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Insights into fetal death—a patient resource

Published:March 19, 2022DOI:https://doi.org/10.1016/j.ajog.2022.02.029
      Evidence supports a role for placental aging in the etiology of the majority of fetal deaths. This knowledge may reduce maternal feelings of guilt following fetal death that frequently exacerbates the distress caused by grief. The accompanying video may be a useful resource for women who have experienced a fetal death.

      Key words

      Families who experience a fetal death or stillbirth are forever changed. Moreover, some parents exhibit long-lasting sadness and increased rates of marriage breakdown.
      • Turton P.
      • Evans C.
      • Hughes P.
      Long-term psychosocial sequelae of stillbirth: phase II of a nested case-control cohort study.
      ,
      • Gold K.J.
      • Leon I.
      • Boggs M.E.
      • Sen A.
      Depression and posttraumatic stress symptoms after perinatal loss in a population-based sample.
      For women, feelings of guilt or self-blame are a major contributing factor to the long-term consequences of the death of the neonate.
      • Gold K.J.
      • Sen A.
      • Leon I.
      Whose fault is it anyway? Guilt, blame, and death attribution by mothers after stillbirth or infant death.
      Recent work strongly supports placental aging as an etiologic factor in most cases
      • Maiti K.
      • Sultana Z.
      • Aitken R.J.
      • et al.
      Evidence that fetal death is associated with placental aging.
      Supporting this view, a histopathologic study of placentas associated with cases of unexplained intrauterine death at term revealed that 91% of cases showed thickening of the maternal spiral artery walls, 54% of cases contained placental infarcts, 10% of cases had calcified areas, and 13% of cases demonstrated vascular occlusion
      • Amir H.
      • Weintraub A.
      • Aricha-Tamir B.
      • Apel-Sarid L.
      • Holcberg G.
      • Sheiner E.
      A piece in the puzzle of intrauterine fetal death: pathological findings in placentas from term and preterm intrauterine fetal death pregnancies.
      ; in contrast, other studies reported increased atherosclerosis.
      • Labarrere C.A.
      • DiCarlo H.L.
      • Bammerlin E.
      • et al.
      Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.
      Interestingly, all changes were associated with aging in other organs. Further supporting a link between placental aging and stillbirth, telomere length is reduced in placentas associated with stillbirth,
      • Ferrari F.
      • Facchinetti F.
      • Saade G.
      • Menon R.
      Placental telomere shortening in stillbirth: a sign of premature senescence?.
      and fetal growth restriction is also associated with both stillbirth and telomere shortening.
      • Biron-Shental T.
      • Sukenik-Halevy R.
      • Sharon Y.
      • et al.
      Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction.
      To try to alleviate some of the maternal distress, we have created a brief educational video that uses the power of animation to explain that the placenta is an organ of the fetus, not the mother, and how aging of this fetal organ may lead to the death of an otherwise healthy fetus.
      Aging is a difficult concept to define. We can all recognize it in our family members, friends, and colleagues, but defining it is less straightforward. Galileo has written that “the book of nature is written in the language of mathematics” and perhaps the most valuable definition of aging is the one proposed by the actuary Benjamin Gompertz in 1820, indicating that, after achieving sexual maturity, aging is the process whereby the probability of death increases with each point in time.
      • Gompertz B.
      A sketch of an analysis and notation applicable to the estimation of the value of life contigencies.
      This is well illustrated with the Gompertz curve describing the mortality rate against age in the United States (Figure 1). The increasing rate of the probability of death implies the presence of interacting factors that provide initial resilience but progressively fail.
      • Kirkwood T.B.
      Deciphering death: a commentary on Gompertz (1825) ‘On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies.’.
      The shape of the curve illustrates the declining likelihood of death before sexual maturity. This occurs during the period of maturation, which is contrasted with the increasing likelihood of death after maturity is reached. There are parallels in obstetrical demise with a high rate of fetal loss early in gestation, which falls as gestation progresses only to rise in late gestation with increased rates of fetal death observed after maturation of the placenta (Figure 2).
      • Sutan R.
      • Campbell D.
      • Prescott G.J.
      • Smith W.C.
      The risk factors for unexplained antepartum stillbirths in Scotland, 1994 to 2003.
      Although these curves represent an observed empirical reality, the biology that underlies these equations has been more challenging to uncover. However, the increasing rates of fetal death in late gestation imply that a process of aging is implicated, likely in the placenta, which has completed its maturational process, but the fetus has not. Empirically, we know that different individuals age at different rates and some fetal deaths occur earlier in pregnancy, especially in association with growth restriction
      • Gardosi J.
      • Francis A.
      Adverse pregnancy outcome and association with small for gestational age birthweight by customized and population-based percentiles.
      and chromosomal anomalies. As an example, fetal death occurs more often in the presence of trisomy 21.
      • Wapner R.J.
      Genetics of stillbirth.
      Interestingly, individuals with trisomy 21 exhibit progeria,
      • Ishikawa N.
      • Nakamura K.
      • Izumiyama-Shimomura N.
      • et al.
      Changes of telomere status with aging: an update.
      and it seems likely that there is also an increased rate of aging in the placenta. Fetal growth restriction has been linked to markers of senescence
      • Sultana Z.
      • Maiti K.
      • Dedman L.
      • Smith R.
      Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction?.
      and is associated with an increased risk of fetal death.
      Figure thumbnail gr1
      Figure 1Estimated probability of a person dying at each age
      Smith. Insights into fetal death. Am J Obstet Gynecol 2022.
      Figure thumbnail gr2
      Figure 2Risk of explained and unexplained ASB per 1000 continuing pregnancies
      Reproduced with permission from Sutan et al.
      • Sutan R.
      • Campbell D.
      • Prescott G.J.
      • Smith W.C.
      The risk factors for unexplained antepartum stillbirths in Scotland, 1994 to 2003.
      ASB, antepartum stillbirth.
      Smith. Insights into fetal death. Am J Obstet Gynecol 2022.
      Data have recently been provided from several different groups on the biological mechanisms that underlie aging. Chris Proud’s laboratory in South Australia has uncovered evidence that animals with a long life-span translate messenger RNA into protein more slowly and more accurately than those with a shorter life span (Figure 3).
      • Xie J.
      • de Souza Alves V.
      • von der Haar T.
      • et al.
      Regulation of the elongation phase of protein synthesis enhances translation accuracy and modulates lifespan.
      Such carefully constructed proteins are more likely to retain their function for longer, as they are built to last. This process is regulated by the mammalian target of rapamycin (mTOR) complex, which inhibits the eukaryotic elongation factor 2 kinase (eEF2K) that slows the ribosomal process of protein synthesis, allowing more accurate translation. Intriguingly, we observed increased mTOR activity in late gestation placentas, which would be expected to lead to inhibition of eEF2K and faster but less accurate protein synthesis, likely to progress to abnormal protein folding.
      • Maiti K.
      • Sultana Z.
      • Aitken R.J.
      • et al.
      Evidence that fetal death is associated with placental aging.
      Moreover, rapid turnover of protein has been identified by Matsuda et al,
      • Matsuda M.
      • Hayashi H.
      • Garcia-Ojalvo J.
      • et al.
      Species-specific segmentation clock periods are due to differential biochemical reaction speeds.
      as linked to life span, with animals with short life span showing rapid turnover leading to short “clock” processes and slow turnover linked to slow clocks and long life span. In addition, evidence for disturbances in protein turnover exists in the late gestation placenta where we have demonstrated enlarged autophagosomes, the organelles responsible for the degradation of abnormally folded proteins and deteriorating mitochondria. Deteriorating mitochondria produce increased free radicals, which oxidize DNA and increase lipid peroxidation, both of which have been observed in the late gestation placenta and placentas associated with fetal death.
      • Maiti K.
      • Sultana Z.
      • Aitken R.J.
      • et al.
      Evidence that fetal death is associated with placental aging.
      The high ratio of guanosine and cytosine in the telomeres at the ends of the chromosome makes them vulnerable to oxidative damage, and shortening of telomeres has been reported in placentas associated with stillbirth.
      • Ferrari F.
      • Facchinetti F.
      • Saade G.
      • Menon R.
      Placental telomere shortening in stillbirth: a sign of premature senescence?.
      Last, Grunewald et al
      • Grunewald M.
      • Kumar S.
      • Sharife H.
      • et al.
      Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span.
      have linked increased circulating soluble vascular endothelial growth factor receptor 1 (sVEGFr1 or soluble fms-like tyrosine kinase-1) to decreasing vascular perfusion and aging in general. This is an area in which obstetrical research has been at the forefront, with increased circulating sVEGFr1 linked to fetal death in several publications.
      • Romero R.
      • Chaiworapongsa T.
      • Erez O.
      • et al.
      An imbalance between angiogenic and anti-angiogenic factors precedes fetal death in a subset of patients: results of a longitudinal study.
      ,
      • Chaiworapongsa T.
      • Romero R.
      • Kusanovic J.P.
      • et al.
      Unexplained fetal death is associated with increased concentrations of anti-angiogenic factors in amniotic fluid.
      Figure thumbnail gr3
      Figure 3eEF2K controls the accuracy of translation and lifespan
      The inhibition of mTOR leads to the activation of eEF2K, which slows the translation elongation process, resulting in more accurate translation and longer life span
      • Xie J.
      • de Souza Alves V.
      • von der Haar T.
      • et al.
      Regulation of the elongation phase of protein synthesis enhances translation accuracy and modulates lifespan.
      eEF2K, eukaryotic elongation factor 2 kinase; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1.
      Smith. Insights into fetal death. Am J Obstet Gynecol 2022.
      The biology of aging is finally catching up with the empirical observations of Gompertz, potentially allowing the development of assays to predict fetal death and, perhaps in the future, to delay placental aging. In the meantime, making this new knowledge available to families who have experienced stillbirth may provide some explanation for their pain and reduce the likelihood that inappropriate guilt exacerbates maternal distress.
      eEF2K: eukaryotic elongation factor 2 kinase
      mTOR: mammalian target of rapamycin complex
      sVEGFr1: soluble vascular endothelial growth factor receptor 1

      Supplementary Data

      References

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