Abstract: The searches identified 161 records; after de-duplication and title and abstract screening 90 full-text articles were retrieved. From these we included three RCTs with a combined total of 613 participants. One study compared prophylactic dactinomycin to no prophylaxis (60 participants); the other two studies compared prophylactic methotrexate to no prophylaxis (420 and 133 participants). All participants were diagnosed with CMs. We considered the latter two studies to be of poor methodological quality. P-Chem reduced the risk of GTN occurring in women following a CM (3 studies, 550 participants; risk ratio (RR) 0.37, 95% confidence interval (CI) 0.24 to 0.57; I² = 0%; P < 0.00001; low-quality evidence). However, owing to the poor quality (high risk of bias) of two of the included studies, we performed sensitivity analyses excluding these two studies. This left only one small study of high-risk women to contribute data for this primary outcome (59 participants; RR 0.28, 95% CI 0.10 to 0.73; P = 0.01); therefore we consider this evidence to be of low quality. The time to diagnosis was longer in the P-Chem group than the control group (2 studies, 33 participants; mean difference (MD) 28.72, 95% CI 13.19 to 44.24; P = 0.0003; low-quality evidence); and the P-Chem group required more courses to cure subsequent GTN (1 poor-quality study, 14 participants; MD 1.10, 95% CI 0.52 to 1.68; P = 0.0002; very low quality evidence). There were insufficient data to perform meta-analyses for toxicity, overall survival, drug resistance and reproductive outcomes. P-Chem may reduce the risk of progression to GTN in women with CMs who are at a high risk of malignant transformation; however, current evidence in favour of P-Chem is limited by the poor methodological quality and small size of the included studies. As P-Chem may increase drug resistance, delays treatment of GTN and may expose women toxic side effects, this practice cannot currently be recommended.

Plain-language summary: We found three randomised studies (randomised controlled trials (RCTs) where people are allocated at random i.e. by chance alone) involving a total of 613 women. Two studies tested methotrexate in all women with a CM and one study tested dactinomycin in women with a CM who were at a high risk of getting GTN. The two methotrexate studies are older studies that used relatively poor research methods, therefore their findings cannot be relied upon. Overall the review findings suggest that P-Chem reduces the number of women developing cancer after molar pregnancy; however, this is probably only true for women with high-risk moles (i.e. CM). In addition, P-Chem might make the time to diagnose the cancer longer and might increase the number of anti-cancer treatments needed to cure the cancer if it develops. We were unable to assess the short- and long-term side-effects of P-Chem in this review because there were not enough available data; however, we are concerned that the five- and eight-day courses of P-Chem used by researchers in these studies are too toxic to be given to women routinely. We consider this evidence to be of a low to very low quality. This conclusion is based on our assessment that two of the included studies were of poor methodological quality and at a high risk of bias; the third study was of a good quality but consisted of only 60 participants. Currently there is insufficient evidence to support giving anti-cancer drugs to women with molar pregnancies. However, GTN is almost always cured with modern care and P-Chem for molar pregnancy would only reduce the risk of needing full-scale chemotherapy, but would not remove that risk. In addition, it would not change the need for careful monitoring and follow-up of women with hydatidiform moles.