title: Placental, lipid, and glucidic effects of mammalian target of rapamycin inhibitors: impact on fetal growth and metabolic disorders during pregnancy after solid organ transplantation.
abstract: BACKGROUND
  Mammalian target of rapamycin inhibitors (mTORi) are a promising new family of immunosuppressive drugs. No teratogenic effects have been reported to date. Their lipid and glucidic effects should not be underestimated, however, especially during pregnancy. Moreover, mTORi may affect fetal growth by mTOR placental activity.
  
  
  OBJECTIVE
  Our purpose was to highlight mTORi placental impact and metabolic implications to detect possible maternal or fetal effects and define management guidelines in pregnant women after solid organ transplantation.
  
  
  METHODS
  A literature search was performed for articles from the Medline and Pubmed databases with the use of the following keywords: mTOR inhibitors, pregnancy, placental transport, lipid metabolism, glucose metabolism.
  
  
  RESULTS
  mTOR works as a positive regulator of system A, system L, and taurine placental amino acid transporter activity, which are critical for the transport of amino acids to the fetus. Exposing trophoblast cells to rapamycin reduces system L activity; therefore, treatment with rapamycin in human pregnancies could alter fetal growth with intrauterine growth restriction (IUGR). Regarding the metabolic effects mTORi increase lipolysis, impair insulin's antilipolytic effect and reduce lipid storage, which may potentially contribute to dyslipidemia. Chronic rapamycin treatment reduces adipose tissue size and β-cell mass/function, causes hyperlipidemia, severe insulin resistance, and glucose intolerance, and promotes hepatic gluconeogenesis.
  
  
  CONCLUSIONS
  The studies on mTORi treatment in transplanted pregnant women have not focused to date on the potential metabolic and placental effects. Selection of women at high risk for metabolic disorders could be needed and consideration of switching to another immunosuppressive drug required if diabetes and abnormal blood lipids have been diagnosed in prepregnancy counseling. It seems to be mandatory to encourage prompt reporting of any additional cases of pregnancy during mTORi exposure to provide a better understanding of the placental effects and safety profile of these immunosuppressive drugs.
authors.affiliation: Department of Gynecologic-Obstetrical and Urologic Sciences, University of Rome Sapienza, Rome, Italy. Electronic address: marialuisa.framarino@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Framarino-dei-Malatesta
authors.affiliation: Department of Gynecologic-Obstetrical and Urologic Sciences, University of Rome Sapienza, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Derme
authors.affiliation: Department of Clinical and Molecular Medicine, University of Rome Sapienza, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Napoli
authors.affiliation: General Surgery and Transplant Unit, University of Rome Tor Vergata, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Iaria
authors.affiliation: General Surgery and Transplant Unit, University of Rome Tor Vergata, Rome, Italy.
authors.forename: T M
authors.initials: TM
authors.lastname: Manzia
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: G
authors.initials: G
authors.lastname: Orlando
authors.affiliation: Department of Gynecologic-Obstetrical and Urologic Sciences, University of Rome Sapienza, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Casorelli
authors.affiliation: Department of General Surgery and Transplant "Paride Stefanini", University of Rome Sapienza, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Berloco
mesh_terms: D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008431:Maternal-Fetal Exchange; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D066027:Transplant Recipients
chemical_list: D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D005947:Glucose