We particularly appreciate the interest that your authors showed in our study. Regarding the clinical relevance of a mild significant increase of nuchal translucency (NT) in the treatment group, we completely agree and have already underlined in the article that clinical/practical implications were not the objective of our study.

Concerning the high grade of statistical difference of NT in the first weeks, we have already explained in our article the possible mechanism of this finding, stating that it is probably related to an immature fetal cardiac function. However, the presence of a difference that is not statistically significant does not mean that the effect on a fetus that is present at 11 weeks’ gestation will be resolved completely later. Therefore, if we wanted to make a clinical recommendation, it would have regarded discouraging the use of progesterone unless it is really necessary.

Your authors wondered if different routes, formulations, and doses of progestin could alter the correct interpretation of data. We have already explained that (in a subanalysis in which we stratified our sample according to treatment, route, and dosage) no statistically significant differences were found.

Another of your points concerns the declaration that there is extensive evidence concerning the lack of influence of progesterone on NT in assisted reproductive technique pregnancies. However, this issue is still very controversial within the scientific community and is the reason that we decided to exclude the assisted reproductive technique pregnancies in the secondary analysis; in any case in which these pregnancies where excluded, the statistically significant difference remained.

We decided not to take into account the indication in favor of progesterone therapy because there is widespread evidence that NT size increases during miscarriages but not during threatened abortions; the latter is characterized by an augmentation of placental blood vessel resistance with a reduction of blood flow to the embryo that does not affect the pregnancy outcome if clinically resolved. We do not agree with the unpublished data of NT multiples of the median because no adjustment for maternal age or other confounders was carried out and no information about the gestational age calculation was available. Finally, twin pregnancy is not particularly useful to demonstrate the absence of any influence of progesterone because it is a natural model rather than iatrogenic as in the case of supplementation.

We believe that further research and well-designed studies are needed to better understand the balances that regulate the development of the fetus. Therefore, we are now testing the CYP17A1 gene, which regulates progesterone metabolism in women who have undergone progestin therapy and also the influence of this gene on NT size.