More than 75% of neonatal puppy deaths occur in the first three weeks of life, with the majority of these occurring in the first week from physiologic, congenital and genetic, and environmental conditions; behavior of the female; and bacterial or viral septicemias. Following recommended husbandry and management practices for the bitch before breeding, during pregnancy, and after whelping can reduce puppy mortality significantly. Unfortunately, there is little research being directed at better identifying and addressing this discipline.

While infectious diseases apparently make up only a small portion of puppy deaths prior to weaning, the most important viral infections during the first 2-5 weeks of life are canine herpesvirus and the minute virus of canines (canine parvovirus 1; CPV-1). Canine adenovirus-1, canine distemper and canine coronavirus, along with bacterial infections, also may cause puppy deaths.

Canine herpesvirus (CHV) is an alpha-herpesvirus more closely related to feline herpesvirus, equine herpesvirus-1, pseudorabies virus and varicella-zoster virus than to other herpesviruses. It is found worldwide in domestic and wild dogs, but not in other species. Seropositivity rates of > 30% are commonly seen, although some infected kennels have antibody prevalence rates as high as 100% without the any evidence of disease in infected puppies. Transmission is by direct contact with infectious body fluids, since CHV is unstable in the environment. Like other herpesviruses, it becomes latent after a primary infection and is shed periodically, primarily in nasal or rarely in genital secretions.

The disease is usually asymptomatic in puppies exposed to CHV after 1–2 weeks of age. However, CHV infection is generally fatal in neonatal pups (1–4 weeks old) that lack maternal immunity. These pups may be infected during passage through their infected dam's birth canal or, more commonly, by contact with oronasal secretions of the dam or other dogs in the kennel or home. Infected littermates, or neighboring dogs that are shedding virus, also can be sources of infection. The incubation period is about 6–10 days, and duration of illness in newborn pups is 1–3 days, with signs of anorexia, dyspnea, pain upon abdominal palpation, incoordination and a typical soft, yellow-green feces. There may be serous or hemorrhagic nasal discharge. Petechia are common on the mucous membranes, and thrombocytopenia may occur. Rectal temperatures are not elevated.

Occasionally, CHV may cause in utero infections that result in the death of fetuses or pups shortly after birth. The virus also has been isolated from dogs with vaginitis, conjunctivitis and respiratory illness. Asymtomatically infected dogs remain latently infected and virus can be excreted for about one week in nasal or genital secretions, and, thereafter, at variable intervals for several months or even years. Recrudescence of latent virus may be provoked by stress (movement to new quarters, introduction of new dogs) or experimentally from use of immunosuppressive drugs; the virus sheds for about one week. Once the virus enters a kennel, it generally spreads and causes asymptomatic infections, except in pregnant dams or very young pups from susceptible bitches. Such intermittent shedding assures the survival of CHV in the dog population and in breeding kennels. Development of CHV immunity in the form of neutralizing antibodies is transferred to pups via the placenta and colostrum.

Pregnant dogs infected at mid-gestation or later, may abort weak or stillborn pups with no signs in the dam; fetal pups infected during late gestation may appear normal at parturition, but die within a few days of birth. Primary genital infections in adult females are characterized by enlargement of the submucosal lymphoid follicles with variable degrees of vaginal hyperemia and petechial or ecchymotic hemorrhages, but without discomfort or unusual vaginal discharges. Vesicular lesions also have been reported during proestrus, but they regress during estrus. In males, similar lesions have been reported over the base of the penis and prepuce. Naturally infected bitches that have lost pups with CHV usually, but not always, give birth to normal litters subsequently, probably because of persistent low levels of maternal antibody. Rarely, pups exposed after 2–3 weeks of age, like adult dogs, can show central nervous signs, including blindness and deafness presumably related to brain damage. The high susceptibility of neonatal pups to generalized infection has been associated with poor thermoregulation, low body temperatures, and their incompletely developed immune systems in early life.

While CHV has been isolated from tracheas of dogs with respiratory disease, it is not considered a significant cause of respiratory illness, in contrast to other agents such as Bordetella bronchiseptica, canine distemper, and canine parainfluenza virus.