Neonatal opiate withdrawal syndrome (NOWS), previously known as neonatal abstinence syndrome (NAS), is a growing public health concern as opiate misuse and opioid-related overdoses, from both prescription and illicit sources, continue to rise in the USA. As more than 90% of females abusing opioids are of child-bearing age, the failure to adequately address the opioid epidemic continues to negatively impact the next generations. Accurate and timely identification of infants at risk for withdrawal from in-utero exposure is critical to ensure high-quality perinatal and neonatal care. Beginning with an evaluation of current best practices and performing a literature review, we identify the challenges to current screening processes and how these limitations limit the ability to provide appropriate care to infants at the risk of withdrawal. We first describe the limitations of the available assays for the detection of opioid and opioid metabolites across different biological sources from both the mother and the infant. We then present a discussion surrounding factors that contribute to maternal willingness to disclose use. Particularly, in light of the limitations of biological screening, any barrier to maternal disclosure further complicates effective care delivery. Barriers to disclosure include legal ramifications and state policies, provider and societal behaviors and biases, and maternal factors. Moving forward, universal prenatal screening surveys coupled with enhanced outreach and education to providers centering on the limitations of both patient report and biological sampling, as well as comprehensive and supportive services for women of reproductive age with substance use disorders, are needed to both enhance detection for NOWS and improve long-term maternal-child health.