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      Forever Connected: The Lifelong Biological Consequences of Fetomaternal and Maternofetal Microchimerism

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          Abstract

          Background

          Originally studied as a mechanism to understand eclampsia-related deaths during pregnancy, fetal cells in maternal blood have more recently garnered attention as a noninvasive source of fetal material for prenatal testing. In the 21st century, however, intact fetal cells have been largely supplanted by circulating cell-free placental DNA for aneuploidy screening. Instead, interest has pivoted to the ways in which fetal cells influence maternal biology. In parallel, an increasing appreciation of the consequences of maternal cells in the developing fetus has occurred.

          Content

          In this review, we highlight the potential clinical applications and functional consequences of the bidirectional trafficking of intact cells between a pregnant woman and her fetus. Fetal cells play a potential role in the pathogenesis of maternal disease and tissue repair. Maternal cells play an essential role in educating the fetal immune system and as a factor in transplant acceptance. Naturally occurring maternal microchimerism is also being explored as a source of hematopoietic stem cells for transplant in fetal hematopoietic disorders.

          Summary

          Future investigations in humans need to include complete pregnancy histories to understand maternal health and transplant success or failure. Animal models are useful to understand the mechanisms underlying fetal wound healing and/or repair associated with maternal injury and inflammation. The lifelong consequences of the exchange of cells between a mother and her child are profound and have many applications in development, health, and disease. This intricate exchange of genetically foreign cells creates a permanent connection that contributes to the survival of both individuals.

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          Most cited references137

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          Epidemiology and causes of preterm birth

          Summary This paper is the first in a three-part series on preterm birth, which is the leading cause of perinatal morbidity and mortality in developed countries. Infants are born preterm at less than 37 weeks' gestational age after: (1) spontaneous labour with intact membranes, (2) preterm premature rupture of the membranes (PPROM), and (3) labour induction or caesarean delivery for maternal or fetal indications. The frequency of preterm births is about 12–13% in the USA and 5–9% in many other developed countries; however, the rate of preterm birth has increased in many locations, predominantly because of increasing indicated preterm births and preterm delivery of artificially conceived multiple pregnancies. Common reasons for indicated preterm births include pre-eclampsia or eclampsia, and intrauterine growth restriction. Births that follow spontaneous preterm labour and PPROM—together called spontaneous preterm births—are regarded as a syndrome resulting from multiple causes, including infection or inflammation, vascular disease, and uterine overdistension. Risk factors for spontaneous preterm births include a previous preterm birth, black race, periodontal disease, and low maternal body-mass index. A short cervical length and a raised cervical-vaginal fetal fibronectin concentration are the strongest predictors of spontaneous preterm birth.
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            Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero.

            As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth.
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              Is Open Access

              Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study

              Objective To investigate whether pre-eclampsia is more common in first pregnancies solely because fewer affected women, who presumably have a higher risk of recurrence, go on to have subsequent pregnancies. Design Prospective cohort study. Setting Swedish Medical Birth Register. Participants 763 795 primiparous mothers who had their first births in Sweden, 1987-2004. Main outcome measures Pre-eclampsia. Results The risk of pre-eclampsia was 4.1% in the first pregnancy and 1.7% in later pregnancies overall. However, the risk was 14.7% in the second pregnancy for women who had had pre-eclampsia in their first pregnancy and 31.9% for women who had had pre-eclampsia in the previous two pregnancies. The risk for multiparous women without a history of pre-eclampsia was around 1%. The incidence of pre-eclampsia associated with delivery before 34 weeks’ gestation was 0.42% in primiparous women, 0.11% in multiparous women without a history of pre-eclampsia, and 6.8% and 12.5% in women who had had one or two previous pregnancies affected, respectively. The proportion of women who went on to have a further pregnancy was 4-5% lower after having a pregnancy with any pre-eclampsia but over 10% lower if pre-eclampsia was associated with very preterm delivery. The estimated risk of pre-eclampsia in parous women did not change with standardisation for pregnancy rates. Conclusions Having pre-eclampsia in one pregnancy is a poor predictor of subsequent pregnancy but a strong predictor for recurrence of pre-eclampsia in future gestations. The lower overall risk of pre-eclampsia among parous women was not explained by fewer conceptions among women who had had pre-eclampsia in a previous gestation. Early onset pre-eclampsia might be associated with a reduced likelihood of a future pregnancy and with more recurrences than late onset pre-eclampsia when there are further pregnancies. Findings are consistent with the existence of two distinct conditions: a severe recurrent early onset type affected by chronic factors, genetic or environmental, and a milder sporadic form affected by transient factors.
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                Author and article information

                Journal
                Clinical Chemistry
                Oxford University Press (OUP)
                0009-9147
                1530-8561
                January 08 2021
                January 08 2021
                Affiliations
                [1 ]National Human Genome Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
                [2 ]Experimental Dermatology Group, The University of Queensland, UQ Diamantina Institute, Brisbane, Queensland, Australia
                [3 ]Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
                [4 ]Center for Maternal-Fetal Precision Medicine and the Department of Surgery, University of California, San Francisco, CA, USA
                [5 ]Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
                [6 ]Irish Centre for Maternal and Child Health (INFANT), University College Cork, Cork, Ireland
                Article
                10.1093/clinchem/hvaa304
                33417673
                2f4d1bad-2616-4b49-a83f-05d0405d6aad
                © 2021

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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