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Ibuprofen early in pregnancy reduces fetal eggs

Ibuprofen taken in the first 24 weeks of pregnancy may reduce fertility of unborn daughters...


Taking the pain killer ibuprofen in the first 24 weeks of pregnancy may be reducing the number of eggs in the ovaries of those women's daughters.

In the first study to look at the effects of ibuprofen on the ovarian tissue of baby girls, researchers found exposure to ibuprofen in the crucial first stages of human development causes a dramatic loss of the germ cells destined to become female eggs. Germ cells either died or failed to grow and multiply at their usual rate.
Ibuprofen crosses the placental barrier.

The study is published in the journal Human Reproduction.

According to Séverine Mazaud-Guittot MD, of INSERM in Rennes, France, study leader: "Baby girls are born with a finite number of follicles in their ovaries which defines their future reproductive capacity as adults. A poorly stocked initial reserve will result in a shortened reproductive life span, early menopause or infertility - all events that occur decades later in life.

Around 30% of pregnant women use ibuprofen in the first three months, or first trimester, of pregnancy. But, it is not recommended after the first semester as it is known to increase risks for fetal malformation.
The research found 2 to 7 days exposure to ibuprofen dramatically reduced germ cell reserves in human fetal ovaries in the first trimester — and germ cells did not recover from the damage.

Dr Mazaud-Guittot: "This suggests that prolonged exposure to ibuprofen during fetal life may lead to long-term effects on women's fertility and raises concern about ibuprofen consumption by women during the first 24 weeks of pregnancy."

"The concentration found in the umbilical cords of fetuses from mothers who ingested 800 mg (four pills of 200 mg) two to four hours before surgery [abortion selected by the mothers] is similar to concentrations found in adult's blood. In simple terms, the fetus is exposed to the same concentration as the mother," said Dr Mazaud-Guittot.
Fetal tissue exposed to concentrations of 10 micromolar of ibuprofen for a week had approximately half the number of ovarian germ cells of fetal tissue not exposed.

There were significant effects after seven days of exposure to 10 micromolars of ibuprofen, and germ cell death as early as two days afterwards. Five days after stopping ibuprofen, harmful effects did not reverse.

Dr Mazaud-Guittot: "The implications of our findings are that, just as with any drug, ibuprofen use should be restricted to the shortest duration and at the lowest dose necessary to achieve pain or fever relief, especially during pregnancy. The wisest advice would be to follow currently accepted recommendations: paracetamol [also known as acetaminophen or APAP] should be preferred to any anti-inflammatory drug up to 24 gestational weeks, and ... not be used thereafter. However, practitioners, midwifes and obstetricians are best placed to give expert advice: every mother and every pregnancy is unique."
In January, the French drug agency ANSM declared that all nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are contraindicated from the 6th month of pregnancy due to their (kidney and cardiopulmonary) toxicity to the fetus or newborn of either sex.

More work needs to be carried out to discover what cellular mechanisms in human ovaries are being affected by ibuprofen and alternative painkillers. The researchers also want research to be conducted in living tissue, a model animal system, over an entire pregnancy to see the long-term effect of these drugs on the ovary.

Abstract
STUDY QUESTION
Does ibuprofen use during the first trimester of pregnancy interfere with the development of the human fetal ovary?

SUMMARY ANSWER
In human fetuses, ibuprofen exposure is deleterious for ovarian germ cells.

WHAT IS KNOWN ALREADY
In utero stages of ovarian development define the future reproductive capacity of a woman. In rodents, analgesics can impair the development of the fetal ovary leading to early onset of fertility failure. Ibuprofen, which is available over-the-counter, has been reported as a frequently consumed medication during pregnancy, especially during the first trimester when the ovarian germ cells undergo crucial steps of proliferation and differentiation.

STUDY DESIGN, SIZE, DURATION
Organotypic cultures of human ovaries obtained from 7 to 12 developmental week (DW) fetuses were exposed to ibuprofen at 1–100 ?M for 2, 4 or 7 days. For each individual, a control culture (vehicle) was included and compared to its treated counterpart. A total of 185 individual samples were included.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Ovarian explants were analyzed by flow cytometry, immunohistochemistry and quantitative PCR. Endpoints focused on ovarian cell number, cell death, proliferation and germ cell complement. To analyze the possible range of exposure, ibuprofen was measured in the umbilical cord blood from the women exposed or not to ibuprofen prior to termination of pregnancy.

MAIN RESULTS AND THE ROLE OF CHANCE
Human ovarian explants exposed to 10 and 100 ?M ibuprofen showed reduced cell number, less proliferating cells, increased apoptosis and a dramatic loss of germ cell number, regardless of the gestational age of the fetus. Significant effects were observed after 7 days of exposure to 10 ?M ibuprofen. At this concentration, apoptosis was observed as early as 2 days of treatment, along with a decrease in M2A-positive germ cell number. These deleterious effects of ibuprofen were not fully rescued after 5 days of drug withdrawal.

LARGE SCALE DATA — N/A.

LIMITATIONS, REASONS FOR CAUTION
This study was performed in an experimental setting of human ovaries explants exposed to the drug in culture, which may not fully recapitulate the complexity of in vivo exposure and organ development. Inter-individual variability is also to be taken into account.

WIDER IMPLICATIONS OF THE FINDINGS
Whereas ibuprofen is currently only contra-indicated after 24 weeks of pregnancy, our results points to a deleterious effect of this drug on first trimester fetal ovaries ex vivo. These findings deserve to be considered in light of the present recommendations about ibuprofen consumption pregnancy, and reveal the urgent need for further investigations on the cellular and molecular mechanisms that underlie the effect of ibuprofen on fetal ovary development.

Key Words: ovary, ibuprofen, oogonia, apoptosis, necrosis, cell proliferation, TP53

A micromolar corresponds to a one millionth molecular weight unit per litre.

Authors: S Leverrier-Penna, R T Mitchell, E Becker, L Lecante, M Ben Maamar, N Homer, V Lavoué, D M Kristensen, N Dejucq-Rainsford, B Jégou, S Mazaud-Guittot.


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Feb 14, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Ibuprofen by other brand names: Advil, Motrin, PediaCare Children's Pain Reliever/Fever Reducer IB, PediaCare Infant's Pain Reliever/Fever Reducer IB. Image credit: Google search


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