Chromosomal abnormalities are a significant cause of pregnancy loss. Solid tissue fetal and neonatal pathology samples are routinely examined by karyotype analysis after cell culture. However, there is a high failure rate, and this approach is expensive and labor intensive. We have therefore evaluated a new molecular strategy involving quantitative fluorescent polymerase chain reaction (QF-PCR) and subtelomere multiplex ligation-dependent probe amplification (MLPA) analysis. A retrospective audit showed that less than 4% of abnormal cases may not be detected by this molecular strategy. We validated this strategy in parallel with cytogenetic analysis on 110 patient samples, which included cases of fetal loss, still birth, neonatal death, termination of pregnancy, recurrent miscarriage, and sudden unexpected death in infancy. This validation showed that 55 of the 57 samples that gave a result for both strategies were concordant. During the 1st year of diagnostic testing, we analyzed 382 samples by the molecular strategy. A 16% abnormality rate was observed. These included trisomies 13, 18, 21, monosomy X, and triploidy detected by QF-PCR (77%), and 23% were other trisomies and subtelomere imbalances detected by MLPA. This strategy had a 92% success rate in contrast to the 20%-30% failure rate observed with cell culture and cytogenetic analysis. We conclude that QF-PCR and subtelomere MLPA is a suitable strategy for analysis of the majority of fetal and neonatal pathology samples, with many advantages over conventional cytogenetic analysis.