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Fetal Safety of Dydrogesterone Exposure in the First Trimester of Pregnancy

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Abstract

Background

The progestin dydrogesterone (DYD) is widely used for threatened and recurrent miscarriages, as well as for dysfunctional bleeding, infertility and other obstetric and gynecological indications. While its apparent efficacy has been compared to other progestins, its fetal safety has been only sparsely investigated.

Objectives

To follow up fetal outcome after gestational exposure to DYD and compare it to a non-exposed comparison group.

Objectives

To follow up fetal outcome after gestational exposure to DYD and compare it to a non-exposed comparison group.

Patients and methods

Using the 2.5 million patient database of Maccabi Health Services, we compared rates of congenital malformations among babies exposed in utero during the first trimester of pregnancy to DYD between Jan 1999 and December 2016, to a comparison group not receiving this medication. From the DYD group we excluded all cases with concomitant exposure to in vitro fertilization (IVF) and other forms of assisted reproductive technology (ART).

Results

There were 8508 children exposed to DYD during the first trimester of pregnancy (4417 males, 4091 females) out of 777,422 cases in the database. After excluding from the DYD group cases with concomitant exposure to IVF and other ART, DYD exposure was associated with increased risk for hypospadias [OR 1.28 (95% confidence interval 1.06–1.55)], for overall cardiovascular malformations [OR 1.18 (91.06–1.33)], spina bifida [OR 2.29 (1.32–3.97)] and hydrocephalus [OR 2.04 (1.28–3.25)]. In a sensitivity analysis, including also cases exposed to IVF and ART in addition to DYD, there were also increased risks for cryptorchidism [1.37 (1.19–1.58)] and congenital dislocation of the hip [OR 1.58 (1.42–1.78)].

Conclusions

DYD confers teratogenic effects after exposure to the recommended doses in pregnant women. The risks of hypospadias and cryptorchidism have biological plausibility by the known effects on male genitalia, as is the risk for spina bifida, by the proven decrease in folic acid levels. Some of these adverse fetal effects appear to be further augmented by concomitant use of IVF and ART.

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Change history

  • 08 January 2020

    The Editor-in-Chief of Clinical Drug Investigation has become aware that the original article contains a number of errors and inconsistencies.

  • 08 January 2020

    The Editor-in-Chief of Clinical Drug Investigation has become aware that the original article contains a number of errors and inconsistencies.

  • 08 January 2020

    The Editor-in-Chief of Clinical Drug Investigation has become aware that the original article contains a number of errors and inconsistencies.

  • 08 January 2020

    The Editor-in-Chief of Clinical Drug Investigation has become aware that the original article contains a number of errors and inconsistencies.

  • 08 January 2020

    The Editor-in-Chief of Clinical Drug Investigation has become aware that the original article contains a number of errors and inconsistencies.

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Author information

Correspondence to Gideon Koren.

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Funding

No source of funding.

Conflicts of interest

None of the authors have a conflict of interest to declare.

Ethics approval

The study was approved by Assuta Hospital Research ethics committee, Tel Aviv.

Informed consent

Being an anonymous database research, informed consent was waivered.

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Koren, G., Gilboa, D. & Katz, R. Fetal Safety of Dydrogesterone Exposure in the First Trimester of Pregnancy. Clin Drug Investig (2019) doi:10.1007/s40261-019-00862-w

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