Canine Neonatal Health PDF

Canine Neonatal Health Sophie A. Grundy, BVSc (Hons), MANZCVS (Small Animal Medicine), DACVIM (Small Animal Internal Medicine) KEYWORDS Neonate Newborn Canine KEY POINTS The canine neonatal period extends from birth to weaning, but factors outside this time have an impact on neonatal health. Detailed history taking is essential when caring for the neonate. Neonates are physiologically unique at birth, and experience rapid growth and organ sys- tem maturation during the first few weeks of life. To identify what’s abnormal and provide appropriate clinical support, it’s important to be familiar with a clinically relevant physi- ology of the neonate and normal developmental milestones. Preventative medicine during the pre-natal period is not always possible as patients are not always presented for care prior to breeding. In these circumstances, owner education regarding the whelping process, and neonatal health monitoring is even more important for positive health outcomes. Available clinical monitoring tools for the canine neonate such as birth weight, weight gain, and APGAR scores are objective, and can be utilized by the lay person in a home environ- ment where whelping and neonate care typically takes place. Early identification of at-risk neonates results in prompt intervention. Veterinarians working with the canine neonate should be familiar with the prevention, iden- tification, and treatment of disorders associated with the neonatal triad (hypothermia, hy- poglycemia, and dehydration). INTRODUCTION During the past 2 decades there has been a shift from linear thinking to a more global approach in medicine. Models such as the Center for Disease Control’s “One Health” and the American Veterinary Medical Association’s “Spectrum of Care” speak to the continuum rather than the finite.1,2 Neonatal care is no exception to this concept. Neonatal health is not defined by events that occur during the neonatal period; rather, it is a continuum of parent genetics, maternal health, gestation, and the birth process itself, in addition to all other events that occur during the neonatal period. Conceptually, this is important to acknowledge because it means that if we view neonatal care from a continuum lens, it begins before conception. Preventative care prior to breeding, Banfield Pet Hospital, 6081 Florin Road, Sacramento, CA 95823, USA E-mail address: [email protected] Vet Clin Small Anim 53 (2023) 1161–1193 https://doi.org/10.1016/j.cvsm.2023.05.008 vetsmall.theclinics.com 0195-5616/23/ª 2023 Elsevier Inc. All rights reserved. 1162 Grundy during gestation, and during the whelping period is an essential component of neonatal health. Neonatal health is not limited to the neonatal period. When a canine neonate is presented to a veterinarian the antecedent event may have occurred well before clinical signs developed or were noted. This adds additional layers of history-taking and eval- uation that are more complex than for the adult patient. Lexicon Within the veterinary literature, there is a lack of clarity regarding the definition of the canine neonatal period. The word perinatal, newborn, and puppy sometimes used as synonyms.3–5 The word neonate is a Latinate noun from: (a) the Latinate root (g)nasci/ (g)natus “to be born,” with the addition of (b) < neo > denoting “new” and (c) denoting that the word is a noun:6 < neo 1 (g)n 1 ate / neonate > The < (g)n > is the same base that is present in the words. (i) pregnant: which is formed from the combination of: (a) < pre > denoting “before,” (b) gn “born,” and (c) < -ant > “adjective” < pre 1 gn 1 ant / pregnant > (ii) peri(g)natal: which is formed from the combination of: (a) < peri > denoting “around,” (b) < (g)n > “born,” (c) < -ate(e) > “noun,” and (d) < - al > “pertaining to” < peri 1 (g)n 1 at(e) 1 al > / perinatal > It is worth mentioning that the word perinatal is unique in that it can refer to either the fetal period or the neonatal period, depending on context; specifically, whether prior to birth, or after. In contrast to Latinate words derived from the base < (g)n >, the word newborn is of Germanic origin with a derivation of niwe "made or established for the first time” and beran “birth.” Neonate and newborn have the same meaning, but different linguistic origins. In this article, the term neonate will be used as the medical lexicon is typically Latinate or Hellenic. Definition There is no inherent denotation or connotation of time included in the word neonate. A review of the veterinary literature reveals that the canine neonatal period is either not defined, or variably defined, depending on the reference. The neonatal period is re- ported to be as short as birth to 3–4 days, as long as birth to 84 days, or the time from birth to weaning.7–10 The lack of consensus with respect to the duration of the neonatal period in the veterinary literature can be problematic when attempting to evaluate mortality rates, and may be a contributing factor to variation in reported canine neonatal mortality rates ranging from 5% to 35%.9,11–14 Some researchers have further divided the canine as an early neonate or late neonate denoting the first 2 days of life, and 2 days of life through the end of the neonatal period respectively, Canine Neonatal Health 1163 which becomes especially relevant when considering disease processes and neonatal mortality rates.13,15–17 Recently, several authors have defined the canine neonatal period more clearly as birth to 21 days (3 weeks) of age, which is consistent with the 2012 American Animal Hospital Association (AAHA) definition of the neonatal stage extending from birth to weaning which typically starts in the canine around 3 to 4 weeks of age, and the pe- diatric stage, from weaning to sexual maturity.4,12,16,18–20 In this article, the canine neonatal period will be consistent with the AAHA life stage definition; specifically, from birth to weaning. Factors impacting The neonatal period is a period of significant physiologic change and transition from the uterine environment to the outside world. Like other species, hypoxia and sepsis are the main causes of canine neonatal death.10,11,21 Hypoxemia is a general term that re- fers to a state of oxygen deficiency which may occur from one or more of the following: a decrease in oxygen intake, hypoventilation, ventilation-perfusion mismatch, or a diffusion barrier. What becomes challenging for the veterinarian is how to objectively define pathological hypoxemia in the canine neonate, as tissue hypoxemia is a physi- ological condition of generally all newborns: The historic use of modifiers such as “severe” or “prolonged” to describe neonatal hypoxemia precludes succinct interpre- tation of risk.22–24 In contrast, the risk of death is quantified and ninefold higher when there is a failure of passive transfer: The neonate is dependent on the intake of colos- trum for local and systemic immune support.25 Early mortality (birth to 2 days of life) occurs in approximately 90% of all hypoxemic neonates, and 70% of septic neonates respectively.11,14,21 suggesting that a focus on (a) the key factors impacting the canine neonatal health during parturition and initial respiration, and (b) early evaluation/identification of at-risk neonates and monitoring tools is a high priority when discussing canine neonatal health.11,14,21 KEY POINTS: INTRODUCTION Neonatal health is a continuum that starts at conception and ends when the neonatal period finishes The canine neonatal period is best defined as birth to weaning; birth to 3 to 4 weeks of age Separation of the canine neonatal prior into early (0–2 days) and late (2 days – weaning) may be helpful clinically when considering preventative care strategies for the canine neonate Hypoxemia and sepsis are the leading causes of death during the neonatal period and are associated with early (0–2 days) neonatal mortality PRE-BREEDING SCREENING Pre-breeding screening should at a minimum consist of a thorough physical examina- tion well in advance of the heat cycle of breeding to identify areas of concern (physical, conformational, behavioral, nutritional, lack of current preventative care, teratogen use). It is medically ideal, and best practice, to include routine endocrinologic and in- fectious disease screening, orthopedic, ophthalmic, cardiac, and genetic screening that may impact maternal health, pregnancy, and neonatal health or be a source of zoonotic disease. Rapid expansion of the PCR market in the 1990’s in conjunction with the mapping of the canine genome resulted in an increase in the availability of 1164 Grundy canine genetic disease screening over the past few decades, and normalized the use of pre-breeding genetic testing to reduce the incidence and/or eliminate specific con- ditions within the canine purebred population.26–30 However, there is not a genetic test for every heritable disease in the dog. The Canine Health Information Center (CHIC) maintains a current, comprehensive, centralized, and searchable open-access canine health database that provides screening recommendations and statistics by breed (https://ofa.org) and represents the best guide for clinicians.28 Further discussion of the impact of body condition score and fertility in the canine can be found elsewhere (see [Body Condition and Fertility in Dogs by Balogh and Sones] of this issue). Addi- tional resources providing more in-depth information about heritable disease screening in a canine breeding program based on organ system have also been dis- cussed in depth (see [Genetic Screening in a Canine Breeding Program by Broeckx] of this issue; [Ophthalmic Disease and Screening in Breeding Dogs by Diehl] of this issue; [Cardiac Disease and Screening in Breeding Dogs by Aherne] of this issue; and [Ortho- pedic Disease and Screening in Breeding Dogs by Todhunter and Hayward] of this issue). KEY POINTS: PRE-BREEDING SCREENING All canines intended for reproductive use should be evaluated in advance of breeding to screen for abnormalities that may impact neonatal health Evaluation should include at a minimum an assessment of patient history, preventative care measures, physical examination, and temperament The CHIC maintains comprehensive screening recommendations for purebred dogs (https:// ofa.org) PREGNANCY It is not uncommon for a veterinarian to commence medical management of a litter around the time of pregnancy confirmation, which may be as early as 3 to 4 weeks gestation, or as late as whelping. Although some preventative care, such as maternal vaccination, is not able to be implemented once the bitch is pregnant, it’s important to educate owners regarding strategies for how to best support neonatal health in the home environment. and offer guidelines regarding what is normal, and when to seek help. Nutrition The ideal diet for canine pregnancy should be complete and balanced, and approved by the Association of the American Feed Control Officials (AAFCO) for growth and lactation so that it meets the nutritional demands of the growing litter, supports maternal health, and may be fed continuously through weaning. Generally, it is best to avoid supplements during canine pregnancy due to potentially negative effects on fetal, and/or neonatal health. Commercially available diets appropriate for growth and lactation are typically formulated to include nutrients, such as calcium and essen- tial fatty acids, in appropriate amounts to support neonatal health and development; additional supplementation may be problematic.31,32 More detailed information regarding the nutritional management of the pregnant bitch can be found elsewhere (see [Body Condition and Fertility in Dogs by Balogh and Sones] of this issue; and [Nutrition for the Pregnant Bitch and Puppies by Wakshlag and Kim] of this issue). Canine Neonatal Health 1165 Drug exposure The administration of pharmacologic or biologic agents in the pregnant bitch should be avoided where possible, except for the routine administration of heartworm pre- vention, anthelmintics, and flea and tick prevention as permitted based on available manufacturer and formulary guidance, and with risk: benefit consideration. This recommendation includes topical medications, as systemic absorption is possible and compounds such as glucocorticoids are associated with birth defects. In 2015 the Federal Drug Enforcement Agency (FDA) replaced the former five preg- nancy risk category system A, B, C, D, and X for people with risk summary narrative sec- tions: pregnancy, lactation, and females and males of reproductive potential. Current veterinary formularies typically maintain a narrative section regarding reproduction/ nursing safety which may sometimes reference the more familiar older letter-based sys- tem. Medical management of the pregnant bitch is further discussed elsewhere (see [Canine Pregnancy, Eutocia, and Dystocia by Davidson and Cain] of this issue). Preparation for whelping Preparation for whelping is an area where client education can have a profound impact on neonatal health. If the dam is presented during pregnancy, although accurate assessment of gestation age can be challenging in the dog, attempts should be made to predict the date, or anticipated time-window during which parturition is ex- pected. As whelping typically occurs in a non-clinic setting it is vital that veterinarians educate owners about the whelping process and neonate care to facilitate early iden- tification and intervention for at-risk neonates. Information regarding the whelping pro- cess, recommended items to have on hand, and immediate evaluation of the neonate has a positive impact on neonatal health. Clients should be given cost-effective and easy-to-implement tools. Table 1 provides a list of items that owners may find useful when working with neonates. Additional information regarding the prediction of partu- rition in the dog and elective cesarean section may be found elsewhere (See [Proges- terone Analysis in Canine Breeding Management by Conley and Gonzales] of this issue; and [Canine Cesarean Section: Emergency and Elective by Cain and Davidson] of this issue). Table 1 Useful items for owners to have in advance of whelping to improve neonatal health Item Use Whelping box that can be cleaned Children’s plastic swimming pool is a cost-effective solution; may be lined with newspaper for ease of cleaning 2% tincture of iodine/dental floss/scissors Umbilical cord care Bulb syringe/De Lee mucous trap To safely clear neonate airway Gram scale Birth weight/weight gain Non-toxic nail polish/clippers Puppy identification Warm blankets/towels Puppy stimulation and warming Gloves Infection prevention Thermometer, covers, and lubricant Temperature monitoring of mum and litter Pen/Paper Record times of delivery, puppy weights, and APGAR scores Canine neonate nipple, bottle, and Supplemental feeding milk replacer 1166 Grundy Immune support for the neonate There are four layers to the zonary endotheliochorial placenta of the bitch, uterine endothelium on the maternal side; and chorionic epithelium, connective tissue, and fetal endothelium on the fetal side. The structure of the canine placental presents a barrier to large molecules and the canine neonate is reliant upon colostrum ingestion for the passive transfer of immunoglobulins. Failure of passive transfer is associated with neonatal mortality, but the timing and volume of ingestion appear to be limiting factors for the canine, rather than the immune quality of the colostrum itself.33 For this reason, it is important that owners are educated regarding the importance of colostrum ingestion within 8 hours of birth. For further discussion, please see “Colostrum”. KEY POINTS: PREGNANCY The first opportunity for a veterinarian to commence a care plan to maximize neonatal health may be when the dam presents for pregnancy diagnosis, or whelping assistance Owner education regarding nutrition and medication use during pregnancy, in addition to information about what to expect and when to seek help can positively impact neonatal health Owners should be provided with information regarding anticipated whelping dates (if known), items to have on hand, and when to seek help Owners should monitor neonates after birth and make sure that colostrum is consumed within 8 hours of birth PARTURITION The fetus undergoes rapid change during birth as it loses maternal supports and as- sumes a more physiologically autonomous role as neonate ex utero. For the canine neonate, this transition occurs at a time when the maturation of several organ systems is still incomplete.10 Birth is a time during which the canine neonate is particularly vulnerable to asphyxia and hypoxemia, hypothermia, and glucose imbalance; all of which decrease survival.34 Minimum gestation length The ability of a fetus to survive outside the uterine environment is dependent upon lung surfactant production and the start of respiration, without which oxygen exchange cannot occur. Prior to a gestational age of 62 days from the luteinizing hormone (LH) surge, the canine fetus lacks sufficient surfactant production for ex utero sur- vival.35 Similar to other species, it is suggested that the female canine fetus is capable of surviving earlier than her male counterpart; this sexual dimorphism is thought to be related to higher levels of Müllerian inhibiting hormone in the male impacting lung sur- factant development.35,36 In the absence of ovulation timing or known gestational age, serum progesterone may be used as a marker for fetal lung development with a serum progesterone concentration of < 2 ng/mL being associated with adequate production of lung surfactant.37 A protocol for the direct evaluation of surfactant production using amniotic fluid and 95% ethanol to evaluate fetal maturation is described in the litera- ture; however, due to the challenges in sampling canine amniotic fluid, this methodol- ogy is not easily clinically applicable.35,37 Future development of a bed side surfactant screen may be useful during cesarean sections, especially when there is a need to Canine Neonatal Health 1167 document a lack of fetal viability versus neonatal loss from other causes. A more in- depth discussion of progesterone analysis in canine breeding management and elec- tive cesarean sections can be found elsewhere (see [Progesterone Analysis in Canine Breeding Management by Conley and Gonzales] of this issue; and [Canine Cesarean Section: Emergency and Elective by Cain and Davidson] of this issue). Dystocia The duration of labor, specifically the second stage of labor (clinically identifiable as the onset of straining or discharge of fetal fluid), has been associated with an increase in neonate mortality with the most favorable outcome when it is < 12 hours dura- tion.3,14,38,39 Dystocia plays a significant role in canine neonatal mortality; asphyxia and hypoxia are associated with more than 60% of neonatal losses during the first 2 days of life.14,21,40 Prompt detection of dystocia and fetal distress during parturition is a vital component of preventative neonatal care and early intervention.41 From a practical perspective, two approaches can be used; firstly, fetal heart rate and toco- dynamic monitoring, and secondly, clinical observation of “red flags” that indicate further evaluation is warranted. Tocodynamic monitoring (eg, Whelpwise Veterinary Perinatal Specialties) of the pregnant bitch in late pregnancy and during parturition provides insight regarding the identification of labor onset, monitoring of contraction strength, and response to medical interventions; it is an excellent clinical tool during the whelping process.42–44 Tocodynamic monitoring for the canine is not always available, which necessitates the consideration of alternate clinically pragmatic options. While it is known that external abdominal contractions do not necessarily accurately reflect uterine activity, a prac- tical and reasonable alternative option in a setting that precludes tocodynamic moni- toring includes a combination of visual monitoring (behavior, external contractions, vaginal discharge), record keeping of the parturition events, and, where possible, fetal heart rate monitoring by hand-held Doppler. Handheld portable fetal heart rate Doppler units are readily available online, and with training can be utilized during preg- nancy and parturition to monitor canine fetal heart rates with or without tocodynamic monitoring. Although fetal heart rate oscillation is normal during parturition during pe- riods of uterine contraction, sustained fetal heart rates below 180 beats per minute are known to be associated with severe fetal distress and presumably greater risk to neonatal health in the first 2 days of life.43,44 Table 2 outlines clinical “red flags” during parturition and why they raise concern for neonatal health. Hypoxemia The normal adult dog maintains a peripheral oxygen saturation (spO2) of 96% or greater, but in the canine neonate normal spO2 values for neonates born via sponta- neous vaginal delivery and elective cesarean section are approximately 90% and 80% respectively.22 After birth, there is a period of adaptation to extra-uterine life and respi- ration with spO2 values stabilizing 1 hour after spontaneous vaginal delivery and 12 hours after elective cesarean section.10,22 As published spO2 data points for the canine neonate between 1 hour and 12 hours post birth are not readily available it is difficult to define what is expected or normal during this time. What can be stated is as follows: (a) this data supports a clinical indication for repeated APGAR evaluations during the early neonatal period and (b) normal canine neonates should have an spO2 on room air within the normal adult range by 1 hour and 12 hours post birth when born by spontaneous vaginal delivery and elective cesarean section respectively. Bradycardia, decreased lung compliance, and sepsis, are three clinically important consequences of hypoxemia in the canine neonate. During parturition, and for the first 1168 Grundy Table 2 Clinical “Red flags” during parturition Observation Clinical Concern for Neonatal Health Fetal heart rate < 180 Fetal distress/hypoxemia Maternal lethargy, collapse, repeated Fetal viability vomiting, permanent moaning, or seizures Green or black vaginal discharge prior to Placental detachment without timely delivery of the first fetus expulsion increasing risk fetal – neonate hypoxemia Protrusion of fetal membranes from the Fetal – neonate hypoxemia vulva for 15 min or longer without delivery of the fetus Duration of stage II labor >12 h Increased risk of neonatal distress Time interval of more than 2 h after the May indicate dystocia and thus increased delivery of the previous fetus risk fetal – neonate hypoxemia Prolonged (>15 min) of ineffective May represent physical obstruction to abdominal contractions with no delivery (narrow birth cancel, malposition, delivery of a fetus is observed malposture, large fetus, or other cause of dystocia; potential increased risk fetal – neonate hypoxemia Adapted from Arlt SP. The bitch around parturition. Theriogenology. 2020;150:452 to 457. https:// doi.org/10.1016/j.theriogenology.2020.02.046 few days of life, there are several factors that increase the risk of circulatory failure in the canine neonate. First, during the neonatal period, the cardiovascular system is a high volume – low-pressure circuit and cardiac output is dependent upon heart rate; second, bradycardia in the canine neonate is not vagally mediated and sympa- thetic innervation of the heart is incomplete; third, anoxia results in profound brady- cardia (less than 45 beats per minute) and hypotension (less than 25 mm Hg).45 Despite these risk factors, during the first days of life, it has been shown that in studies of anoxic death that circulation continues for a long time with a pulse being detected in some neonates for as long as 30 mins after the last breath.46 The canine neonate is remarkably resistant to circulatory failure and can be resuscitated after a hypoxemic or anoxic event, providing systolic blood pressure is maintained above 8 mm Hg.45,46 In addition to altered cardiovascular physiology, there are important changes in the respiratory tract of the canine neonate that warrant mention. First, upper airway obstruction may occur more readily due to the relatively large tongue and less rigid airway cartilage; second, the amount of work and pressure required by a neonate to maintain breathing is increased as the ribcage is more pliable, intercostal muscles weaker, and lungs less compliant; third, the neonate is susceptible to relative hypox- emia due to a large metabolic oxygen requirement, and immature carotid chemore- ceptors; and fourth, hypoxia in the canine neonate increases inspiratory resistance and decreases lung compliance.10,47 The effect of these changes is that the canine neonate is predisposed to airway collapse, respiration fatigue, hypoxemia, and rapid oxygen desaturation. Sepsis is an important cause of loss during the early neonatal period. Bacterial pop- ulations exist within the normal gravid canine reproductive tract, and those same bacterial isolates may be present in the dam, her colostrum, and her neonates.48–50 As an aid in the prevention of sepsis, umbilical cords should be ligated, trimmed to approximately 0.5 to 1.0 cm from the abdominal wall and dipped in 2% tincture of Canine Neonatal Health 1169 iodine.9 Aside from cardiovascular and respiratory compromise, management of hypoxia is a high priority in the canine neonate as bacterial translocation is known to occur in the absence of gastrointestinal mucosal lesions and contributes to the development of sepsis.51 Resuscitation Prompt medical intervention is indicated for neonates that do not exhibit rapid spon- taneous respiration regardless of birth method. As neonates are small, wet at birth, and unable to generate their own body heat, care must be taken to keep them warm during the resuscitation process. Standard approaches to resuscitation focusing on airway maintenance, breathing, and circulation are appropriate for the canine neonate; however, due to physiologic differences in the neonate, the primary focus is on support of the onset of respiration, and the maintenance of oxygenation and normal body temperature. Hypoxemia in the canine neonate is associated with bradycardia, and decreased lung compliance. Neonates with low heart rates need an open airway, and oxygen. Parasympatholytic agents, such as atropine or glycopyrrolate, are not indicated during the resuscitation of the canine neonate because in this cohort, bradycardia is not vagally mediated.10 Canine neonatal airways are prone to obstruction and should always be cleared by suction rather than “swinging” due to the risk of trauma.52 Various respiration stimula- tion points have been described in the literature (genital and umbilical area at birth, JenChung acupressure point) and may be considered once the airway is cleared.9,53,54 Pharmacologic respiratory stimulants such as doxapram are controversial as carotid chemoreceptors are immature at birth in the dog, and the respiratory stimulatory ef- fects of doxapram are obliterated during states of hypoxemia.55,56 For those cases where delivery involves anesthesia, it is difficult to prevent in utero anesthetic drug exposure as, with the exception of dexmedetomidine, induction and gaseous anesthetic agents routinely used in small animal practice cross the placenta, and epidural anesthesia alone for the canine is not practical.57–62 A variety of anes- thesia protocols for cesarean sections in the bitch are available, all of which focus on maintaining oxygenation and reducing fetal depression by using multi-modal ap- proaches.59,63 Neonatal resuscitation and the management of neonates born by elec- tive cesarean section is described in more depth elsewhere (see [Canine Cesarean Section: Emergency and Elective by Cain and Davidson] of this issue). Generally, canine neonates respond well to warming, rubbing/tactile stimulation, and oxygen support.64 KEY POINTS: PARTURITION Lung surfactant production is insufficient to support life at a gestational age less than 62 days from the LH surge Dystocia is a significant contributor to neonatal mortality; asphyxia and hypoxemia are associated with 60% of neonatal deaths Tocodynamic and fetal heart rate monitoring, and observation for “red flags” during parturition can help improve neonatal health outcomes Sustained fetal heart rates less than 180 beats per minute are associated with fetal distress At birth, the normal canine neonate has a lower spO2 than the adult dog 1170 Grundy Neonate spO2 values increase after birth and plateau at 1 hour and 12 hours after spontaneous vaginal birth and cesarean birth respectively Resuscitation efforts should focus on maintaining an open airway and oxygen delivery whilst keeping neonates warm At birth, umbilical cords should be trimmed, ligated and 2% tincture of iodine applied to help prevent sepsis THE NEONATE Defining normal Neonates are not miniature versions of the adult dog, and it is important for both vet- erinarians and owners to have an appreciation of what is normal at each develop- mental age. Suggested ambient temperature guidelines, normal vital signs, clinically relevant physiology, and developmental milestones for the canine neonate are pro- vided in Tables 3–6. The early neonate The early canine neonate (0–2 days) has recently transitioned to ex utero life and the onset of respiration; these events, and the neonate’s unique physiology increases sus- ceptibility to hypoxemia, hypoglycemia, hypothermia, and dehydration. It is important to provide owners with practical and cost-effective ways for them to identify at-risk ne- onates as whelping typically takes place in the home environment. Separating a sick neonate from the dam and transporting it to a veterinary clinic presents a logistical challenge. Although virtual visits in veterinary medicine are more commonplace post–COVID-19 and present an option for neonatal care, depending on location virtual visits may not establish a valid client–patient relationship. Owner education plays a vi- tal role in improving canine neonatal health outcomes. The late neonate The late neonatal period (3 days – weaning) is a time of rapid growth and organ matu- ration: The normal canine neonate will more than double its body weight during this time; eyes and ears open; more controlled ambulation and independent excretory functions begin as neurologic reflexes mature; and nephrogenesis is completed. Pas- sive transfer of maternal immunoglobulins provides the canine neonate protection from some infectious diseases, but parasitism and sepsis remain a clinical concern through weaning. During this period of rapid growth and maturation skeletal malformations and other abnormalities may become more apparent. Neonate survival from a nutrition lens is Table 3 Recommended ambient temperature guidelines for the canine neonate Age Temperature Range C ( F) 0–7 d 29.4–32.2 (85–90) 8–14 d 26.6 (80) 15–21 d 26.6 (80) 22–28 d 26.6 (80) Adapted from Monson WJ. Orphan rearing of puppies and kittens. Vet Clin North Am Small Anim Pract. 1987;17(3):567 to 576. https://doi.org/10.1016/s0195-5616(8750054-7) Canine Neonatal Health 1171 Table 4 Normal vital signs for the canine neonate Systolic/Diastolic Heart Rate Mean Respiratory Rate Temperature (Mean) Blood Age (Beats/min) Mean (Breaths/min) Range C ( F) Pressure (mm Hg) 0–24 h 200–250 15–35 34.4–36.0 (94–96.8) 54/30 (40) 1 wk 220 36.1–37.2 (97–99) 2 wk 212 36.4–37.1 (97.6–98.8) 3 wk 192 37.2–38.1 (99–100.5) 4 wk 137–156 20–36 37.7 (100) 70/45 (60) Adapted from Moon PF, Massat BJ, Pascoe PJ. Neonatal critical care. Vet Clin North Am Small Anim Pract. 2001;31(2):343 to 365. https://doi.org/10.1016/s0195-5616(0150209-0) dependent upon adequate production and consumption of the dam’s milk. Maintain- ing adequate nutrition planes for the dam is vital. The reader is referred elsewhere for further details (see [Nutrition for the pregnant bitch and puppies by Wakshlag and Kim] of this issue). KEY POINTS: THE NEONATE The canine neonate is not just a small dog; understanding what’s normal for the canine neonate helps the owner and clinician know when something is wrong Tables 3–6 provide useful information regarding temperature needs, vital signs, normal physiology, and expected developmental milestones Health risks during the neonatal period include hypoxemia, hypoglycemia, hypothermia, and dehydration, and infectious disease CLINICAL TOOLS Canine neonates can be challenging to work with. Many clinicians have limited expo- sure to the canine neonate and are unfamiliar with their specific needs. Venous access can be more challenging, and there are not well-established guidelines regarding spO2 values requiring intervention. Even when incubators are available for use, FiO2 parameters and the maximum recommended duration of oxygen support are not well defined. Mechanical ventilatory support for the canine neonate is typically cost- prohibitive and technically challenging even in a tertiary care setting. Prevention and early detection are a central component to care and improve canine neonatal health outcomes. When the neonate is not evaluated during the early neonatal period, sepsis and other morbidities are detected later when the patient is in a more debilitated state. In this section, options for monitoring canine neonatal health will discussed, many of which can be performed by the lay person and outside of a clinic setting. Birth weight Across mammalian species, it is well documented that low birth weight is associated negatively with short-term survivial.65 Low birth weight neonates are physiologically at a disadvantage due to a combination of low energy reserves and high surface area to mass ratio predisposing them to hypothermia and hypoglycemia.10,66 Hypothermic 1172 Grundy Table 5 Clinically relevant physiology of the canine neonate Organ System Neonate Clinical Implication Ocular Eyelids are closed at birth Ocular examination is not possible in the canine neonate The cornea has a higher water content during the neonatal until the eyelids open period and may appear cloudy Pupillary light reflexes are not intact until retinal The iris has low pigmentation at birth and typically appears development is completed at around 2 wk of age blue The normal neonate tapetum is blue-gray Retinal vascular development is incomplete at birth Cardiovascular Low resistance, high flow circuit Dependent on heart rate and blood volume to maintain Chronotropic responses are incomplete until 14 d of age cardiac output Bradycardia occurs in response to hypoxemia Plasma volume is expanded, and heart rate elevated Relative resistance to circulatory failure Bradycardia is not vagally mediated Bradycardia is an indication for oxygen support Respiratory Prone to upper airway obstruction (relatively large tongue, The canine neonate is susceptible to hypoxemia soft cartilage) Mechanisms controlling respiratory function mature during the post-natal period Large oxygen demand Increased work to maintain tidal volume Gastrointestinal Dentition eruption typically starts around 2–3 wk Hypothermia is associated with ileus which increases the risk Ileus develops at rectal temperatures of 94ºF of reflux and aspiration Hepatobiliary Neonatal liver and biliary system are functionally immature Serum bile acids may be used as early as 4 wk of age to detect at birth hepatocirculatory abnormalities; a single urine bile acid to Bile secretion is reduced as compared to the adult dog creatine ratio may be used to replace a resting or random Alkaline phosphatase (ALP) and gamma-glutamyl serum bile acid concentration transferase (GGT) are markedly elevated at 0–2 wk Drugs requiring hepatic metabolism or excretion should be At 4 wk of age, P450-specific activity is around 85% of that used with care seen in the adult dog Microsomal enzyme is not comparable to that of the adult dog until around 4.5 mo of age Urinary System Neonatal kidney is immature and nephrogenesis continues Low urine specific gravity is normal, as is the detection of for at least 2 wk post birth protein, glucose, and various amino acids Glomerular filtration rates are low with decreased amino Care should be taken to maintain fluid balance without acid absorption overhydration or oncotic loading Natriuresis in the proximal tubule is increased Renally excreted or metabolized drugs should be used with Renal blood flow is best correlated to blood pressureuntil care around 6 wk of age Hematopoietic System Macrocytosis at birth, decreasing to that of the adult by 4 wk Age-based reference ranges should be used of age Red blood cell counts decrease from birth to 3 wk, and then increase Immune System At birth, the canine neonate is immunologically Effective passive transfer is dependent upon colostrum incompetent consumption and increased gastrointestinal permeability Only 5%–10% canine neonate antibodies are derived from Canine neonates should be monitored to ensure colostrum transplacental transfer; canine neonates are dependent intake within hours of birth upon the effective passive transfer of immunoglobulins Gastrointestinal permeability is highest at birth and decreases dramatically after 8 h Metabolism Normal birth weight is dependent upon breed Recording neonate birth weight, and daily weight gain, is an Growth patterns (weight gain) are typically breed easy way to monitor metabolic health independent Neonates need access to a heat source to make sure they can Canine neonates are poikilothermic and susceptible to maintain body temperature chilling, due to a higher body surface area/mass ratio Neonates require regular feeding to maintain serum glucose During the first 24 h, hepatic glycogen stores decrease concentrations dramatically Canine Neonatal Health Adapted from Grundy SA. Clinically relevant physiology of the neonate. Vet Clin North Am Small Anim Pract. 2006;36(3):443-v. https://doi.org/10.1016/j.cvsm.2005. 12.002 1173 1174 Grundy Table 6 Developmental milestones for the canine neonate Development Age of Onset (days) Notes: Mental State Typically sleeping or nursing 0–14 Normal canine neonates are typically easily roused from sleep Gait and Posture Righting reflex 0 Vestibular function is present at birth, but muscle Flexion dominance 0–4 tone is lacking Extensor dominance 4–5 Early movement involves a “swimming” like Stepping movements (with thoracic limb support) 5–6 thoracic limb movement whilst sliding on the Upright posture 10–14 abdomen Pelvic limb can support body weight 14–16 Neonates can raise their head at birth Uncoordinated gait 18–21 Adult posture and balance develop around 6– 8 wk of age Cranial Nerve Reflexes Swallow reflex 0 Eyelids open around 14 d Rooting Reflex 0 Reflexes to protect the eye develop prior to the Suckling 1–2 eyelids opening Dazzle 1–2 Ear canals open between 12 and 14 d Vibrissopalpebral 1–2 Rooting reflex is evoked by cupping the fingers Palpebral 2–4 around the muzzle and is strongest during the Startle response 12–14 first 14 d, disappearing around 25 d Corneal 10–16 Pupillary Light Reflex 10–16 Menace response 10–28 Adapted from Lavely JA. Pediatric neurology of the dog and cat. Vet Clin North Am Small Anim Pract. 2006;36(3):475-v. https://doi.org/10.1016/j.cvsm.2005.12.009 Canine Neonatal Health 1175 neonates do not have normal gastrointestinal motility or vigor, and maintenance of effective nursing is difficult.10 One of the challenges in veterinary medicine is the considerable breed variation in neonate size, and the lack of breed-specific data regarding critical canine neonate weight.15,18,65,66 What is known is that lower birth weight (from the first quartile) has been associated with an increase in mortality during both the early and late neonatal period, whilst being born to a highly heterogenous litter (based on birth weight) is asso- ciated with an increase in mortality during the early neonatal period.15 Consideration of birth weight in the context of litter weight heterogenicity, and trending of early growth rate are far more useful than birth weight alone for both the identification of the at-risk canine neonate, and for ongoing monitoring of canine neonatal health. Weight gain Weight loss in excess of 4% of birth weight during the first 24 hours is known to be a risk factor for mortality in the canine neonate.67 Measurement of daily weight gain is an effective, objective, and simple way to monitor neonatal health. Growth curve analysis of multiple breeds supports that a daily weight gain of 5%–10% can be used as a marker of clinical health across all breeds and birth weight is expected to double by 7 to 10 days of age.68 Clinical evaluation is indicated for any neonate deviating from this general rule. Assessment of maternal milk production is advised if more than one neonate is failing to thrive. Alternate nutritional support for the canine neonate is best provided by a complete and balanced canine milk replacement formula. Canine milk is 2 and 3 times more calorie dense than caprine or bovine milk, respectively, and the nutrient breakdown significantly different.69,70 Bottle feeding using a canine neonate nipple is the preferred method. Neonates should be normothermic and the nipple aligned with the oral cavity so that the tongue forms a seal and prevents aero- phagia. The stomach volume of the neonate is estimated to be 4 mLs per 100 gm body weight, and daily caloric requirements are estimated to be 200 kcal per kilogram of body weight up to 4 weeks of age.33,71 Suggested intervals between feeding are 3– 4 hours for the first week and 4–6 hours thereafter. Feeding may be extended to every 6 hours when oral feeding begins. Tube feeding may be considered for sick neonates or those with a poor suckle reflex. APGAR (modified) score The APGAR score is a standardized scoring system for infants based on 5 markers of health: color, heart rate, reflexes, muscle tone, and respiration. It is not a predictor of neonatal mortality; rather, by assigning a numeric value to each parameter, the APGAR score objectively quantifies both neonatal depression and response to resuscitation.72 A modified canine APGAR scoring system was first proposed in 2009 (Table 7) and an alternate version by a second author in 2010.3,14 The 2009 version has been used most consistently in the literature and provides an easily accessible objective tool that identifies the at-risk neonate: this means early intervention and need-based support for the neonates that will benefit the most.73–78 Canine APGAR scoring can be used with equal success in the clinic and home setting. The canine APGAR scoring system assigns a numeric value to each criterion, and the cumulative score used to categorize neonates into one of the 3 viability classes. The original cutoff values for viability class have been refined and now include consid- eration to the dam’s breed-body-size; the updated canine neonate APGAR score cutoff values according to breed-body-size are shown in Table 8. Clinically, lower APGAR scores are associated with decreased mammary gland searching as compared to the normal APGAR group, as well as an increased risk of 1176 Grundy Table 7 Modified canine APGAR scoring system Score Parameter 0 1 2 Heart Rate < 180 bpm 180–220 bpm > 230 bpm Respiratory Rate No crying/< 6 rr Mild crying/6–15 rr Crying/> 15 rr Reflex irritability Absent Grimace Vigorous Motility Flaccid Some flexions Active motion Mucous membrane color Cyanotic Pale Pink Abbreviations: bpm, beats per minute; rr, respiratory rate (breaths per minute). From Veronesi MC, Panzani S, Faustini M, Rota A. An Apgar scoring system for routine assessment of newborn puppy viability and short-term survival prognosis. Theriogenology. 2009;72(3):401 to 407. https://doi.org/10.1016/j.theriogenology.2009.03.010 poor sucking reflex.14 Neonates in the “critical” category are those with the highest risk of death despite neonatal assistance or resuscitation.77 Specialized interventions are indicated for this group consisting of the following: immediate measures such as resuscitation and active warming, and ongoing respiratory, immunoglobulin, and nutri- tional support until stable. The refined canine APGAR scores in the “critical” category, those that are less than 3, are independent of breed body size at both 24 hours and 7 days. It is worth stressing that the canine APGAR score represents the evaluation of the neonate at a single snapshot in time. A low score does not determine the prognosis for survival or predict the effectiveness of response to intervention. Rather, the canine APGAR score identifies those neonates in need of immediate intervention; subsequent APGAR scores assess the response to therapy and need for additional treatment. Neonatal viability reflex score The neonatal viability reflex (NVR) score is a way to evaluate canine neonate vigor, and is based on the strength of the sucking, righting, and rooting reflex as evaluated by an examiner. Effective milk consumption is difficult without the sucking, righting, and rooting reflex: A low NVR score indicates that a neonate should be further evaluated. The NVR score may be used alone, or in conjunction with the canine APGAR score when evaluating the health of the canine neonate. The NVR scoring system is shown in Table 9. Cumulative scores of 0 to 2 are consistent with weak vigor or vitality, 3 to 4 moderate vigor or vitality, and 5 to 6 normal vigor or vitality.79 Colostrum Canine neonates are antibody deficient at birth and dependent upon effective inges- tion and absorption, “passive transfer,” of colostrum as a source of immunoglobulins, nutrients, microbes, and hormones, which in turn impact organ maturation, promote intestinal barrier closure, and improve nutrient absorption.16,49,80 During the last weeks of pregnancy, maternal IgG accumulates in mammary tissue and is subsequently released early in lactation resulting in colostrum IgG levels three to four times higher than in maternal circulation.16,33,81 Colostrum contains both IgG, and IgA which is produced locally in the mammary gland, thus meeting both systemic and local immunity needs for the neonate.16,33 High concentrations of IgG in colostrum results in adequate passive-transfer of immunoglobulins requiring as little as 1.3 mL of colostrum per 100-g of puppy weight but the timing is vital, and ingestion needed Table 8 Refined canine neonate APGAR score cutoff values, and viability classes according to breed body size Small Mediuma Large £10 kgs (£22 Pounds) 11–20 kgs (24.2–44 Pounds) > 20 kgs (>44 Pounds) Severe Distress Moderate No Distress Severe Distress Moderate No Distress Severe Distress Moderate No Distress “Critical” Distress “Critical” Distress “Critical” Distress < 24 h 0–3 4 5–10 0–3 4–5 6–10 0–3 4–5 6–10 24 h – 7 d 0–3 4 5–10 0–3 4–5 6–10 0–3 4–7 8–10 Abbreviation: ROC, receiver operating characteristic curve. a In medium-sized neonates the newly detected viability classes were merely cautiously suggested, because they were not calculated by ROC, and data were drawn from a limited number of newborns. Modified from Veronesi MC, Panzani S, Faustini M, Rota A. An Apgar scoring system for routine assessment of newborn puppy viability and short-term survival prognosis. Theriogenology. 2009;72(3):401-407. doi:10.1016/j.theriogenology.2009.03.010. Canine Neonatal Health 1177 1178 Grundy Table 9 Neonatal viability reflex (NVR) scoring Parameter Weak (0 Score) Moderate (1 Score) Normal (2 Score) Suckle Absent Weak (>3 suckles/min) Strong (5 suckles/min) Rooting Absent Slow muzzle fitting Immediate fitting inside circle muzzle within circle Righting Reflex Absent (continues in Slow body repositioning Fast body repositioning initial position) From Vassalo FG, Simões CR, Sudano MJ, et al. Topics in the routine assessment of newborn puppy viability. Top Companion Anim Med. 2015;30(1):16 to 21. https://doi.org/10.1053/j.tcam.2015.02. 003 within the first 8 hours.16,33 Variation in colostrum IgG concentrations between teat pairs is normal in the bitch; however, this is clinically unimportant as canine neonates do not develop a nipple preference.82,83 Serum markers for colostrum consumption in the canine neonate have been evalu- ated; however, for intervention to be effective, blood sampling would be required prior to 8 hours of age and there is currently not a practical bedside test for this purpose. There is not a complete canine colostrum substitute currently available. When colos- trum intake is known to be impaired pooled adult dog serum (2–4 mL per 100-g body weight, divided and administered subcutaneously in two sites) will raise serum IgG levels to a minimum protective level (>230 mg/dL) in colostrum deprived neonates; however, side effects include fluid pockets and/or skin necrosis.19,84 Hematologic and serum chemistry values Reference ranges for the adult dog are not applicable to the canine neonate. It is important for clinicians to have access to age-based reference ranges for the dog; some analytes such as serum alkaline phosphatase, which is a marker for colostrum consumption, have a wide reference range. During the past decade, point-of-care an- alyzers have become standard in-practice equipment and evaluation of clinical pathol- ogy data is more readily available than ever especially when sample requirements are small. Tables 10–12 provide hematologic and biochemical reference ranges for the canine neonate. Future areas of research Every clinician knows that there are few things as rewarding as saving the life of an an- imal, and there is a special kind of joy seeing a neonate take its first breath and cry. The development of the canine APGAR score advanced canine neonatal medicine, but there have been few additions to the clinician’s toolbox since. As research in the field of canine neonatology continues, our ability to positively influence neonatal health out- comes will improve. Biological fluids Recently there has been an interest in evaluating neonate biological fluids including fluids such as amniotic fluid and umbilical blood with a goal of identifying objective markers that can predict neonate survival when used alone, or in conjunction with a modified canine APGAR score. Candidates have included blood gas, lactate, glucose, cortisol, urine specific gravity, cardiac troponin 1, and amniotic fluid composition in addition to serum IgG, and the ALP, and GGT as markers for evidence of colostrum consumption.3,34,38,85–89 Further studies are needed to better define clinically useful Table 10 Normal Hematologic values for canine neonates Hematologic Age Parameter Birtha 7 da 14 da 21 da 28 da RBC (x 106/mL) 4.7–5.6 (5.1) 3.6–5.9 (4.6) 3.4–4.4 (3.9) 3.5–4.3 (3.8) 3.6–4.9 (4.1) Hemoglobin (g/dL) 14.0–17.0 (15.2) 10.4–17.5 (12.9) 9.0–11.0 (10.0) 8.6–11.6 (9.7) 8.5–10.3 (9.5) PCV (%) 45–52.5 (47.5) 33.0–52.0 (40.5) 29.0–34.0 (31.8) 27.0–37.0 (31.7) 27.0–33.5 (29.9) MCV (fL) (93.0) (89.0) (81.5) (83.0) (73.0) MCH (pg) (30.0) (28.0) (25.5) (25.0) (23.0) MCHC (%) (32.0) (32.0) (31.5) (31.0) (32.0) nRBC/100WBC 0–13 (2.3) 0–11 (4.0) 0–6 (2.0) 0–9 (1.6) 0–4 (1.2) Reticulocytes (%) 4.5–9.2 (6.5) 3.8–15.2 (6.9) 4.0–8.4 (6.7) 5.0–9.0 (6.9) 4.6–6.6 (5.8) Total WBC (x 103/mL) 6.8–18.4 (12.8) 9.0–23.0 (14.1) 8.1–15.1 (11.7) 6.7–15.1 (11.2) 8.5–16.4 (12.9) Segmented neutrophils 4.4–15.8 (8.60) 3.8–15.2 (7.4) 3.2–10.4 (5.2) 1.4–9.4 (5.1) 3.7–12.8 (7.2) Band neutrophils 0–1.5 (0.23) 0–4.8 (0.50) 0–1.2 (0.21) 0–0.5 (0.09) 0–0.3 (0.06) Lymphocytes 0.5–4.2 (1.9) 1.3–9.4 (4.3) 1.5–7.4 (3.8) 2.1–10.1 (5.0) 1.0–8.4 (4.5) Monocytes 0.2–2.2 (0.9) 0.3–2.5 (1.1) 0.2–1.4 (0.7) 0.1–1.4 (0.7) 0.3–1.5 (0.8) Eosinophils 0–1.3 (0.4) 0.2–2.8 (0.8) 0.08–1.8 (0.6) 0.07–0.9 (0.3) 0–0.7 (0.25) Basophils – 0–0.2 (0.01) – – 0–0.15 (0.01) Canine Neonatal Health Platelets (x 103/mL) 178–465 (302) 282–560 (352) 210–352 (290) 203–370 (272) 130–360 (287) Values in parentheses are mean values. Abbreviations: MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; nRBC/100WBC, number of nucleated red blood cells per 100 white blood cells; PCV packed cell volume, RBC red blood cell; Total WBC total white blood cell count. a Normal ranges and/or mean values from Earl FL, Melveger BE, Wilson RL. The hemogram and bone marrow profile of normal neonatal and weanling beagle dogs. Lab Anim Sci. 1973;23(5):690 to 695. From von Dehn B. Pediatric clinical pathology. Vet Clin North Am Small Anim Pract. 2014;44(2):205 to 219. https://doi.org/10.1016/j.cvsm.2013.10.003 1179 1180 Grundy diagnostic criteria for biological fluids and proteomics as for the early identification of the at-risk canine neonate. Microbiome Advances in molecular biology have improved our ability to evaluate biological sam- ples for not only the presence of bacteria using 16S ribosomal RNA as a marker, but also rapidly sequence bacterial populations, identify species, resistance patterns, and more using techniques such as matrix-assisted laser desorption/ionization time- of-flight (MALDI-TOF) and next generation sequencing. As more biological samples are evaluated across species, historical medical concepts such as the “sterile womb” are being challenged and further defined. We are just beginning to discover the complex relationship between microbial populations and canine reproductive and neonatal health. There appear to be species differences, but for the canine, current research sup- ports that microbial colonization begins prior to birth and that amniotic fluid, the placenta, uterus, and fetal gastrointestinal tract are not sterile environ- ments.48,50,90,91 For the canine, similar to humans, there is evidence that delivery type alters canine neonate microbiome colonization patterns and colostrum micro- biota composition, and that in turn neonate microbiota populations influence neonate growth rates.48–50 Canine microbial biodiversity is noted to be lowest in colostrum and neonates of dams post emergency cesarean section.49 Canine neo- nates with culturable placental or meconium microbiota exhibit higher relative weight gains during the first few days of life when neonatal mortality rates are known to be higher; however, these benefits were short term and not found to be correlated with survival or long term weight gain.48 It’s an exciting area of research with vast and far reaching clinical implications for both the reproductive management of the bitch, and neonatal medicine. Immunoglobulin Y IgY is the main immunoglobulin produced by chickens. Inoculating hens with canine pathogens results in the presence of IgY for those specific pathogens in the yolk of her eggs, which can subsequently be harvested and dried for oral administration to puppies.19,92 Products containing immunoglogulin Y (IgY) are available for use in the dog and there is evidence to support improved weight gain in colostrum fed neo- nates receiving IgY supplementation during the first 8 hours of life. Further studies are needed to define the therapeutic role of IgY when there is a failure of passive transfer. KEY POINTS: CLINICAL MONITORING TOOLS A variety of clinical tools for monitoring the neonate are available; many of which can be performed in the home environment, and by the lay person Birth weight and weight gain, especially for the first 7 to 10 days of life, is an excellent marker of canine neonatal health Modified canine APGAR and neonatal viability reflex (NVR) scores can be used to identify neonates that benefit from assistance and monitor response to intervention Neonates should be monitored to ensure colostrum ingestion within the first 8 hours of life Reference ranges for the canine neonate should be used when interpreting hematologic and biochemical data Canine Neonatal Health 1181 Biological fluids, the microbiome, and IgY administration are current areas of research with respect to neonatal health THE NEONATAL TRIAD The neonatal triad is an elegant term that refers to 3 clinical signs often associated with sepsis and clinical demise in canine neonates: hypothermia, hypoglycemia, and dehy- dration. The normal canine neonate is active, vocal, and vigorously seeks to nurse. Sick canine neonates have low vigor and do not nurse robustly or seek out warmth; without nutritional support and warming, the neonatal triad develops placing neonates at great risk for sepsis and demise. Although not pathognomonic for neonatal sepsis, diarrhea is known to be present in 93% of canine neonates with sepsis; for this reason, the peri- neal area should be closely monitored for signs of diarrhea such as wetness, staining, proctitis, or erythema.11 Changes to mucous membrane color, swelling or erythema of the umbilicus or abdomen, extremity changes such as sloughing, and the failure to gain weight, are other clinician signs associated with canine neonatal sepsis.9–11 Hypothermia The canine neonate is poikilothermic (lacks the ability to generate heat). Shivering and vasoconstrictive reflexes are not functional in the newborn.93 Body temperature is known to have a dramatic effect on gastrointestinal movement, and at rectal tempera- tures less than 94 F (34.4 C), ileus occurs, which increases the risk of aspiration pneu- monia. Hypothermic neonates are at increased risk of infection.93 Well-established heat-seeking behavior in the neonate is typically able to maintain a stable rectal temper- ature providing there is access to available heat sources. The risk of hypothermia is greater for low-birth-weight neonates due to a higher body surface area-to-mass ratio. For this reason, neonates with lower birth weights (lower quartile), and/or neonates born to litters with high birth-weight variability, should be provided with supplemental heat forms.10,15,64 To decrease the risk of thermal burns, direct contact with any heat source should be avoided; heating pads (whether electronic or microwavable gel) should always be covered. Maintenance of a temperature gradient in the nursery Table 11 Reference intervals for the canine neonate using a point-of-care analyzer and whole blood Age Analyte 4d 10–12 d 16 d 28 d pH 7.36–7.60 7.39–7.52 7.34–7.53 7.36–7.50 Na (mmol/L) 136.1–148.9 138.8–146.0 140.9–145.6 141.3–145.6 K (mmol/L) 3.90–5.20 4.10–5.30 4.40–5.80 4.10–5.70 Cl (mmol/L 101.1–107.5 105.2–110.8 105.8–111.9 105.5–112.1 iCa (mmol/L) 1.31–1.61 1.42–1.59 1.45–1.61 1.46–1.59 Glucose (mg/dL) 70.9–136.2 94.2–148.0 107/9–144.9 118.4–147.2 BUN (mg/dL) 10.1–26.8 13.6–24.5 8.7–18.6 0.0–16.2 HCO3 (mmol/L) 26.1–33.6 24.2–29.9 23.8–31.5 21.9–31.5 From O’Brien MA, McMichael MA, Le Boedec K, Lees G. Reference intervals and age-related changes for venous biochemical, hematological, electrolytic, and blood gas variables using a point of care analyzer in 68 puppies. J Vet Emerg Crit Care (San Antonio). 2014;24(3):291 to 301. https:// doi.org/10.1111/vec.12162 1182 Grundy Table 12 Normal biochemical chemistry values for canine neonates Age Biochemical Parameter 0–3 d 8–10 d 28–33 d Albumin (g/dL) 1.76–2.75 1.71–2.5 2.17–2.97 ALP (U/L) 452–6358 195–768 153–490 ALT (U/L) 9.1–42.2 4.1–21.4 4.3–17.4 Bilirubin (mg/dL) 0.04–0.38 0.01–0.18 0.02–0.15 BUN (mg/dL) 29.5–118 29.1–66.7 13.1–46.2 Total Ca (mg/dL) 10.4–13.6 11.2–13.2 10.4–13.2 Cholesterol (mg/dL) 90–234 158–340 177–392 Creatinine (mg/dL) 0.37–1.06 0.28–0.42 0.25–0.83 GGT (U/L) 163–3558 – – GLDH (U/L) 1.8–17.0 0.2–17.7 1.2–9.0 Glucose (mg/dL) 76–155 101–161 121–158 Total protein (g/dL) 3.7–5.77 3.26–4.37 3.71–4.81 Triglycerides (mg/dL) 45–248 52–220 36–149 Phosphorous (mg/dL) 5.26–10.83 8.35–11.14 8.66–11.45 From von Dehn B. Pediatric clinical pathology.Vet Clin North Am Small Anim Pract. 2014;44(2):205 to 219. https://doi.org/10.1016/j.cvsm.2013.10.003 area is advantageous as it allows neonates to move as needed and can help reduce over-heating; this can be difficult to achieve if using heated air for thermal support. Ambient temperature can rise quickly in contained environments and judicious temper- ature monitoring at the level of the neonate is advised. Hypoglycemia At birth, placental glucose support is terminated, and the neonate is reliant on endoge- nous food stores for glucose production. Colostrum provides a calorie dense initial en- ergy source for the neonate (1400–1800 kcal/L).94 The canine neonate is capable of glycogenolysis and gluconeogenesis but has limited glycogen stores and ability to main- tain serum glucose concentrations as compared to the adult: normal serum glucose con- centrations are lower than the adult and neonates require regular feeding to maintain blood glucose concentrations.93,95,96 Nutritional requirements in the dam must be met as energy deficits in the dam will negatively impact glucose production in the neonate.95 From a clinical lens, prolonged hypoglycemia in the early neonate should raise concern for sepsis, and the underlying cause treated.11 Other differentials include ju- venile hypoglycemia in toy breeds, hepatic vascular anomalies, and storage diseases. Oral glucose supplementation may be considered for non-nursing or symptomatic ne- onates short-term; high concentrations of dextrose can cause phlebitis, and intra- venous access can be challenging. More complete nutritional support such as frozen-thawed canine milk or milk replacer is advised longer term. Feeding guidelines may be found in section 6.2 of this article, and [Nutrition for the Pregnant Bitch and Puppies by Wakshlag and Kim] of this issue). Dehydration Neonates are predisposed to dehydration as compared to the adult dog for several reasons; they have a high surface area to body weight ratio, inability to concentrate urine, and increased skin permeability.7 Hydration is difficult to evaluate in the canine Canine Neonatal Health 1183 neonate as skin turgor is unreliable, and mucous membranes may be tacky from dried milk.93 As red blood cell concentration is higher in the neonate, measurement of packed cell volume is not also particularly clinically useful. Daily fluid requirements for the canine neonate are best via oral liquid nutrition; gastric volume may be esti- mated based on body weight at 4 mL per 100-g body weight.33 If intravenous fluid therapy is needed, fluids should be warmed to body temperature prior to administra- tion to avoid contributing to hypothermia. Daily fluid requirements are higher in the early neonate (80–120 mLs/kg/d or 4–5 mLs/kg/h) and decrease to that of an adult dog by around 4 months of age.97 KEY POINTS: THE NEONATAL TRIAD The neonatal triad refers to three clinical signs associated with clinical demise in the neonate: hypothermia, hypoglycemia, and dehydration. INFECTIOUS DISEASE Effective passive transfer of immunoglobins plays an important role in the prevention of infectious disease in the neonate; but not all infections, for example, internal and external parasites, are able to be prevented this way. The use of preventative care measures such as heartworm prophylaxis, basic hygiene, and environmental barriers such as outside shoe removal in the nursery area can minimize neonate exposure. When losses do occur, it’s helpful to have tissue samples for analysis. The placenta, which is often discarded after delivery, represents the maternal – fetal interface and can be used to problem solve causes of reproductive and neonatal loss. Placental tis- sue can be stored chilled for 1 to 3 days post-partum and submitted for histology, PCR, and/or culture. As zoonotic diseases such as Brucella canis can concentrate in the placenta, risk: benefit assessment and strict handling guidelines should be communicated to owners to prevent the transmission of zoonotic disease. Canine tis- sue should never be stored in a cooling unit or container used to store items for human consumption. The reader is referred elsewhere for additional recommendations and further discussion (see [Pathology of Neonatal Disorders by Agnew and Wiliams] in this issue). Sepsis and canine herpesvirus are 2 diagnoses associated with neonatal loss: For both conditions, early monitoring and preventative measures improve canine neonatal health outcomes. Sepsis Sepsis in the canine neonate presents differently as compared to the adult dog. Suc- cessful treatment is dependent upon early identification and appropriate treatment. Clinical signs consistent with canine neonatal sepsis include: the neonatal triad, low NVR scores, diarrhea, proctitis, cyanotic mucous membranes or extremities, necrosis of the extremities, omphalitis/omphalophlebitis, weight loss, and lethargy.11 Table 13 provides further detail regarding the frequency of clinical signs associated with neonatal sepsis. In one study, Escherichia coli was noted to be the most common bacterial agent associated with sepsis. Treatment of consists of antimicrobial and fluid support, ther- moregulatory support, and maintenance of nutrition. Broad-spectrum beta-lactams such as potentiated amoxicillin, ceftriaxone, or ceftiofur are appropriate for use in 1184 Grundy Table 13 Frequency of clinical signs presented by neonates with sepsis Clinical signs N (%) Hypothermia (65/113) 57.5% Hypoglycemia (74/113) 65.5% Dehydration (72/113) 63.7% Apathy (52/113) 46% Reduced muscle tone (56/113) 49.5% Reduced sucking reflex (70/113) 62% Reduced rooting reflex (67/113) 59.2% Reduced vestibular righting (55/113) 48.6% Vocalization (17/113) 15% Failure to gain weighta (37/113) 32.7% Hyperthermia (8/113) 7% Congested or cyanotic mucous membranes (59/113) 52.2% Diarrhea (105/113) 93% Bloody diarrhea (18/113) 16% Hematuria (26/113) 23% Vomiting (5/113) 4.4% Procitis (32/113) 28.3% Abdominal/body erythema (77/113) 68.1% Omphalitis/omphalophlebitis (29/113) 25.6% Neonatal conjunctivitis/opthalmia (12/113) 10.6% Mucopurulent nasal discharge/pneumonia (4/113) 3.5% Skin desquamation (scaled skin syndrome) (5/113) 4.4% Abscesses (9/113) 8% Seizures (5/113) 4.4% Abdominal bruises or hematomas (16/113) 14.1% Violaceous (cyanotic) extremities of limbs, tail, or ears (33/113) 29.2% Tissue necrosis in limbs, pads and other body extremities (15/113) 13.2% Bradycardia (62/113) 54.8% Dyspnea (22/113) 19.4% Bradypnea (19/113) 16.8% Agonal breathing (19/113) 16.8% Epistaxis (7/113) 6.2% Pale mucous membranes (16/113) 14.1% Oliguria/anuria (19/113) 16.8% Reduced peripheral So2 (31/113) 27.4% a Failure to gain weight was described only in litters whose weight was recorded daily by owners. From Nobre Pacifico Pereira KH, Fuchs KDM, Hibaru VY, et al. Neonatal sepsis in dogs: Incidence, clinical aspects and mortality. Theriogenology. 2022;177:103 to 115. https://doi.org/10.1016/j. theriogenology.2021.10.015 the neonate. Administration of subcutaneous or oral medication, fluid support, and nutrients may be sufficient for some cases of sepsis; however, for those patients pre- senting moribund or in septic shock, intravenous access is advised. Clinical markers delineating sepsis from septic shock are shown in Table 14. Intravenous drug Canine Neonatal Health 1185 Table 14 Useful clinical markers for the differentiation of sepsis versus septic shock in the canine neonate. Values listed are mean and standard deviation Parameter Healthy Sepsis Septic Shock HR (bpm) 238 19.5a 200 7.68b 110 44.3c Blood glucose (mg/dL) 125.4 22.6a 81 36.5b 37.6 32.3c Temperature (ºC) 36 0.61 a 34 1.6 b 32.5 0.85c Peripheral spO2 (%) 99 0a 98.6 0.65 a 66.2 19.8b Reflex Score 5.9 0.44 a 3.9 0.40 b 0.4 0.46c Abbreviations: HR heart rate, bpm beats per minute. a Means followed by different letter indicate significant differences among the evaluated groups (P <.05). b Means followed by different letter indicate significant differences among the evaluated groups (P <.05). c Means followed by different letter indicate significant differences among the evaluated groups (P <.05). From Nobre Pacifico Pereira KH, Fuchs KDM, Hibaru VY, et al. Neonatal sepsis in dogs: Incidence, clinical aspects and mortality. Theriogenology. 2022;177:103 to 115. https://doi.org/10.1016/j. theriogenology.2021.10.015 administration should be considered until clinical improvement is noted. Depending on the body-weight and physiological status of the canine neonate, standard periph- eral venous access may be possible; however, for some patients, the use of jugular or intra-osseous routes may be required. Tables 15 and 16 provide information regarding fluid rates, and antimicrobial dosing for the neonate. Herpesvirus Canine herpesvirus (CHV-1) is an alpha herpesvirus capable of causing disease in a variety of organ systems.98 Neonatal losses occur when an immunologically naı̈ve bitch is infected for the first time during the last 3 weeks of pregnancy, or when neo- nates born to an immunologically naı̈ve bitch are infected during the first weeks of life. Two strategies can be implemented to minimize this risk: (a) pre-breeding screening to identify seronegative females so that they may be isolated during pregnancy and for 6 weeks post-partum, as discussed in this issue (see [Canine pregnancy, eutocia, and dystocia by Davidson and Cain] in this issue) (b) vaccination of the bitch prior after breeding, and 6 weeks later if canine CHV-1 vaccination is available. Biosecurity Table 15 Fluid bolus rates for the canine neonate Fluid Rate Bolus: Hypovolemia 3–4 mL/100 gm body weight Bolus: Hypoglycemia 1 mL to 3 mL of 12.5% dextrosea Bolus: Colloid 2 mL/kg to 5 mL/kg, followed by 1 mL/kg/h as neededb Whole blood 10–20 mL/kg (for anemia correction) a 1:3 dilution of 50% dextrose with sterile water. b After crystalloid boluses have failed. Adapted from Lee JA, Cohn LA. Fluid Therapy for Pediatric Patients. Vet Clin North Am Small Anim Pract. 2017;47(2):373 to 382. https://doi.org/10.1016/j.cvsm.2016.09.010 1186 Grundy Table 16 Select drug dosing for the canine neonate Class Drug Dose Notes: Antimicrobiala Amoxicillin/Clavulanic acid 20 mg/kg PO q 12 hr The author prefers Ceftiofur 2.5 mg/kg SC q 12 h for no more than Ceftiofur 2.2–4.4 mg/kg SC q 12 hr 5 consecutive days Analgesicb Buprenorphine 0.005–0.010 mg/kg SC q 6 hr Pediatric dose is shown; lower doses are advised in the neonate and Butorphanol 0.1–0.2 mg/kg SC q 1–4 hr dosing should be titrated up to effect Hydromorphone 0.05–0.1 mg/kg SC q 2–4 hr Naloxone should always be available when using an opioid in a Methadone 0.1–0.5 mg/kg SC q 1–4 hr canine neonate Morphine 0.1–0.5 mg/kg SC q 1–4 hr SC dosing is advised for the canine neonate, but listed doses may be administered IM, or slow IV Abbreviations: hr hour, IM intramuscular; IV intravenous, kg kg; mg mg, PO per esophagus/by mouth; SC subcutaneous. a From Nobre Pacifico Pereira KH, Fuchs KDM, Hibaru VY, et al. Neonatal sepsis in dogs: Incidence, clinical aspects and mortality. Theriogenology. 2022;177:103 to 115. https://doi.org/10.1016/j.theriogenology.2021.10.015. b Adapted from Mathews KA. pain management for the pregnant, lactating, and neonatal to pediatric cat and dog. Vet Clin North Am Small Anim Pract. 2008;38(6):1291-vii. https://doi.org/10.1016/j.cvsm.2008.07.001. Canine Neonatal Health 1187 measures are an important preventative management strategy for kennels within the United States where vaccination is not possible, as the introduction of new breeding stock presents a risk for both CHV-1, and other infectious disease.99 The clinical course of CHV-1 infection in the canine neonate varies depending on when infection occurs. Transplacental infection generally results in in utero death; spe- cifically, mummification or stillbirth or neonatal infection. As the incubation period is 6 to 10 days, neonates infected with CHV-1 during the first week of life were most likely infected in utero. Post-natal transmission occurs via contact with mucosal secretions; both vaginal and oro-nasal secretions from the dam and infected littermates are po- tential sources. Clinical disease in the neonate is typically fatal despite intervention. The most frequently observed clinical signs include: poor weight gain; abdominal pain; dyspnea; diarrhea; nasal discharge; and petechiation or echymosis. Treatment options are limited. Antiviral therapy has been described (oral acyclovir solution at 10 mg/kg PO q 6 hr for 5–7 days).100 Although not frequently discussed, neonates do feel pain and analgesia may be warranted. Table 16 provides analgesia options for the canine neonate.CHV-1 replication is supported at temperature ranges be- tween 91.4 and 85ºF (33–35ºC): Anti-viral treatment in conjunction with increased ambient temperatures is currently the best option to decrease mortality especially if implemented prior to exposure. Necropsy of affected puppies, and/or PCR screening confirms the diagnosis (see [Pathology of Neonatal Disorders by Agnew and Wiliams] in this issue). Once a bitch has been exposed, subsequent immune response and passive transfer of anti-CHV-1 immunogluobulins is expected. Where available, the administration of CHV-1 booster vaccination is advised for each breeding cycle. KEY POINTS: INFECTIOUS DISEASE The clinical signs of sepsis are different for the canine neonate as compared to the adult dog The frequency of clinical signs associated with neonatal sepsis may be found in Table 13, and septic shock in Table 14 Broad-spectrum beta-lactams are the antimicrobial of choice for the septic neonate The breeding bitch should be screened for antibodies to CHV-1 and vaccinated where possible prior to breeding Neonatal infection with CHV-1 is typically fatal; treatment options are limited to supportive care, acyclovir, and increased ambient temperature CLINICAL APPROACH TO THE NEONATE The 2 most important components of health for the early neonate are oxygenation and temperature. Hypoxemia and hypothermia, especially during the first 2 days of life, trigger a cascade of physiological events that ultimately threaten life. As neonates are typically in the home environment during this life-phase, and owners sometimes reluctant to separate them from the bitch and transport them to a veterinary clinic, owner education becomes a major factor in the ability of a veterinarian to influence neonatal health outcomes. Essential components of care include the following: umbil- ical cord care; neonate identification for weight monitoring; initial birth weight and daily weight recording for at least the first 10 days; APGAR score assignment at birth; and use of correct resuscitation methods such as airway suctiion and warming. 1188 Grundy The late neonate (3 days – weaning) experiences dramatic growth, and continued or- gan development. During this time developmental abnormalities may become more apparent. Infectious diseases continue to be a risk during as the canine neonate’s im- mune system is immature, and environmental exposure to pathogens increases along with the ability to ambulate. Essential components of care include the following: hy- giene maintenance; daily weight recording for at least the first 10 days; 7-day APGAR score evaluation; monitoring for clinical signs of sepsis; and maintenance of an adequate plane of nutrition for the dam. CLINICS CARE POINTS History Taking When evaluating a neonate, it’s important to obtain as much information as possible from the owner. For the canine neonate, detailed history taking can help clinicians make diagnoses such as failure of passive transfer (lack of colostrum intake at birth), Brucella Canis (intermittent litter losses), or aspiration secondary to hyperthermia and ileus (outside housing). Clinical Tools (Dam) Progesterone: For the normal canine pregnancy, a maternal serum progesterone concentration less than 2 ng/mL is a clinical marker of adequate fetal lung development. Labor: More favorable neonate outcomes are associated with stage II labor less than 12 hours in duration. Clinical Tools (Neonate) Birth Weight: At birth, neonates should be individually identified, and their body weight recorded. This forms a baseline for weight gain/loss in the first week of life. APGAR scores: A neonate with an initial APGAR score less than 3 is considered “critical”: these neonates should receive resuscitation efforts, active warming, and nutritional support. Subsequent APGAR scores are used to assess the response to intervention. Colostrum Ingestion: Passive transfer is dependent upon the ingestion of 1.3 mLs colostrum per 100-g body weight by mouth during the first 8 hours of life. When intake is impaired, 2 to 4 mL per 100-g body weight may give given subcutaneously, divided between two sites. Weight Gain/Loss: Weight loss greater than 4% of birth weight in the first 24 hours is a risk factor for mortality and evaluation by a veterinarian is indicated. Expected daily weight gain is 5% to 10% for the first week, with birth weight doubling by 7 to 10 days of age. Daily Caloric Requirement: Neonate caloric requirements are estimated to be 200 kcal per kilogram of body weight up to 4 weeks of age. DISCLOSURE The Author is currently employed by Banfield Pet Hospital. The views expressed do not necessarily represent those of Banfield. ACKNOWLEDGMENTS Gina Cooke, PhD and Autumn Davidson, DVM, DACVIM. REFERENCES 1. Brown CR, Garrett LD, Gilles WK, et al. Spectrum of care: more than treatment options. J Am Vet Med Assoc 2021;259(7):712–7. 2. Mackenzie JS, Jeggo M. The One Health Approach-Why Is It So Important? Trop Med Infect Dis 2019;4(2):88. Canine Neonatal Health 1189 3. Groppetti D, Pecile A, Del Carro AP, et al. Evaluation of newborn canine viability by means of umbilical vein lactate measurement, apgar score and uterine toco- dynamometry. Theriogenology 2010;74(7):1187–96. 4. Mila H, Guerard C, Raymond-Letron I. Guidelines for postmortem examination of newborn dogs. Anim Health Res Rev 2021;22(2):109–19. 5. Uchan ska O, Ochota M, Eberhardt M, et al. Dead or Alive? A Review of Perinatal Factors That Determine Canine Neonatal Viability. Animals (Basel) 2022;12(11): 1402. 6. Lewis C, Short C, Freund W. A new Latin dictionary: founded on the translation of freund’s Latin-German lexicon. Harper; 1891. https://archive.org/details/Lewis ShortLatnDiccionary. 7. Lawler DF. Neonatal and pediatric care of the puppy and kitten. Theriogenology 2008;70(3):384–92. 8. Papich MG, Davis LE. Drug therapy during pregnancy and in the neonate. Vet Clin North Am Small Anim Pract 1986;16(3):525–38. 9. Davidson AP. Neonatal resuscitation: improving the outcome. Vet Clin North Am Small Anim Pract 2014;44(2):191–204. 10. Grundy SA. Clinically relevant physiology of the neonate. Vet Clin North Am Small Anim Pract 2006;36(3):443. 11. Nobre Pacifico Pereira KH, Fuchs KDM, Hibaru VY, et al. Neonatal sepsis in dogs: Incidence, clinical aspects and mortality. Theriogenology 2022;177:103–15. 12. Gill MA. Perinatal and late neonatal mortality in the dog. PhD Thesis. 2001. Fac- ulty of Veterinary Science, University of Sydney, Australia. http://hdl.handle.net/ 2123/4137 13. Chastant-Maillard S, Guillemot C, Feugier A, et al. Reproductive performance and pre-weaning mortality: Preliminary analysis of 27,221 purebred female dogs and 204,537 puppies in France. Reprod Domest Anim 2017;52(Suppl 2):158–62. 14. Veronesi MC, Panzani S, Faustini M, et al. An Apgar scoring system for routine assessment of newborn puppy viability and short-term survival prognosis. Ther- i

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