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clinical implications of basic r esearch

Th e n e w e n g l a n d j o u r n a l o f medicine

Elizabeth G. Phimister, Ph.D., Editor

n engl j med 370;26 nejm.org june 26, 20142534

Cell-free Fetal DNA A Trigger for ParturitionMark Phillippe, M.D.

For decades, researchers have unsuccessfullysought to understand the mechanisms underly-ing the onset of parturition. The apparent varia-tion in mechanisms between other mammals andhumans has further confounded these efforts.And yet, it does not make sense that an event soessential for successful reproduction and thepropagation of evolutionarily related specieswould have radically diverged in signaling mech-

anisms. Multiple lines of evidence now suggestthat an inf lammatory process is involved in trig-gering parturition, a process that is modulatedand influenced by maternal, fetal, and placentalendocrine events. However, another importantfactor may be cell-free fetal DNA.

In 1998, Lo et al.1 observed cell-free fetalDNA in maternal plasma at concentrations of3.4 to 6.2% of the total cell-free DNA in plasma,along with a dramatic increase in levels of cell-free fetal DNA between early and late gestation.Subsequent studies have shown that cell-freefetal DNA is derived from placental trophoblastsas they undergo cellular apoptosis and necrosis.Others studies have documented an increase by afactor of 12 in cell-free fetal DNA levels through-out gestation, with levels peaking at the end ofpregnancy,2and an inverse correlation betweencell-free fetal DNA levels and the interval be-tween blood collection and birth.3

Confirming the relationship between increasedlevels of cell-free fetal DNA and parturition is theobservation that pregnant women who deliver

prematurely were found to have twice the levelsof cell-free fetal DNA as compared with womenin a control group or those with threatened pre-term labor.4 Other studies have shown thatlevels of cell-free fetal DNA above the 95th per-centile are associated with increased rates ofpreterm delivery. Notably, levels of cell-freefetal DNA have been reported to be 30% higherin twin gestations; such increases could be re-sponsible for the shortened gestational lengthin multifetal pregnancies.

The presence of cell-free fetal DNA derivedfrom fetal or placental sources is not unique tohuman pregnancies, since cell-free fetal DNAhas also been detected in the plasma of preg-nant mice, cows, horses, sheep, and primates.In mice and macaques, levels of cell-free fetalDNA have been reported to increase markedlyduring late gestation and then drop to undetect-able levels after birth.5,6

The association between elevated levels of cell-free fetal DNA and parturition is interesting,but how might these observations be mechanis-tically linked? The pattern-recognition receptorTLR9, which is activated by free-circulatinghypomethylated DNA, is an excellent candidatelinker. TLR9 agonists have induced preterm de-liveries when injected into pregnant mice. FetalDNA injected into pregnant mice produces ges-tational losses (resorptions), which do not occurwhen adult DNA is used or when TLR9-deficientmice are injected with fetal DNA.7

Multiple previous studies have provided com-pelling support for the premise that spontane-ous parturition is mediated by the activation ofinflammation-related signaling pathways, lead-ing to the increased secretion of proinflamma-tory cytokines and chemokines, the influx ofneutrophils and macrophages into the pregnantuterus, and increased production of uterine-acti-vation proteins, including the oxytocin receptor,prostaglandin F receptor, and connexin 43. Theseevents also stimulate the activity of matrix metal-

loproteinases and the release of uterotonins,leading to cervical ripening, membrane rupture,and phasic myometrial contractions.

The missing link has been the fetal or pla-cental signal that triggers these proinflamma-tory events in the absence of microbial invasionand intrauterine infection. In aggregate, severalstudies provide solid support for the hypothesisthat increased levels of cell-free fetal DNA, whichare released during placental maturation orsenescence and peak at the end of gestation, ac-

The New England Journal of Medicine

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n engl j med 370;26 nejm.org june 26, 2014 2535

clinical implications of basic research

Mature placenta

Myometrium

Decidua

Pooledmaternal

blood

Umbilical arteriesand vein

Chorion

Maternal veinand artery

Placental maturation and senescence ofplacental trophoblast cells

Increased cell-free fetal DNA inmaternal plasma

TLR9activation

Leukocyte Macrophage

Cervical

ripening

Membrane

rupture

Phasic uterine

contractions

Parturition

Term gestation

Increased proinflammatory

cytokines and chemokines

Innate immune response by thechorion, decidua, myometrium,

and cervix

Increased uterine-activation proteinexpression by the chorion, decidua,

myometrium, and cervix

:i

l ll

l

I

l

ll l

Figure 1.Proposed Signaling Pathway Leading from Placental Production of Cell-free Fetal DNA to Parturition.

Several studies have suggested that levels of cell-free fetal DNA increase during placental maturation and peak at the end of gestation,

activating the innate immune system through stimulation of TLR9 (or another DNA-sensing pattern-recognition receptor). This activitytriggers an innate immune response and the production of uterine-activation proteins, resulting in cervical ripening, rupture of the fetal

membranes, and phasic myometrial contractions and leading to parturition.





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n engl j med 370;26 nejm.org june 26, 20142536

clinical implications of basic research

tivate the innate immune system through stimu-lation of TLR9 (or another DNA-sensing pattern-recognition receptor), leading to parturition(Fig. 1). If the hypothesis is true, this mechanismis potentially responsible for triggering the onsetof parturition in all mammals.

Disclosure forms provided by the author are available with the

full text of this article at NEJM.org.

From the Vincent Center for Reproductive Biology, Departmentof Obstetrics and Gynecology, Massachusetts General Hospital,Boston.

This article was updated on June 26, 2014, at NEJM.org.

1. Lo YM, Tein MS, Lau TK, et al. Quantitative analysis of fetalDNA in maternal plasma and serum: implications for noninva-sive prenatal diagnosis. Am J Hum Genet 1998;62:768-75.2. Birch L, English CA, ODonoghue K, Barigye O, Fisk NM,Keer JT. Accurate and robust quantification of circulating fetaland total DNA in maternal plasma from 5 to 41 weeks of gesta-tion. Clin Chem 2005;51:312-20.

3. Majer S, Bauer M, Magnet E, et al. Maternal urine for prena-tal diagnosis an analysis of cell-free fetal DNA in maternalurine and plasma in the third trimester. Prenat Diagn 2007;27:1219-23.4. Leung TN, Zhang J, Lau TK, Hjelm NM, Lo YM. Maternalplasma fetal DNA as a marker for preterm labour. Lancet 1998;352:1904-5. [Erratum, Lancet 1999;354:780.]5. Khosrotehrani K, Wataganara T, Bianchi DW, Johnson KL.Fetal cell-free DNA circulates in the plasma of pregnant mice:

relevance for animal models of fetomaternal trafficking. HumReprod 2004;19:2460-4.6. Mitsunaga F, Ueiwa M, Kamanaka Y, Morimoto M, Naka-mura S. Fetal sex determination of macaque monkeys by a nest-ed PCR using maternal plasma. Exp Anim 2010;59:255-60.7. Scharfe-Nugent A, Corr SC, Carpenter SB, et al. TLR9 pro-vokes inf lammation in response to fet al DNA: mechanism forfetal loss in preterm birth and preeclampsia. J Immunol 2012;188:5706-12.

DOI: 10.1056/NEJMcibr1404324

Copyright 2014 Massachusetts Medical Society.




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