While first discovered in the African country of Uganda in 1947, Zika virus, carried by mosquitos and endemic in many tropical areas of the Americas, Asia and Africa was not well understood until its recent outbreaks in South America in 2015 and 2016 [2]. In adults, the virus causes mild symptoms including fever, rash, headache, joint and muscle pain and red eyes, however in many cases it is asymptomatic [6]. During the 2015 outbreak in Brazil, Zika brought great fear because little was known about its effects on the developing fetus and risk of microcephaly [3]. Microcephaly is a malformation making the perimeter of a developing fetus’s head smaller than normal, which can also lead to epilepsy and vision problems [6]. Between October 2015 and January 2016, approximately 4,000 babies were born with microcephaly in Brazil [1]. By June 2016, the World Health Organization (WHO) recommended people in affected areas to delay getting pregnant to avoid birth risks and defects [1].
Zika virus is now known for its cause of brain abnormalities in babies exposed in utero, called congenital Zika syndrome [6]. Microcephaly is the best known birth defect, but cases of it represent only a small proportion of children affected by the virus [4]. The disease can cause a series of complications during pregnancy besides microcephaly, including calcium deposits in the brain indicating brain damage, excess fluid in brain cavities and surrounding the brain, absent or poorly formed brain structures, abnormal eye development, hearing loss, and damage to the brain that affects the nerves, muscles or bones, such as clubfoot or inflexible joints [5]. The virus poses the greatest risks to the fetus early in the pregnancy and can even result in miscarriage [4]. It has been shown that the virus is able cross the placenta, which provides blood flow and nutrients to the fetus; damage to the placenta can lead to growth restriction and poor outcomes, either fetal growth restriction or fetal death [2].
According to more recent studies, the Zika virus’s ability to cause miscarriage poses a much greater threat to pregnancy than previously thought [2]. Researchers in Sao Paulo say that not only do women infected with Zika have higher rates of miscarriage, but also that Zika may be more likely to produce miscarriages than microcephaly [3]. Studies showed that in a sample of 125 women, Zika infections were linked to 10%-15% increased likelihood of miscarriage [1]. Another study in pregnant women showed that among infected women, 5% did not lead to full term pregnancy or had stillborn children [6], compared to 0.2% in non-infected women [3].
When Zika first appeared in Brazil in 2015, symptoms were mild and the outbreak was not of serious concern until months later, when babies began being born with abnormally small heads [3]. However, data from Brazil in 2016 suggests the country was also experiencing fewer live births around the same time [1]. Although Brazil’s decrease in birth rates could have been due to family planning, miscarriages from Zika infection could also have been to blame. It is hypothesized that Zika may have caused very early miscarriages in women before they even knew they were pregnant. It is possible that an increase of miscarriages was missed in the first wave of the Zika outbreaks due to women being asymptomatic or not knowing they were pregnant or had a miscarriage; all before Zika and its effects were brought to the public’s attention [3]. In fact, researchers later found a correlation between the drop in birth rates and the number of Zika cases recorded 40 weeks prior – 40 weeks being the average duration of a pregnancy [1].
In 2016, almost half of pregnant women infected with Zika in Rio de Janeiro experienced a serious complication such as a miscarriage or birth defect [4]. One study found that among women who were infected by the virus in their third trimester, 29% developed complications that affected their babies. In another study conducted by the Oswaldo Cruz Foundation in Rio de Janeiro, 55% of women infected in the first trimester experienced adverse outcomes that included miscarriage, calcifications in baby’s brain, microcephaly, and brain hemorrhages. Among women infected in the second trimester, 51% experienced the aforementioned adverse outcomes. Overall, of the infected pregnant women, 46% were affected, with 3.4% specifically experiencing cases of microcephaly in their infants. This indicates a very high risk of poor birth outcomes for infected pregnant women. Among women who did not test positive for Zika virus, only 11.5% had any adverse outcome [4].
While these statistics may be startling, it may still not be representative of the true proportion of affected cases in Brazil or South America. Babies who appear healthy and normal at birth may have brain damage and not show symptoms until they grow older [4]. Additionally, previous research on Zika only measured the number of miscarriages and stillbirths in women who showed signs/symptoms of infection [6]. Researchers know that about half of people who have Zika do not present with any symptoms, therefore, studies on pregnancy may not be taking into account a large percentage of infected people. It is also difficult to perform human studies that are representative of true rates of miscarriage because Brazil lacks strong public health surveillance systems. Women may also be underreporting miscarriages because they may not know they are pregnant or choose not to report their miscarriage for cultural or personal reasons, particularly due to the resemblance to induced abortions, which are still illegal in Brazil [3].
Studies in primates have shed some light on the mechanism of the virus as well as more plausible rates of miscarriage in Brazilian women infected with Zika. A study from California National Primate Research Center (CNPRC) collected data from various individual studies looking at Zika and vaccines, the virus’s effect on the placenta and pregnancy, and its progression in different monkey species [2]. Experiments showed that 26% of primates infected with Zika early during pregnancy, most of which were asymptomatic, suffered miscarriages or had stillborn young [6]. These rates are four times higher than those normally observed in non-infected monkeys. These studies are also evidence of pathological lesions in fetal and placental tissues causing fetal death. A lead author of the study expects the true rate of human miscarriages to be less than 26%, but still higher than what previous human studies have shown [2]. The advantage to research at NPRC labs is the ability to control timing and methods of infection in primates, which cannot be imitated in humans. Studies on Zika’s effect on pregnancy and birth outcomes in humans are very limiting and may underestimate true rates because it is difficult to identify asymptomatic cases, or identify women who themselves do not know are pregnant. Researchers studying primates found that the Zika virus infection (using strains from recent Asian and American outbreaks) affected the tissues connecting the mother to the developing monkey fetus, causing damage to the placenta, and cell death [2].
Studies both in humans and in primates provide important information to better understand the pregnancy and birth consequences caused by viruses such as Zika. Their data are essential both in identifying the source and mechanisms causing negative birth outcomes as well as in aiding in the prevention of maternal mortality around the world.
Sources:
[1] Baranuik, Chris. “Zika Outbreak May Have Led to Fewer Births in Rio De Janeiro.” New Scientist, New Scientist, 24 Apr. 2017, www.newscientist.com/article/2128642-zika-outbreak-may-have-led-to-fewer-births-in-rio-de-janeiro/.
[2] Barncard, Chris. “Zika Virus Infection May Multiply Risk of Miscarriage, Stillbirth.” News, University of Wisconsin-Madison, 2 July 2018, news.wisc.edu/zika-virus-infection-may-multiply-risk-of-miscarriage-stillbirth/.
[3] Beaubien, Jason. “Did Zika Cause More Miscarriages Than Microcephaly?” NPR, NPR, 10 Nov. 2017, www.npr.org/sections/goatsandsoda/2017/11/10/563364000/did-zika-cause-more-miscarriages-than-microcephaly.
[4] Vogel, Gretchen. “First Hard Look at Zika Pregnancies Finds Nearly Half Result in Miscarriage or Birth Defects.” Science | AAAS, American Association for the Advancement of Science, 13 Dec. 2016, www.sciencemag.org/news/2016/12/first-hard-look-zika-pregnancies-finds-nearly-half-result-miscarriage-or-birth-defects.
[5] “Zika and Pregnancy.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 26 June 2018, www.cdc.gov/pregnancy/zika/data/pregnancy-outcomes.html.
[6] “Zika Causes More Abortions than Doctors Thought, Research Shows.” O Globo, gda, 2 July 2018, oglobo.globo.com/sociedade/saude/zika-causa-mais-abortos-do-que-medicos-pensavam-mostra-pesquisa-22843698.
