Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities.

During its most recent outbreak across the Americas, Zika virus (ZIKV) was surprisingly shown to cause fetal loss and congenital malformations in acutely and chronically infected pregnant women. However, understanding the underlying pathogenesis of ZIKV congenital disease has been hampered by a lack of relevant in vivo experimental models. Here we present a candidate New World monkey model of ZIKV infection in pregnant marmosets that faithfully recapitulates human disease. ZIKV inoculation at the human-equivalent of early gestation caused an asymptomatic seroconversion, induction of type I/II interferon-associated genes and proinflammatory cytokines, and persistent viremia and viruria. Spontaneous pregnancy loss was observed 16-18 days post-infection, with extensive active placental viral replication and fetal neurocellular disorganization similar to that seen in humans. These findings underscore the key role of the placenta as a conduit for fetal infection, and demonstrate the utility of marmosets as a highly relevant model for studying congenital ZIKV disease and pregnancy loss

Publisher Correction: Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities.

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Developmental Origins of Pregnancy Loss in the Adult Female Common Marmoset Monkey (<i>Callithrix jacchus</i>)

<div><p>Background</p><p>The impact of the intrauterine environment on the developmental programming of adult female reproductive success is still poorly understood and potentially underestimated. Litter size variation in a nonhuman primate, the common marmoset monkey (<i>Callithrix jacchus</i>), allows us to model the effects of varying intrauterine environments (e.g. nutrient restriction, exposure to male womb-mates) on the risk of losing fetuses in adulthood. Our previous work has characterized the fetuses of triplet pregnancies as experiencing intrauterine nutritional restriction.</p><p>Methodology/Principal Findings</p><p>We used over a decade of demographic data from the Southwest National Primate Research Center common marmoset colony. We evaluated differences between twin and triplet females in the number of pregnancies they produce and the proportion of those pregnancies that ended in fetal loss. We found that triplet females produced the same number of total offspring as twin females, but lost offspring during pregnancy at a significantly higher rate than did twins (38% vs. 13%, p = 0.02). Regardless of their own birth weight or the sex ratio of the litter the experienced as fetuses, triplet females lost more fetuses than did twins. Females with a male littermate experienced a significant increase in the proportion of stillbirths.</p><p>Conclusions/Significance</p><p>These striking findings anchor pregnancy loss in the mother’s own fetal environment and development, underscoring a "Womb to Womb" view of the lifecourse and the intergenerational consequences of development. This has important translational implications for understanding the large proportion of human stillbirths that are unexplained. Our findings provide strong evidence that a full understanding of mammalian life history and reproductive biology requires a developmental foundation.</p></div

Pregnancy loss in twin and triplet adult females across three tertiles of the females’ own birth weights.

<p>Pregnancy loss in twin and triplet adult females across three tertiles of the females’ own birth weights.</p

Number of fetuses lost by females who had zero vs. one or more male littermates (unpaired T-test).

<p>Number of fetuses lost by females who had zero vs. one or more male littermates (unpaired T-test).</p

Multiple regression models predicting pregnancy loss in adult female marmosets (n = 62).

<p>****<i>p</i>< = 0.0001,</p><p>***<i>p< = </i>0.001,</p><p>**<i>p< = </i>0.01,</p><p>*<i>p< = </i>0.05.</p

Distribution of brothers with whom twin and triplet females shared the womb during their own fetal period.

<p>Distribution of brothers with whom twin and triplet females shared the womb during their own fetal period.</p

Pregnancy loss across all adult females according to number of brothers with whom they shared the womb during their own fetal period.

<p>Pregnancy loss across all adult females according to number of brothers with whom they shared the womb during their own fetal period.</p

Simple regression models predicting pregnancy loss in adult female marmosets (n = 62).

<p>****<i>p</i>< = 0.0001,</p><p>***<i>p< = </i>0.001,</p><p>**<i>p< = </i>0.01,</p><p>*<i>p< = </i>0.05.</p