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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Developmental Biology - Birth Complications

Placenta Accreta

How 'natural-killer' cells might help women avoid a deadly risk in childbirth...

One of the most dangerous risks expectant moms face as delivery approaches is a surprisingly common condition with a little-known name: placenta accreta.

In normal childbirth, the placenta sustains fetal development during pregnancy and is delivered shortly after the baby. Sometimes, however, the placenta is so deeply attached to a woman's uterus it can't be removed without causing massive, sometimes fatal bleeding. In many cases, an emergency hysterectomy to save the mother's life leaves her unable to have more children.

And yet, many women don't know about placenta accreta, even though the number of women suffering through it has quadrupled since the 1980s. Today one of every 272 births experiences placenta accreta. While the increase is associated with a rise in c-section rate, accreta risk increases if a woman has any uterine scarring, such as that left by caesarean sections, surgeries to remove uterine fibroids, or dilation and curettage (D&C) procedures used to empty the uterus after a miscarriage or abortion.

"I had never heard the word accreta until it happened to me, and I barely survived," explains Kristen Terlizzi, who founded the California-based National Accreta Foundation in 2017. "A reliable biomarker to detect this would be incredible. And if there ever were a way to proactively treat accreta, that would be enormous." That day may have moved a step closer thanks to a discovery made through research out of the Cincinnati Children's Hospital and the University of Cincinnati in Ohio. The study published Aug. 2, 2019, in Science Immunology.
The authors made a surprising connection between accreta risk and a gene mutation preventing healthy formation of "natural killer" cells. These are white blood cells that help fight cancers and viral infection. Their appearance, demonstrated in mice, suggests accreta can be stopped.

"This is a huge issue for maternal health. Currently, the only way to diagnose accreta is to spot it mid-pregnancy on ultrasound, usually past 18 to 20 weeks. Many women [and their physicians] never know they have it until they arrive at the hospital for labor and delivery," says Helen Jones PhD in the departments of General Pediatric and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, and study co-author.

According to Jones, if future studies confirm that women facing accreta also have malfunctioning NK cells, it may be possible to prevent over-attachment and reduce the need for fertility-ending hysterectomies.

Connecting Accreta to Malfunctioning NK Cells

This new finding traces back to a basic-science project led by Kasper Hoebe PhD also at Cincinnati Children's. His team was searching for gene mutations that can affect NK cells, when one of his graduate students, Anna Sliz, encountered a problem.

"In one of our colonies, we observed an abnormally high frequency of breeding dams [female mice] having unsuccessful pregnancies. When I attempted to culture NK cells from these mice, I tended to have a lower yield compared to my wild-type [normal] control animals," explained Sliz.

Hoebe and Sliz consulted with Jones, who rapidly recognized that pregnant female mice were experiencing retained placentas with significant trophoblast cell invasion. Trophoblast cells form the outer layer of a blastocyst, and provide nutrients to the early embryo and later develop into the placenta. Although human accreta is rarely seen in mice, the observation prompted a new investigation.
Soon, the collaborators discovered these mice carry a mutation in a protein called Gab3, that prevents normal NK cells expansion in the uterus. Disrupting NK cells turns off a growing embryo'sattachment to tissues inside the uterus.

This process is called the trophoblast invasion, and normally continues throughout 20 weeks of pregnancy. In women with accreta, however, the invasion process continues for much longer.

"For normal placental development, the growth of fetal cells must be held in check by NK cells. Our study shows that in the absence of Gab3, placenta NK cell function is impaired, leading to an over growth of fetal cells into the uterus," explains Hoebe.

The Impact On Pregnancy

Much more work must be done before human testing can begin. Although NK cells have been transplanted to treat people with certain cancers, impact on a pregnancy is unknown. "We are working now on an international collaboration to try to work this out," explains Jones.

For now, these findings serve as a caution on C-sections. Previous studies have shown that accreta risk rises sharply with multiple C-sections.

The scaffolding protein Grb2-associated binding protein 3 (Gab3) is a member of the Gab family, whose functions have remained elusive. Here, we identify Gab3 as a key determinant of peripheral NK cell expansion. Loss of Gab3 resulted in impaired IL-2 and IL-15–induced NK cell priming and expansion due to a selective impairment in MAPK signaling but not STAT5 signaling. In vivo, we found that Gab3 is required for recognition and elimination of “missing-self” and tumor targets. Unexpectedly, our studies also revealed that Gab3 plays an important role during pregnancy. Gab3-deficient mice exhibited impaired uterine NK cell expansion associated with abnormal spiral artery remodeling and increased trophoblast invasion in the decidua basalis. This coincided with stillbirth, retained placenta, maternal hemorrhage, and undelivered fetoplacental units at term. Thus, Gab3 is a key component required for cytokine-mediated NK cell priming and expansion that is essential for antitumor responses and limits trophoblast cell invasion during pregnancy.

Anna Sliz, Kathryn C. S. Locker, Kristin Lampe, Alzbeta Godarova, David R. Plas, Edith M. Janssen, Helen Jones, Andrew B. Herr and Kasper Hoebe.

The authors thank M. Kofron for excellent support in conducting confocal imaging and microscopy studies. We also thank the staff of the CCHMC Core facilities including the research flow cytometry core, the Transgenic Animal and Genome Editing Core, and the pathology research core for providing exceptional technical support. We thank the Veterinary Services Core at CCHMC for their excellent animal care, and last, we thank the Genomics, Epigenomics and Sequencing Core at the University of Cincinnati for support in the RNA-seq studies.

The research was funded by NIH grant P30 DK078392 (Integrative Morphology Core of the Cincinnati Digestive Disease Research Core Center), NIH grant R21 AI135380, and the Maren Foundation.

Author Contributions
A.S. performed and designed experiments, analyzed the data, and contributed in writing. K.C.S.L., K.L., and A.G. performed experiments. D.R.P., E.M.J., H.J., and A.B.H. helped with the experimental design and data analyses, and K.H. was involved in experimental design, data analyses, and writing of the manuscript.

Competing Interests
A.B.H. serves as a Scientific Advisory Board member for Hoth Therapeutics Inc. and has equity interests in Hoth Therapeutics Inc. and Chelexa BioSciences LLC. The other authors declare that they have no competing interests.

Data & Materials Availability
The RNA-seq data is available from the Gene Expression Omnibus under accession number GSE133313. The Gab3 mutant mouse strains and the Gab3-GFP fusion proteins are available through a material transfer agreement with the Cincinnati Children’s Hospital Medical Center. Requests for mice should be directed to H.J., and requests for the fusion proteins should be directed to A.B.H. All other data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.

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Aug 12 2019   Fetal Timeline   Maternal Timeline   News  

There are 3 errors of placental attaachment: (1) Placenta Accreta is the most common error of attachment (2) Placenta Increta or invasion attachment deeply into uterine wall and (3) Placenta Percreta or perforation by the placenta into the bladder.
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