part of routine obstetric care during the first and second trimesters for asymptomatic pregnant women who have an ongoing risk for Zika virus exposure (i.e., residence in or frequent travel to an area with active Zika virus transmission) (Figure). Reflex rRT-PCR testing is recommended for women who have a positive or equivocal Zika virus IgM antibody test results because rRT-PCR testing provides the potential for a definitive diagnosis of Zika virus infection. Negative rRT-PCR results after a positive or equivocal Zika virus IgM antibody test result should be followed by PRNT. The decision to implement testing of asymptomatic pregnant women with ongoing risk for Zika virus exposure should be made by local health officials based on information about levels of Zika virus transmission and laboratory capacity.

Symptomatic and asymptomatic pregnant women who seek care >12 weeks after symptom onset or possible Zika virus exposure. For symptomatic and asymptomatic pregnant women with possible Zika virus exposure who seek care >12 weeks after symptom onset or possible exposure, IgM antibody testing might be considered. If fetal abnormalities are present, rRT-PCR testing should also be performed on maternal serum and urine. However, a negative IgM antibody test or rRT-PCR result >12 weeks after symptom onset or possible exposure does not rule out recent Zika virus infection because IgM antibody and viral RNA levels decline over time. Given the limitations of testing beyond 12 weeks after symptom onset or possible exposure, serial fetal ultrasounds should be considered.

Updated Recommendations for Prenatal Management of Pregnant Women with Laboratory Evidence of Confirmed or Possible Zika Virus Infection

Laboratory evidence of a confirmed recent Zika virus infection includes 1) detection of Zika virus or Zika virus RNA or antigen in any body fluid or tissue specimen or 2) positive or equivocal Zika virus or dengue virus IgM antibody test results on serum or cerebrospinal fluid with a positive (≥10) PRNT titer for Zika virus together with a negative (<10) PRNT titer for dengue virus (8). However, given that serology test results can be difficult to interpret, particularly in persons who were previously infected with or vaccinated against flaviviruses, and because the adverse outcomes caused by Zika virus infection during pregnancy are not fully described, pregnant women with laboratory evidence of recent flavivirus infection are considered to have possible Zika virus infection and should be monitored frequently (Table).

Pregnant women with confirmed or possible Zika virus infection should be managed in accordance with the updated CDC Interim Guidance (Table). In addition, pregnant women with presumptive recent Zika virus or flavivirus infection (i.e., positive or equivocal Zika virus or dengue virus IgM antibody test result that needs to be confirmed by PRNT) should also be managed in accordance with this updated guidance (Table) until final results are available. Serial fetal ultrasounds (every 3–4 weeks) should be considered to assess fetal anatomy, particularly neuroanatomy, and to monitor growth. Ultrasound findings that have been associated with congenital Zika virus syndrome include microcephaly, intracranial calcifications, ventriculomegaly, arthrogryposis, and abnormalities of the corpus callosum, cerebrum, cerebellum, and eyes (1,14). Consideration of amniocentesis should be individualized, because data about its usefulness in diagnosing congenital Zika virus infection are limited (13). The presence of Zika virus RNA in the amniotic fluid might indicate fetal infection (5,15); however, a negative result does not exclude congenital Zika virus infection (13). In addition, persistent detection of Zika virus RNA in serum has been reported during pregnancy (7). The clinical implications of prolonged detection of Zika virus RNA in serum are not known; however, repeat rRT-PCR testing has been performed in some cases (5,7).

Updated Recommendations for Postnatal Management of Pregnant Women with Laboratory Evidence of Confirmed or Possible Zika Virus Infection

Infants born to women with laboratory evidence of confirmed or possible Zika virus infection should be evaluated for congenital Zika virus infection in accordance with CDC interim guidance for health care providers caring for infants with possible Zika virus infection (16). Zika virus testing is recommended for these infants regardless of the presence or absence of phenotypic abnormalities (14). Previous published guidance recommended that testing be performed on cord blood or infant serum; however, the use of cord blood to diagnose other congenital viral infections, such as HIV and syphilis, has sometimes yielded inaccurate results (17–20). Maternal blood can contaminate cord blood specimens leading to false-positive results, whereas Wharton’s jelly in the umbilical cord can yield false-negative results (19,20). Cord blood samples can also become clotted, which does not allow for appropriate serologic testing. Therefore, although collection and testing of cord blood for Zika virus testing can be performed, these results should be interpreted in conjunction with infant serum results. Pathology evaluation of fetal tissue specimens (e.g., placenta and umbilical cord)*** is another important diagnostic tool to establish the presence of maternal Zika virus infection and can provide a definitive diagnosis for pregnant women with Zika virus infection whose serology results indicate recent unspecified flavivirus infection. In addition, pathology findings might also be helpful in evaluating pregnant women who seek care >12 weeks after symptom onset or possible exposure; Zika virus RNA has been reported to persist in tissue specimens including placenta and fetal brain (21). A positive rRT-PCR or immunohistochemical staining on the placenta indicates the presence of maternal infection (21).

Pregnant women with laboratory evidence of confirmed or possible Zika virus infection who experience a fetal loss or stillbirth should be offered pathology testing for Zika virus infection; testing includes rRT-PCR and immunohistochemical staining of fixed tissue (21). This testing might provide insight into the etiology of the fetal loss, which could inform a woman’s future pregnancy planning. Additional information is available at http://www.cdc.gov/zika.