Zika Infection Late in Pregnancy May Impact Fetal Neurologic Development

On February 25, 2017, at The First International Zika Conference, Carmen D. Zorrilla, MD, professor of obstetrics and gynecology, University of Puerto Rico, School of Medicine, shared her research which aimed to evaluate the growth patterns of fetuses whose mothers acquired Zika virus during pregnancy “and showed no prenatally detectable structural anomalies or maternal conditions that could affect fetal growth.”

Dr. Zorrilla opened her presentation by providing conference attendees with a brief overview of the Zika epidemic in Puerto Rico, sharing that the first case was reported back in December 2015. She said, “It was estimated that 50% of the Puerto Rican population would get infected with Zika virus, so we estimated that maybe 6,000 to 7,000 pregnant women would get infected during 2016.”

When it comes to Zika testing in Puerto Rico, the Puerto Rico Department of Health followed the Centers for Disease Control and Prevention’s guidelines and started testing all pregnant women during their 1st and 2nd trimester regardless of whether they were presenting with symptoms or not. Later, they expanded testing to include the 3rd trimester as well. Healthcare officials used the Trioplex Real-time reverse transcription polymerase chain reaction (RT-PCR) to detect the Zika virus and distinguish it from Dengue and Chikungunya.

Dr. Zorrilla shared that, as of February 17, 2017, Puerto Rico had 38,733 cases of confirmed Zika virus infection. Of these confirmed cases, 3,076 were pregnant women and 57% of these women had been diagnosed while symptomatic; 43% “were diagnosed by routine testing during pregnancy.” Dr. Zorrilla then showed a graph depicting the confirmed Zika cases in pregnant women from January 29, 2017 to February 4, 2017, noting that, “the curve is flattening, but we are still seeing new cases of pregnant women diagnosed.”

“Severe brain damage caused by Zika virus infection has been well-documented with rates of congenital Zika syndrome (CZS) between 1-11%,” according to Dr. Zorrilla. She continued, “It can be diagnosed by ultrasound. Some of the most characteristic patterns of ultrasound findings include: ventricular dilatation and abnormal cerebral development, [and] also intracranial calcifications that are scattered all over the fetal brain without a significant pattern or flow.”

As mentioned in previous presentations at the conference, Dr. Zorrilla shared that the full spectrum of Zika virus remains to be defined. She explained, “We believe that we already have the CZS, the most severe manifestation of the infection, but we believe that there is a full range of disease that might go from normal to severe. We wanted to see and examine what was happening in the fetuses of women diagnosed with Zika infection who showed no brain abnormalities from ultrasound [and in] fetuses that looked normal on ultrasound, in terms of the brain, [we wanted to know if Zika had] any impact on their [head] growth.”

For their study, Dr. Zorilla and her team selected, “fetuses whose mothers contracted Zika virus infection during pregnancy and showed no prenatal intracranial abnormalities [and] evaluated them prospectively.” Dr. Zorilla stated, “We selected women who had Zika diagnosed during pregnancy because they had symptoms and they had a positive PCR.”

The patients were grouped based on when they got infected in pregnancy. “We chose to include one study [for the prospective research] performed more than 6 weeks after the documented Zika to allow time to identify any impact on growth,” Dr. Zorilla said. The fetuses’ biometric data was then compared to a reference population consisting of “normal fetuses [studied between] 2014 and 2015, prior to the onset of the Zika epidemic in Puerto Rico.”

For the reference population as well as the Zika-affected population, the exclusion criteria included any condition that would cause abnormal fetal growth, including: maternal drug use, uncertain gestational age, multiple gestation, fetal structural abnormalities, documented fetal genetic abnormalities, abnormal placentation, abnormal amniotic fluid volume at the time of examination, and single umbilical artery. In addition, the researchers eliminated any pregnancy that “was affected with Zika where we did not know when it happened. So, women who had Zika but were asymptomatic were not included in analysis.”

A graph depicting the reference population, which included over 2,000 fetuses “that had absolutely normal conditions during pregnancy,” was shown to attendees during the presentation. It also illustrated the “mean for fetal growth” for Puerto Rico (in red) and United States (in blue) fetuses. Dr. Zorilla explained, “As you can see, the Puerto Rico fetuses behave the same as the United States fetuses in terms of Zika [impacted] growth [pertaining to] head circumference.”

A total of 620 fetuses had been referred to their unit for evaluation, and of those, 14 had brain damage (2.3%), 298 (48%) met the exclusion criteria (due to the fact that the researchers were unsure of exactly when the infection happened), and 322 (52%) met the inclusion criteria, meaning that they did not have any brain abnormalities, they knew when infection occurred, and they had Zika-positive PCRs for the women.

The researchers then divided the women into four groups:

Group 1: Women who acquired Zika prior to 7 weeks of gestation: 33 patients

Group 2: Women who acquired Zika between 7 and 14 weeks of gestational age: 85 patients

Group 3: Women who acquired Zika between 14 and 26 gestational age: 170 patients

Group 4: Women who acquired Zika after 26 weeks: 34 patients

Dr. Zarrillo then illustrated the growth parameter curves for fetuses of each group. In Group 1, the fetuses “presented similar to the controls” when it came to head circumference, femur growth, and abdominal circumferences. Group 2 showed similar results, to which Dr. Zarrillo noted, “So far, so good.” When it came to Group 2, Dr. Zarrillo pointed out, “This is when we are starting to see some lagging of the head circumference lines and you can actually see that they are somewhat different, but see these fetuses fall somewhere between within the normal range.” Then she showed the graph depicting Group 4: “This is the most concerning for us,” Dr. Zarrillo stressed. “You can see the head circumference growth curve is almost flat; this was statistically significant for two different types of tests.” Femur length and abdominal circumferences were mostly similar.

Dr. Zarrillo went on to explain her team’s findings. First, “fetuses with normal brain imaging whose mothers were affected with Zika infection during pregnancy have smaller head circumferences than controls (P = .0000154). Fetuses whose mothers are affected by Zika during pregnancy prior to 26 weeks of gestation that show no evidence of brain damage on sonography appeared to have a normal growth pattern throughout the rest of the pregnancy.” However, infections that occurred after 26 weeks of gestation “produced a tendency towards smaller head size (p = 0.0175) while other biometric parameters grew within the expected range. These findings require close attention and follow-up since they may be a marker for future developmental anomalies that cannot be prenatally detected.” Lastly, the finding of “postnatal microcephaly, may be the result of such infections occurring late in pregnancy.”

Dr. Zarrillo concluded, “Zika infection during pregnancy can affect brain growth, as measured by the head circumference, even in the presence of normal sonographic imaging. This effect over the growth of the brain is not manifested in other biometric measures such as the femur or abdomen. The significance of such growth patterns on the infant’s future neurologic development is uncertain but definitively worrisome.”

DISCLOSURES

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SOURCE

First International Conference on Zika Virus

PRESENTATION

Session 6: Pregnancy and the Fetus

Head Growth Patterns Among Structurally Normal Fetuses with Symptomatic Zika Viral Infection During Pregnancy in Puerto Rico