This study aimed to investigate a case of confined placental trisomy 16 mosaicism (CPM16) with abnormal amniotic fluid, placental lake, and other abnormalities. Maternal serum screening was performed to assess the risk of foetal aneuploidy, and massively parallel sequencing was used to detect cell-free fetal DNA. The abnormalities of the fetus, amniotic fluid, and placenta were detected by ultrasonic inspection. Maternal serum screening indicated a high risk for trisomy 21, and the non-invasive prenatal testing (NIPT) result was positive for trisomy 16. The pregnancy was terminated and karyotype analysis of fetal heart blood revealed a 46, XX karyotype. Copy number variation (CNV) sequencing of placental tissues indicated that CPM16 is the main cause of false-positive NIPT results and intrauterine growth retardation (IUGR) diagnoses. Combining molecular genetics technologies, such as CNV sequencing, can be complementary, and provide an effective strategy to determine the cause of such abnormalities.