Background: Severe acute respiratory syndrome coronavirus 2 (COVID-19) can result in systemic inflammatory reactions that could disrupt endocrine and placental physiology in the course of pregnancy. The presence of the key pregnancy-supportive hormones, which are critical to keep the gestation and placental activity, includes progesterone, estradiol, and 2-human chorionic gonadotropin (2-hCG), whereas cortisol and thyroid-stimulating hormone (TSH) indicates the maternal stress and thyroid-regulatory pathways. Although the evidence of COVID-19-induced changes in physiological changes is accumulating, the impact of severe infection on maternal hormonal profiles during pregnancy is not defined well enough. Aim: This research was meant to assess the effect of severe COVID-19 on chosen maternal hormonal parameters in second-trimester pregnant women. Methods: The study was a hospital-based case-control study carried out at Al -Nasiriyah Teaching Hospital in Dhi Qar Province in the year 2020. It involved 200 pregnant women between the ages of 25 and 40 years with a gestation period of 1620 weeks. The sample was split into two groups of which 100 women were confirmed to have severe COVID-19 that needed oxygen therapy and 100 healthy pregnant controls. Each of the participants was a singleton, with comparable body weight (73 75 kg), and chronic disease or thyroid disorders were excluded. Blood samples were taken to the venous blood used to measure serum progesterone, estradiol (E2), 8-hcg, cortisol and TSH concentrations in the serum by the use of enzyme linked immunosorbent assay (Elisa) kit. The levels of hormones in the infected group were measured about one month after infection and statistical comparisons with the appropriate parametric or non-parametric tests were conducted on the levels. Results: The women with the worst cases of COVID-19 had much lower progesterone, estradiol and 2-hCG levels than the controls. On the other hand, the levels of cortisol were dramatically increased in the infected group, whereas the levels of TSH have decreased slightly but significantly. Conclusions: Major endocrine changes in severe COVID-19 in the second trimester comprise low placental hormones, high cortisol, and low TSH. These results indicate possible effects of a serious case of viral infection on placental endocrine functions and maternal stress mechanisms, and hormonal surveillance of such pregnancies is critical.