INTRODUCTION: Ghana adopted the revised WHO recommendation on intermittent preventive treatment in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) in 2012. This study has assessed the effectiveness and safety of this policy in Ghana. METHODS: A total of 1926 pregnant women enrolled at antenatal care (ANC) clinics were assessed for birth outcomes at delivery, and placental histology results for malaria infection were obtained from 1642 participants. Association of reduced placental or peripheral malaria, anaemia and low birth weight (LBW) in women who received ≥4 IPTp-SP doses compared with 3 or ≤2 doses was determined by logistic regression analysis. RESULTS: Among the 1926 participants, 5.3% (103), 19.2% (369), 33.2% (640) and 42.3% (817) of women had received ≤1, 2, 3 or ≥4 doses, respectively. There was no difference in risk of active placental malaria (PM) infection in women who received 3 doses compared with ≥4 doses (adjusted OR (aOR) 1.00, 95% CI 0.47 to 2.14). The risk of overall PM infection was 1.63 (95% CI 1.07 to 2.48) in 2 dose group and 1.06 (95% CI 0.72 to 1.57) in 3 dose group compared with ≥4 dose group. The risk of LBW was 1.55 (95% CI 0.97 to 2.47) and 1.06 (95% CI 0.68 to 1.65) for 2 and 3 dose groups, respectively, compared with the ≥4 dose group. Jaundice in babies was present in 0.16%, and 0% for women who received ≥4 doses of SP. CONCLUSION: There was no difference in the risk of PM, LBW or maternal anaemia among women receiving 3 doses compared with ≥4 doses. Receiving ≥3 IPTp-SP doses during pregnancy was associated with a lower risk of overall PM infection compared with 2 doses. As there are no safety concerns, monthly administration of IPTp-SP offers a more practical opportunity for pregnant women to receive ≥3 doses during pregnancy.