Various challenges and their implications encountered during the periconceptional period are listed in this chapter. Though their implications have not been fully understood; identifying modifiable risk factors prior to conception can contribute to better fertility and pregnancy outcomes. Surveillance for adverse outcomes as a consequence of dysfunctional placentation should be initiated during the peri-implantation phase—extended inverted pyramid of prenatal care shifting the focus too much earlier to clinical pregnancy. Several mechanisms influence immune tolerance at the maternal-fetal interface which involves effective angiogenesis and trophoblastic invasion. Natural killer cell malformations have been attributed to infertility and recurrent pregnancy loss (RPL). Isolated Antinuclear antibodies positivity could influence fertility and pregnancy outcomes. Thyroid peroxidase antibody positivity is known to be associated with adverse pregnancy outcomes. High levels of the antibody and high levels of thyroid-stimulating hormone could have a negative effect on in vitro fertilization. Mapping inflammatory responses could be indirect but specific methods of measuring hostile autoimmunity in the body. Effective surveillance initiated periconceptionally for the identification of the probable risk factors that could complicate pregnancy helps to avert adverse irreversible changes in the genome aiding good in utero fetal programming. The perinatal outcomes of assisted reproduction technique (ART) pregnancies do not differ significantly from non-ART pregnancies and effective surveillance for risk factors in ART pregnancies could result in better perinatal outcomes.