New Perspectives on the Late-Term Mare and Newborn Foal

IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE

Wendy Vaala, VMD, Diplomate ACVIM

1. Introduction dotal observations and conclusions can be inferred, A successful perinatal program requires the col- because there is not a large enough number of clin- laborative efforts of those trained in reproduction ical cases with similar problems from which to and neonatology. In ambulatory situations, one draw significant conclusions. Until larger, multi- person must often specialize in both areas; addition- centric collaborative trials validate the usefulness of ally, that person must have the equipment and monitoring specific hormones or the efficacy of var- expertise available to manage obstetrical complica- ious therapies designed to manage and maintain tions and to provide neonatal resuscitation and complicated pregnancies, it is the author’s recom- nursing care. Periparturient complications during mendation that no one therapy or monitoring aid late pregnancy may include severe maternal illness should be relied on exclusively. Any mare receiv- or colic, reproductive tract disease, or fetal anoma- ing therapy to prolong an abnormal pregnancy lies. The most serious threats to uteroplacental should receive frequent assessment. That way, the health and foal survival are perinatal sepsis, hypox- clinician can promptly determine if silent or unde- ia/ischemia, and maturation disorders. The chal- tected fetal demise occurs without ensuing abortion lenge is to improve our ability to recognize mares or if parturition occurs without the customary warn- with jeopardized pregnancies at an earlier stage in ing signs. gestation or in the disease process. This goal can This paper will focus on new or controversial man- be accomplished in two ways: (1) more proactive agement strategies and monitoring techniques for antepartum monitoring and reporting of clinical the late-term mare with periparturient complica- cases in the field and (2) the use of controlled exper- tions. The current understanding of pregnant- imental disease models designed to improve our un- mare physiology will be reviewed when applicable to derstanding of the evolution of uteroplacental help practitioners decide if and how they might in- dysfunction. corporate some of these interventional therapies Many clinical trials designed to examine hormone into their daily practice. Newborn foal evaluation changes in the at-risk mare or evaluate the efficacy will conclude this section with an emphasis on nor- of various treatment modalities on pregnancy out- mal behavior guidelines and a brief review of neo- come are underpowered statistically. Only anec- natal immunity.

NOTES

AAEP PROCEEDINGS ր Vol. 53 ր 2007 281 IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE 2. Controversies Regarding Hormone Therapy in the In healthy, late-term mares, progestagens are pro- Late-Term Mare duced by the uteroplacental tissues from the precur- sor, P5, supplied by the fetal adrenals.2,11 Fetal- Hormonal Profiles derived P5 is then converted to P4 by uteroplacental The search continues in equine perinatology for hor- metabolism and secreted into the umbilical circula- mones that reflect fetal and placental wellbeing. tion or metabolized further to 5␣-DHP in the endo- Progestagens and estrogens remain the most likely metrium or other progestagens within the fetus or candidates, but the specific endocrine mediators re- uteroplacental tissues. At least 10 progestagens sponsible for maintenance of pregnancy during late have been identified and measured in the late-term gestation and stimulation of the final stages of fetal mare.1 Seven of these metabolites increase with maturation and initiation of parturition remain the advancing gestational age, but levels of P4 remain focus of considerable research and controversy. virtually undetectable. Little is known about the In many compromised equine pregnancies, the pre- biological activity of most of these compounds, al- partum changes of these hormones and their metab- though 5␣-DHP is known to inhibit myometrial con- olites may be too acute to provide advanced warning tractility in women.12 It also binds more strongly of impending fetal demise. Non-lethal forms of fe- than P4 to the uterine progesterone receptor in tal compromise associated with infection, hypoxia, mares.13 or disrupted patterns of fetal development may be During the last week of gestation, an unknown even harder to detect using the hormonal assays stimulus results in an increase in fetal adrenocorti- currently available. cotropin hormone (ACTH) and the appearance of the enzyme 17 ␣-hydroxylase. This enzyme is respon- Progestagens sible for the conversion of progesterone to cortisol.14 The pre-partum hormonal changes in the mare are This pre-partum surge in fetal cortisol is associated different from those of other large-animal species. with the initiation of a critical cascade of endocrine In most other species, progesterone (P4) is the dom- events in the fetus that result in readiness for birth inant progestagen during pregnancy, and concentra- and an ability to adapt to extra-uterine life. Corti- tions of P4 decline before spontaneous labor, which sol stimulates an increase in the neutrophil:lympho- suggests that P4 withdrawal is conducive to active cyte (N:L) ratio and a rise in thyroid hormones that labor. In the mare, P4 is produced by the ovaries in turn have a positive impact on skeletal muscle until days 120–150 of gestation; at that time, the tone, body temperature regulation, and glucose ho- feto-placental tissues begin to synthesize P4 from meostasis. Maturation of the fetal hypothalamic- the pregnenolone (P5) supplied by the fetal adrenal pituitary-adrenal (PHA) axis is essential for glands. After days 180–240 of pregnancy, P4 con- triggering parturition and ensuring the final phase centrations are negligible in both maternal and fetal of fetal maturation. circulations. Instead, P4 is metabolized into a It is appealing to surmise that pregnancies jeop- number of other progestagens that include satu- ardized by placental anomalies or fetal compromise rated pregnanes and unsaturated pregnenes.1,2 will have altered concentrations of progestagens be- In the mare, progestagens other than P4 remain cause of disrupted or altered metabolic pathways relatively constant until 3 wk pre-partum. After within the feto-placental unit. A number of trials that time, progestagen levels rise gradually before have studied mares with either naturally occurring parturition.1,3,4 In particular, the concentration of high-risk pregnancies or with experimentally in- 5␣-pregnane,3,20-dione (5␣-DHP), a direct metabo- duced placental disease. Theses studies have doc- lite of P4, increases gradually during the last few umented wide variations in maternal concentrations weeks of gestation and then declines precipitously of plasma progestins including premature eleva- within days or hours of delivery.5,6 Interestingly, tions and precipitous declines.1,6,10,15,16 in human females, 5␣-DHP, rather than P4, under- Several patterns of progestagen activity during goes a pre-partum decline.7 late pregnancy begin to emerge. The worst sce- Commercial radioimmunoassays (RIAs) and en- nario is a pattern of rapidly declining progestagen zyme-linked immunosorbent assays (ELISAs) used concentrations with values approaching zero. In to measure “progesterone” concentrations in preg- pregnancies complicated by acute fetal distress, nant mares can be used to measure some of these there is a dramatic decline in progestagen produc- other progesterone metabolites that predominate tion, which reemphasized the importance of a during late pregnancy. This is possible, because healthy feto-placental unit for normal production the antibodies used in these assays cross-react with and metabolism of progestagens.1 Most of these many of the other progestagens, particularly the pregnancies were associated with fetal death and ␣-pregnanes. Values may vary between labs be- abortion. The second pattern is one of precociously cause of the different levels of cross-reactivity be- elevated levels of nearly all progestagen metabolites tween the different assay technologies.2,8,9 Using a that is often associated with bacterial placentitis, validated ELISA, progestagen values reported for enhanced fetal adrenocortical activity, and promis- mares between 180 and 310 days of gestation range ing neonatal survival.1,6,10 A few pregnancies com- from 2 to 6 ng/ml.10 promised by placental anomalies other than

282 2007 ր Vol. 53 ր AAEP PROCEEDINGS IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE bacterial placentitis, such as placental edema or vil- ture delivery, to have an infant of low birth weight, lous atrophy, exhibited a slightly different pattern. and to have an infant diagnosed with interventricular Levels of certain progestagens such as P4 were ele- hemorrhage.24–27 However, the use of progesterone vated, but other metabolites, including P5, were de- in pregnant women remains controversial, and its pre- creased, which possibly reflects a lack of functional cise mechanism of action, optimal formulation, route placenta.1 A third pattern of progestagen activity of administration, dose, and optimal gestational age at occurs when maternal progestins fail to show the initiation have yet to be determined.25 normal pre-partum rise. Mares experiencing prolonged gestations because of fescue toxicosis or other Estrogens 8,17,18 causes fall into this category. There are two groups of estrogens in the mare: Clinical Implications the common phenolic estrogens, estrone and estradiol 17␤, and the ring unsaturated estrogens, equilin Progestagen supplementation is a popular, yet con- and equilenin that are unique to the horse. The troversial, treatment for mares with placentitis and a fetal gonads provide the precursors that are ulti- other at-risk pregnancies. Oral altrenogest, a syn- mately converted by the uteroplacental tissues to thetic progestin, has been administered at doses of estrogens. Plasma-estrogen concentrations peak 0.088 mg/kg once daily to help prevent abortion and during months 7 and 8 of gestation; this is followed premature delivery in mid- to late-term mares.b19–21 by a gradual decline thereafter, which parallels the Alternatively and anecdotally, some clinicians pre- rise and fall in the size of fetal gonads. Between fer using injectable progesterone (300 mg, q 24 h, days 150 and 280 days of gestation, estrogen levels IM). The author recommends using a short-acting Ͼ1000 ng/ml are considered normal, and levels form of progestin supplementation rather than prep- Ͻ1000 ng/ml are indicative of fetal arations claiming longer duration of action. This stress.10 Estrogen levels Ͻ500 ng/ml are associ- allows for daily adjustments in therapy as war- ated with severely compromised or dead fetuses. ranted. It has been the author’s experience that The significance of elevated estrogen concentrations mares can deliver live foals as well as abort while has not received much attention, although higher receiving oral altrenogest at doses up to 0.044 mg/kg than normal levels of estradiol-17␤ have been re- (q 24 h, orally). If mares on progestin supplemen- ported in late-term mares exposed to endophyte- tation do reach their anticipated foaling dates, then infected tall fescue.28 Higher than normal it is recommended to decrease the dose of altreno- concentrations of estradiol-17␤ may contribute to gest gradually rather than discontinuing therapy the agalactia observed in mares suffering from fes- abruptly. cue toxicosis. Advocates of progestagen supplementation cite its The role of estrogen in the late-term mare remains ability to promote uterine quiescence and inhibit uncertain. One frequently referenced study evalu- prostaglandin-mediated abortion.10,19 Anecdotal ated the effect on pregnancy outcome of removing reports report on the apparent ability of progestagen estrogen precursors by gonadectomizing horse fe- supplementation to prevent pre-term labor in late tuses in mid to late gestation.29 Mares experienced gestational mares with placentitis. Critics of such dramatic decreases in plasma estrogen concentra- therapy question the benefit of using progestagen tions accompanied by prolonged, effective labor, de- supplementation in mares that may already have creased prostaglandin production, and the birth of elevated concentrations of progesterone metabo- dysmature foals.29 In other species, estrogen has lites.1,22 Most mares at risk for premature delivery an effect on uterine contractility and uterine blood are also receiving other therapy including antibiot- flow.30 Proposed mechanisms of action for estrogen ics, non-steroidal medication such as flunixin meglu- include promoting formation of uterine oxytocin re- mine, and anti-cytokine drugs such as ceptors, increasing uterine gap junction formation, pentoxifylline. Therefore, it is difficult to separate 31 the impact of altrenogest administration from the and alterating uterine blood flow, which may help effects of other concurrently administered medica- explain the weak labor in estrogen-deficient mares. tions. Researchers are beginning to provide an- Limited studies in late-term mares stressed by med- swers to this dilemma by studying mares with ical or surgical disease or induced abortion con- experimentally induced bacterial placentitis and cluded that maternal serum concentrations of estrone sulfate (ES) were not a sensitive indicator of evaluating the impact of administering or withhold- 15,32 ing altrenogest supplementation as well as other fetal compromise or death. Maternal ES con- therapeutic agents.21,23 centrations declined only after severe fetal stress or Pre-term birth is a leading cause of neonatal infant abortion had occurred. morbidity and mortality in the developed world. Pro- gesterone supplementation has been used in women Clinical Implications with a history of pre-term birth since the 1970s. There are no controlled clinical trials examining the In reviews of multicentric trials, women receiving pro- effects of estrogen supplementation in the late ges- gesterone were statistically and significantly less tational mare. Therefore, no specific recommenda- likely to experience recurrent miscarriage and prema- tions regarding the form of estrogen, the dosage, or

AAEP PROCEEDINGS ր Vol. 53 ր 2007 283 IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE the route of administration can be offered for its use assayable progestins, cortisol, T4, and tri-iodothyro- 38,43 in the late-term mare. nine (T3). Insight into the pathophysiology of this condition Relaxin may help improve our understanding of endocrine In the horse, the peptide hormone relaxin is pro- events associated with other causes of prolonged duced primarily by the placenta.33 Relaxin pro- gestation and lack of readiness for delivery in the motes uterine and cervical growth and remodeling mare and maladaptation/dysmaturity in the foal. that is essential for normal fetal growth and partu- Some of the speciﬁc therapies used to ameliorate the rition. Relaxin decreases the collagen content in endocrine abnormalities and clinical signs of fescue the extracellular matrices of the pubic symphysis toxicity may ﬁnd application in other periparturient and cervix, inhibits uterine contractility, and plays a conditions. role in mammary gland development. Relaxin has Ergopeptine alkaloids are the predominant toxins angiogenic and vasodilatory effects on endometrial associated with fescue toxicosis and are believed to and mammary tissues. This effect may be medi- cause the impaired reproductive function and aga- ated through up-regulation of vascular endothelial lactia through stimulation of D2-dopamine recep- growth factor (VEGF). The maternal concentration tors. Dopaminergic stimulation results in of relaxin begins to increase after day 75 of gestation decreased prolactin secretion.9,18 Prolactin plays and peaks at day 175. It remains elevated until an active role in the endocrine regulation of steroi- foaling, and then, it declines precipitously post-par- dogenesis and lactogenesis.18 The initiation of partum.34,35 Low maternal concentrations of relaxin turition in the mare involves proper maturation and during late gestation have been associated with function of the fetal hypothalamic-pituitary-adrenal high-risk pregnancies and complicated deliveries. (HPA) axis.9 Prolonged gestation length associated Some of the periparturient problems associated with with fescue toxicosis may be caused by hypopro- low relaxin levels have included premature placen- lactinemia-induced changes in uterofetoplacental tal separation, placentitis, hydrops, symptomatic steroid metabolism or inhibition of D2-dopamine re- maternal pituitary neoplasia, oligohydramnios, and ceptors on corticotrophs in the fetal anterior pitu- fescue toxicosis.35,36 itary gland.9,18,44 The ideal management strategy for mares con- Clinical Implications suming infected tall fescue is strategic withdrawal Currently, there are no commercially available as- of mares from infected pasture or hay 60–90 days says for equine relaxin. Perhaps with the recent prepartum. If this is not possible or practical, the 37 production of recombinant equine prorelaxin, administration of D2-dopamine receptor antagonists there will be new research reevaluating relaxin as a including domperidone (1.1 mg/kg, q 24 h, orally), marker of uteroplacental function in the mare. sulpiride (3.3 mg/kg, q 24 h, orally), or perphenazine (0.3–0.5 mg/kg, q 12 h, orally) have been used suc- Domperidone, Fescue Toxicosis, and Post-Term cessfully, beginning on day 300 of gestation, to pre- Pregnancy vent the endocrine alterations and clinical signs of As a dopamine receptor antagonist, domperidone fescue toxicosis in late-term mares.1,38,45 Unlike represents an interesting therapeutic intervention the other D2 antagonists, domperidone does not to treat fescue toxicosis and potentially other peri- cross the blood-brain barrier. parturient complications involving prolonged gesta- Domperidone (1.1 mg/kg, q 12–24 h, PO) has also tion and agalactia in the mare and lack of readiness enjoyed success in treating post-partum mares suf- for birth in the foal. Fescue toxicosis is an intrigu- fering from agalactia not caused by fescue toxicosis. ing model of maternal and fetal disease. In the A treatment protocol to induce non-pregnant mares mare, it is characterized by a lack of readiness for to lactate and become foster dams for orphan foals parturition that leads to prolonged gestation, abor- also incorporates the use of domperidone. The reg- tion, dystocia, and agalactia accompanied by placen- imen consists of a minimum 7-day course of domp- tal abnormalities that include premature placental eridone (1.1 mg/kg, q 24 h, PO), altrenogesta (44 mg, separation, thickening, and edema. In the foal, the q 24 h, PO), and estradiol-benzoate-in-oil (10 mg, q lack of readiness for birth is associated with an 24 h, IM).46 In the author’s experience, this proto- increased incidence of sepsis, peripartum asphyxia col has been used effectively to treat certain post- syndrome, failure of passive transfer, and dysmatu- partum mares that are rejecting their foals and rity or failure “to adapt” after delivery.38–40 Late- showing varying degrees of agalactia. term mares grazing endophyte-infected tall fescue Another poorly characterized syndrome in the show decreased concentrations of prolactin and re- mare is prolonged gestation length not caused by laxin18,38,40,41 and fail to exhibit the normal late obvious fescue toxicosis. There are benign causes gestational surge in progestins.9,17,18,38 Some stud- that are usually associated with normal parturition ies report increased levels of estrogens18 and de- and the birth of a healthy foal of average size. 42 creased levels of thyroxine (T4) in exposed mares. Explanations include human error and miscalcula- Foals exposed to ergopeptine alkaloids during late tion of the foaling date based on an inaccurate gestation have decreased plasma levels of immuno- breeding date. Prolonged gestation has also been

284 2007 ր Vol. 53 ր AAEP PROCEEDINGS IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE attributed to delayed embryonic development, espe- prostaglandin E (PGE) to induce cervical relaxation, cially during the first 2 mo.47 Duration of gestation more aggressive management of post-term pregnan- is partly controlled by nutrition and genotype of the cies has been recommended. foal.48,49 Colts tend to have longer gestation In cattle, fetal adenohypophyseal aplasia has been lengths than fillies. Mares due to foal earlier in the associated with prolonged gestation in the cow and year may have longer gestation lengths as a result of skeletal immaturity in the calf.56 In this case, the the shorter photoperiod. Older mares tend to have absence of fetal cortisol secretion as the endocrine longer gestations.50 However, the mare’s reported trigger to initiate parturition is the proposed mech- range of “normal” gestation lengths is quite elastic, anism for prolonged gestation. Other cases of pro- and some references describe normal pregnancies that longed gestation in cattle have been ascribed to fetal endure for up to 374 days or longer.47,48 Therefore, it adrenocortical hypoplasia and primary fetal adrenal is difficult to define what constitutes a post-term preg- insufficiency, both of which are associated with glu- nancy by days of gestation alone. cocorticoid deficiency.57 In the mare, there seems to be three types of foals Using the diagnostic tools available to us, more of associated with prolonged gestations: (1) foals that these post-term equine pregnancies should, at the are normal in size and adaptation, (2) large “post- vary least, be evaluated. Transrectal and/or trans- mature” foals that are thin with long hair coats, abdominal ultrasound can be used to assess fetal ineffective suckle reflexes, erupted incisors, poor size and activity, fetal heart rate reactivity in re- muscle development, and overgrown hooves with or sponse to fetal movement, placental thickness and without concurrent limb contracture, and (3) small, integrity, and quality and quantity of fetal fluids. dysmature foals that are thin with weak suckle re- Maternal hormone concentrations, including proges- flexes, underdeveloped musculature, short, fine hair tins, estrogen, and possibly prolactin and relaxin, coats, periarticular laxity, and varying degrees of can be monitored, and electrolyte profiles in mam- incomplete ossification. Dysmature and post-ma- mary secretions can be evaluated using commer- ture foals may exhibit poor thermoregulation, gas- cially available milk or water-hardness test kits. trointestinal dysfunction, glucose instability, renal A multiparous mare, with an uneventful past his- immaturity, and other endocrine abnormalities. tory of normal pregnancies, can serve as her own Some of these individuals may be stillborn. In control. If she begins to exceed previous gestation western Canada, prolonged gestations have been lengths by more than several weeks, reevaluation of associated with the birth of foals suffering from con- the pregnancy is justified, especially if there are genital hypothyroidism, dysmaturity, and a variety other concerning signs such as agalactia of musculoskeletal lesions including mandibular A mare with a post-term pregnancy associated prognathia, forelimb contracture, rupture of the with a large fetus, agalactia, low maternal progestin common digital extensor tendons, and incompletely levels, or unfavorable milk electrolyte profile would ossified cuboidal bones.51,52 Affected mares have be a candidate for domperidone therapy based on significantly longer gestation lengths, and ϳ25% of the suspicion that there is a lack of the normal these mares experience premature lactation and stimulus for parturition and fetal maturation as is dystocia.51 reported with fescue toxicosis. In the author’s ex- Post-term pregnancies in female humans have perience, this category of mare has responded favor- been associated with two types of outcomes: (1) an ably to domperidone therapy with udder aging placenta and “post-mature” fetus that contin- development, cervical relaxation, and spontaneous ues to grow in utero and is unusually large but thin delivery of a viable foal. Little is known about the at birth, and (2) an unfavorable uterine environment cause of many prolonged equine pregnancies, be- and placental insufficiency associated with the birth cause they are not investigated and are simply al- of a small, dysmature infant suffering from in utero lowed to take their own course; many end in growth retardation (IUGR).53 Both post-mature neonatal demise of undetermined cause. and dysmature infants are at increased risk for perinatal morbidity and mortality. Many post-term 3. Biophysical Parameters human pregnancies are complicated by decreased amniotic fluid volume (oligohydramnios)54 and Transrectal and Transabdominal Ultrasonography meconium staining/aspiration. Management strat- This topic is covered in detail in presentations58 and egies vary for human females with prolonged preg- other review articles.59,60 nancies exceeding 42 wk, but induced delivery is often pursued if gestation dates are accurate and Doppler Velocimetry there is a favorable cervix.55 If gestation dates are Another diagnostic tool that has had minimal appli- uncertain or there is lack of cervical ripening, then cation in the pregnant mare is Doppler velocim- management strategies vary and often focus on con- etry.61 This technique is used in women to tinued fetal surveillance using biophysical scoring, examine fetoplacental circulation in an attempt to evaluation of fetal activity and heart rate accelera- identify pregnancies at risk for fetal IUGR and ma- tion in response to fetal movement, and uterine con- ternal toxemia. Using a hand-held Doppler trans- tractions.53 More recently, with the use of ducer, umbilical and uterine arteries can be

AAEP PROCEEDINGS ր Vol. 53 ր 2007 285 IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE evaluated and displayed as wave forms. Different cose gradient that exists between dam and fetus vessels have different wave-form profiles based on across the equine placenta results in efficient glu- the dynamics of blood flow during systole and dias- cose transfer between mare and fetus.67,68 Oxygen tole. To evaluate relative flow velocity and placen- exchange between maternal and fetal circulations is tal perfusion, the systolic to diastolic ratio (S/D) in also very effective.68,69 the umbilical and uterine vessels is measured. Fasting of the late-term mare for 12–30 h has In normal pregnancies, the S/D ratio decreases; ad- been shown to increase production of uterine pros- vancing gestation reflects decreasing placental vas- taglandin F metabolites (PGFM). Likewise, refeed- cular resistance and increasing umbilical blood flow ing or infusion of glucose produces a rise in plasma required by the growing fetus.62 McGladdery et glucose and immediate fall in uterine PGFM concen- al.61 used this technique to examine a small group of trations. This fasting-induced surge in PGFM was pregnant pony mares. Preliminary results showed greatest in late-gestational mares. In one study, a similar decline in S/D ratio with advancing five of eight fasted mares delivered prematurely gestation.61 within 1 wk of the period of food withdrawal.70 Umbilical and uterine circulations are high-flow, low-resistance systems, and their wave forms are Clinical Implications characterized by a persistent diastolic component. Hypoglycemia in the pregnant mare can adversely Disappearance of flow during diastole is abnormal and affect placental metabolism and glucose delivery to indicates increasing vascular resistance. Changes in the fetus. Late-term mares that must be fasted, as flow dynamics may proceed for many weeks until is often prescribed after abdominal surgery, should changes in fetal wellbeing are detected by transab- be maintained on glucose infusions to prevent hypo- dominal ultrasonography. Increases in placental glycemia and to reduce the risk of prostaglandin- vascular resistance have been associated with infants mediated pre-term labor. IV infusions of 2.5% or suffering from IUGR or small size for gestational age 5.0% dextrose in 0.45% saline administered at fluid as well as maternal hypertension, toxemia, and other rates of 1–2 mg/kg/min of dextrose are recom- perinatal complications.62–64 Doppler velocimetry mended. Pregnant mares that are anorexic be- has also been used to evaluate the effect of various cause of systemic illness should be supplemented treatment strategies, including low-dose aspirin ther- through nasogastric intubation or through paren- apy, to improve uteroplacental perfusion by reducing teral nutrition to prevent a similar cascade of pros- vascular resistance. This technique still offers prom- taglandin-mediated events. ise for clinical application in equine perinatology. Oxygen therapy for pregnant mares with compromised placental function has been advocated to re- Placental Function duce the risk of fetal hypoxia before and during The placenta is more than just a blue print of the parturition. Effective oxygen administration using intrauterine environment. It is a dynamic organ in intranasal insufflation and oxygen flow rates of its own right. It has long been appreciated as the 10–15 l/min has been documented.71,72 gatekeeper of nutrient delivery and oxygen exchange throughout pregnancy, but it also synthe- Parturition sizes a number of hormones, including steroids, Delivery is divided into three stages. Stage I is peptides, glycoproteins, and eicosanoids. The pla- variable in length and associated with subtle clinical centa also inactivates other hormones such as cat- signs in the mare that include restlessness, nesting, echolamines, glucocorticoids, thyroxine, and frequent urination and defecation, loss of appetite, prostaglandins.65 In the horse, the growth of the and separation from the herd. It is associated with placental exchange surface is controlled by both the the critical but under appreciated period of fetal maternal and fetal genome.66 When the genetic repositioning in preparation for delivery. Stage II potential for placental growth is constrained (illus- labor commences with the rupture of the allantocho- trated when a horse fetus is placed in a smaller rion at the cervical pole. It is short in duration and surface density of microcotyledons in a pony mare is characterized by strong uterine contractions. uterus), the chorionic villi elongate, which increases Stage III labor is associated with milder post-par- the total surface area of fetomaternal contact. This tum uterine contractions and the passage of the fetal results in a larger fetus than would be produced by membranes. a pony genotype within a pony uterus.66 However, In a study using direct radiography to monitor the very little is known about the factors that regulate position, posture, and presentation of the equine placental growth or the critical windows in gestation fetus during late gestation and delivery,73 the im- when placental structure and function can be mod- portant sequence of events during stage I was ified by interventional therapies. clearly shown. During naturally occurring stage I The equine placenta is 5–7 times more efficient in labor, the full-term fetus undergoes purposeful nutrient transfer per unit area than either the cow movements to rotate the head and forelimbs into the or sheep placenta.67 This may be attributed to the dorsal position; this is followed by extension of the countercurrent blood-flow exchange mechanism in forelimbs and neck into the pelvic canal. The stim- the equine placenta. The high transplacental glu- ulus for initiation of these movements is not known.

286 2007 ր Vol. 53 ր AAEP PROCEEDINGS IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE Given the relatively low incidence of dystocia in cervical application of prostaglandin E2 has been spontaneously foaling mares, the mechanism that used in female humans84 and mares85 to induce controls this in utero fetal “dance” is normally quite cervical ripening before induction of parturition. efficient. The increased incidence of dystocia and If medical conditions warrant induction or if pre- premature placental separation associated with var- mature delivery seems imminent despite therapy, ious methods of induction74–76 stresses the impor- then the delivery of the foal becomes the next focus tance of limiting chemical induction of the mare to a of therapy. Fetal organ maturation is regulated by select group of periparturient emergencies. the HPA axis, and a rise in fetal plasma cortisol The optimal dose of oxytocin and route of adminis- concentrations usually occurs during the last 2–3 tration for induction remains controversial. Some re- days before delivery.86 Administration of ACTH di- searchers and clinicians believe that the use of low rectly to the equine fetus in utero promotes preco- doses of oxytocin are more physiologic and less likely to cious fetal maturation and early delivery but is too induce untoward delivery complications.77,78 invasive a technique to use safely in practice.87 ACTH administration to late-term mares stimu- Clinical Implications lated fetal maturation in some but not all mares.88 Whenever possible, induction should only be under- In 1975, Alm et al.89 used high doses of dexameth- taken in late-term mares that are close to their own asone (100 mg, q 24 h, IM for 4 days) to induce mares physiologic foaling dates. Indications for induction to foal. Maternal glucocorticoid administration sig- should be limited to conditions that would seriously nificantly reduced gestation length and resulted in threaten maternal or fetal health if the pregnancy the birth of foals that were small but reportedly were allowed to continue or if unsupervised, sponta- mature. Another study performed using the same neous delivery would occur. Examples of such con- pre-partum dose of steroids resulted in dystocia and ditions include hydrops, pre-pubic tendon rupture, fetal death.74 Anecdotal reports from clinical prac- imminent death of the mare because of colic or other tice suggest that varying doses of dexamethasone systemic illness, and maternal history of severe dys- administered pre-partum to mares resulted in im- tocia requiring mandatory assistance during deliv- proved fetal survival. Evaluation of the potential ery. Criteria used to assess readiness to foal benefits of maternal steroid therapy was revisited include normal udder development, the presence of recently by Ousey et al.90 Five Thoroughbred colostrum in the teats, a favorable electrolyte profile mares received 100 mg of dexamethasone one time in pre-partum mammary secretions,79 and a dilated daily from 315 to 317 days of gestation. Dexam- or softening cervix. ethasone-treated mares delivered significantly ear- Pre-foaling mammary secretion electrolytes are lier than control mares. Duration of second- and related to fetal readiness for birth in normal preg- third-stage labor did not differ between treated and nancies.80 Calcium concentration increases were control mares. One steroid-treated mare experi- accompanied by an inversion of sodium and potas- enced premature placental separation, but the al- sium concentrations.81 Mature, term foals are usu- lantochorion ruptured spontaneously before manual ally produced from deliveries associated with the intervention. All of the foals seemed healthy and following mammary electrolyte profile: calcium Ն mature and exhibited normal post-partum behavior. 40 mg/dl, sodium Յ 30 mEq/l, and potassium Ն 35 Steroid-treated mares had poorer quality colostrum mEq/l.80,81 Stall-side test kits that measure cal- at the time of delivery, and four foals in the treated cium concentrations alone are commercially availa- group required colostrum supplementation. ble.c,d Mares with precocious udder development Administration of dexamethasone to pre-partum and lactation because of placentitis may have early, mares remains an attractive and inexpensive and misleading, elevation of mammary secretion method of inducing precocious fetal development. calcium concentration.82 However, caution is urged before using this therapy. The optimal dose of oxytocin and route of admin- The number of mares treated under controlled con- istration for induction remains controversial.76– ditions has been small, and the few studies examining 78,81,83 Some researchers and clinicians promote this induction strategy have differed in their results. the use of low doses of oxytocin (2.5–5.0 IU, q 15–30 The optimal dose of dexamethasone and the frequency min, IV) as being more physiologic and less likely to and timing of administration require further research. induce untoward delivery complications.77,79 Some In particular, the time of gestation at which this clinicians advocate a continuous infusion of oxytocin therapy is initiated may be critical in terms of fetal at a rate of 1 IU/min. Maintaining a continuous endocrine development and response to treatment. infusion can be problematic in some mares that pace Antenatal steroid administration has been used in hu- and roll during stage I labor. Regardless of the man females at risk for premature delivery, and its oxytocin method selected, induced deliveries are as- use remains controversial. sociated with an increased risk of delivery complications including premature placental separation and The Placenta dystocia. If induction is imperative and the cervix The mare should pass her placenta within3hof is unfavorable, topical instillation of prostaglandin delivery. A normal placenta weighs ϳ10–11% of E2 gel to the cervix should be considered. Intra- the foal’s birth weight. Heavier than normal fetal

AAEP PROCEEDINGS ր Vol. 53 ր 2007 287 IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE membranes may be caused by edema associated garded as possible sources of infectious diseases with placentitis and/or insufficiency. Detailed re- should unexplained cases of strangles infection, views of the systematic examination of the equine EHV-1 abortion, or Salmonella diarrhea show up on placenta are presented elsewhere.91–95 If placental a breeding farm or other facility where pregnant pathology or dysfunction is suspected, tissue sam- mares are in residence. All incoming mares should ples should be submitted for histopathology from be quarantined for a minimum of 21–28 days, and representative areas of the chorioallantois, includ- they should be monitored for signs of fever and in- ing the fetal and non-fetal horns, body of the pla- fectious diseases before allowing them entry into the centa, cervical star, umbilical cord, and amnion. resident mare population. Pathological lesions that might be missed on gross If mares have never been vaccinated against ra- inspection alone include hypoplastic or atrophic bies, it is recommended that they receive their ini- changes in the microcotyledons associated with pla- tial priming dose pre-breeding rather than during cental insufficiency, acute bacterial placentitis, and pregnancy to ensure a consistent immune response.e Equine Herpes Virus 1 (EHV-1)-induced vascular Other selected therapies used in late-term mares changes. with complicated pregnancies are presented in Ta- Umbilical cord anomalies may be overlooked but ble 1. can contribute to fetoplacental compromise. Aver- age cord length in Thoroughbreds is between 36 and The Newborn Foal 83 cm.94 Unusually long cords (Ͼ80 cm) have been Healthy full-term foals are precocious neonates that associated with hypoperfusion of the allantochorion. have an effective suckle reflex and can sit sternal They may be prone to cord torsion, which may con- within 20 min of birth. Tactile stimulation inside tribute to fetal strangulation, hypoxia, death, and the pinnae or inside the nares should elicit a vigor- abortion.94,96,97 Excessively short cords place in- ous attempt at avoidance with an ear twitch and creased traction on the placenta during delivery and grimace, respectively. Immediately post-partum, may predispose the mare to premature placental the foal’s heart rate is relatively slow at 50–60 separation. beats/min, but then, it rises steadily to Ͼ100 beats/ min within the first 1 h. The neonate’s respiratory Clinical Implications rate is rapid, shallow, and Ͼ50–60 breaths/min, Clients and foaling attendants should be trained to because the lungs that were filled with amniotic save and weigh the placenta. Unusually heavy or fluid only minutes before are now being expanded. light placentas are a reason to prompt an earlier Body temperature should stabilize between 99°F than normal veterinary examination of the foal and and 102°F. Most foals should be standing within fetal membranes. Heavy placentas may be associ- 1 h and nursing from the udder within2hofdeliv- ated with edema, congestion, and/or infection, and ery. Thereafter, they should remain bright and in- they may increase the risk of sepsis and hypoxic- quisitive when approached and be able to return to ischemic encephalopathy in the neonate. A thin, the udder to nurse consistently. light placenta often corresponds to villous atrophy or hypoplasia, and it may be associated with smaller Clinical Implications than normal foals with increased susceptibility to Clients and foaling attendants should be familiar metabolic and endocrine instabilities during early with the above sequence of post-partum events. post-natal life. Foals suffering from in utero sepsis, periparturient asphyxia, serious forms of dysmaturity, or a variety Late Pregnancy and Immunosuppression of congenital musculoskeletal disorders will often Because of the stress and/or immunosuppressive ef- deviate from this simple, but important, behavioral fects of pregnancy, late-term mares may be at in- time line. If this occurs, a veterinarian should be creased risk to experience recrudescence of EHV-1 contacted, and a complete examination should be infection with subsequent abortion and/or to begin performed on the foal, placenta, and mare as soon as nasal shedding of Streptococcus equi or fecal shed- possible. ding of Salmonella sp if they are inapparent carriers of these pathogens. Pregnant mares also show in- Colostrum and Passive Immunity consistent or unpredictable immune responses when Colostrum ingestion is critical not only for passive immunized for the first time against novel antigens transfer of IgG but for many other reasons. Co- that they have never been exposed to either by nat- lostrum is a rich source of calories, vitamins A and ural infection or previous vaccination.e E, white blood cells, cytokines, growth factors, and other hormones and enzymes.98,99 Laxative prop- Clinical Implications erties have also been ascribed to its ingestion. The Pregnant mares should be maintained on a regular predominant immunoglobulins in equine colostrum vaccination schedule against EHV-1 during months are IgG(T), IgGa, and IgGb, and there are lesser 5, 7, and 9 of pregnancy and should be protected amounts of IgM and IgA in colostrum. At parturi- from unnecessary stress, such as shipping or show- tion, normal colostrum should have an IgG concen- ing, during late pregnancy. They should be re- tration of Ͼ3000 mg/dl. The colostral IgG

288 2007 ր Vol. 53 ր AAEP PROCEEDINGS IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE

Table 1. Selected Therapies for Late-Term Mares With High-Risk Pregnancies

Therapeutic Agent Suggested Dosage References Proposed Mechanism of Action

Trimethoprim sulfa 25 mg/kg, PO, q 12 h 107–110 Antimocrobial Potassium penicillin G 22,000 IU/kg, IV, q 24 h 111 Antimicrobial Gentamicin 6.6 mg/kg, IV, q 24 h 111, 112 Antimicrobial Altrenogest* 0.088 mg/kg, PO, q 24 h 19 Tocolysis; prevent prostaglandin mediated abortion Isoxsuprine 0.4–0.6 mg/kg, PO, q 24 h 113 Tocolysis Clenbuterol 0.8 ␮g/kg, PO, q 12 h 115, 116 Tocolysis Flunixin meglumine 0.25 mg/kg, PO/IV,q8h 19, 111 Anti-inflammatory, prevent prostaglandin-mediated abortion 1.1 mg/kg, IV, q 24 h Pentoxifylline 8.5 mg/kg, PO, q 12 h 110, 111, 114, 117 Block endotoxin-induced tumor necrosis factor, IL-6; Anti-cytokine activity Vitamin E 1000–10,000 IU, PO, q 24 h 118 Antioxidant Oxygen insufflation Intranasal oygen @ 10–15 71, 72 Reduce risk of fetal hypoxia l/min Dextrose administration 2.5–5.0% dextrose, IV, @ 1–2 Prevent hypoglycemia to mg/kg/min of dextrose reduce uteroplacental prostaglandin production during materna fasting Dexamethasone Insufficient information to 90 Induce parturition and hasten recommend dose and fetal maturation frequency

concentration may exceed 9000 mg/dl in some maternal age, and breed. If poor-quality colostrum is mares.100 However, colostral immunoglobulin con- detected, an alternate source of colostrum can be ad- centrations may decline rapidly to negligible levels ministered in a timely fashion. within 12 h of delivery in mares that are being Radioimmunoassay (RIA) has long been consid- nursed regularly by healthy foals. The ability of ered the gold standard used to measure and vali- the newborn foal’s intestinal tract to non-selectively date IgG concentration. The disadvantage is that absorb these large immunoglobulins peaks immedi- the test requires 18–24 h to obtain results. A ately after delivery and decreases dramatically variety of screening tests are available to measure within the first 3–6 h of life. Absorptive efficiency serum IgG in foals. These tests include glutaral- is only 22% within3hofdelivery.101 Maternally dehyde coagulation, zinc sulfate turbidity, and derived antibodies can be detected in foal blood semiquantitive ELISA. For a more complete dis- within6hofcolostrum ingestion. cussion of FPT, the diagnostic tests available, and Healthy foals consuming adequate amounts of recommended therapies, the reader is referred to good-quality colostrum should have serum IgG con- several excellent review articles.104–106 Many centrations of Ͼ800 mg/dl by 12–24 h of age. Fail- veterinarians prefer to use commercial kits based ure of the foal to ingest or absorb adequate colostral on either glutaraldehyde coagulation or ELISA. immunoglobulins is termed failure of passive trans- In a recent comparison of glutaraldehyde coagula- fer (FPT). A foal with FPT is defined as a foal with tion and ELISA,h both tests were appropriate a serum IgG concentration of Ͻ400 mg/dl at 24 h of screening tests with high sensitivity and negative age. Partial FPT is defined as a foal with a serum predictive value. However, the ELISA was better concentration between 400 and 800 mg/dl. The re- than the glutaraldehyde coagulation in specificity ported incidence of complete or partial FPT in foals and positive predictive value, meaning that foals varies from 3% to 37.8%.102,103 with FPT were correctly identified. Therapy for FPT includes colostrum administration if the foal Clinical Implications has normal gut function and is still young enough Colostral quality can be evaluated immediately after to absorb colostral antibodies. Older foals and delivery by measuring specific gravity using a co- those neonates with compromised gastrointestinal lostrometerf or by measuring refractive index using tracts benefit from plasma administration. a sugar refractometer.g Poor-quality colostrum may be caused by a variety of factors including premature 4. Conclusion lactation, poor maternal immune or nutritional status, Equine perinatology has evolved rapidly over the exposure to endophyte-infected pasture, advancing last two decades. However, most mares will con-

AAEP PROCEEDINGS ր Vol. 53 ր 2007 289 IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE tinue to foal in locations other than in large clinics 17. Brendemeuhl JP. Effects of Acremonium coenophialum- and university hospitals. Therefore, it will remain infected tall fescue on progestagen production in pregnant mares, in Proceedings. Society of Theriogenology Meeting in the hands of clinicians in private practice to help 1992;108–112. improve our knowledge of the high-risk mare by 18. Cross DL, Redmond LM, Strickland JR. Equine fescue tox- using and reporting on the use of the antepartum icosis: signs and solutions. J Anim Sci 1995;73:899–908. monitoring techniques and interventional strategies 19. Daels PF, Besognet B, Hansen B, et al. Effect of proges- discussed in this presentation. terone on prostaglandin F-2 alpha secretion and outcome of pregnancy during cloprostenol-induced abortion in mares. Am J Vet Res 1996;57:1331–1334. References and Footnotes 20. Troedsson MHT. Myometrial activity and progestin sup- 1. Ousey JC, Houghton E, Grainger L, et al. Progestagen plementation, in Proceedings. Society of Theriogenology profiles during the last trimester of gestation in Thorough- Meeting 2000;17–24. bred mares with normal or compromised pregnancies. The- 21. Macpherson ML. in Proceedings. Society of Theriogenol- riogenology 2005;63:1844–1856. ogy Meeting 2006. 2. Holtan DW, Houghton E, Silver M, et al. Plasma progesta- 22. Holtan DW. Progestin therapy in mares with pregnancy com- gens in the mare, fetus and newborn foal. J Reprod Fertil plications: necessity and efficacy, in Proceedings. Am Assoc 1991;44(Suppl):511–519. Equine Pract 1993;39:165–166. 3. Barnes RJ, Nathanielsz PW, Rossdale PD, et al. Plasma 23. Macpherson ML. Treatment strategies for mares with pla- progestagens and oestrogens in fetus and mother in late centitis. Theriogenology 2005;64:528–534. pregnancy. J Reprod Fertil 1075;23(Suppl):617–622. 24. Lamont RF, Jaggat AN. Emerging drug therapies for pre- 4. Pashen RL. Maternal and foetal endocrinology during late venting spontaneous preterm labor and preterm birth. Ex- pregnancy and parturition in the mare. Equine Vet J 1984; pert Opin Investig Drugs 2007;16:337–345. 16:233–236. 25. Vidaeff AC, Ramin SF. From concept to practice: the re- 5. Hamon M, Clarke SW, Houghton E, et al. Production of cent history of preterm delivery prevention. Part II. Sub- 5␣-dihydroporgesterone during late pregnancy in the mare. clinical infection and hormonal effects. Am J Perinatol J Reprod Fertil 1991;44(Suppl):529–535. 2006;23:75–84. 6. Rossdale PD, Ousey JC, Cottrill CM, et al. Effects of pla- 26. Di Renzo GC, Mattei A, Gojnic M, et al. Progesterone and cental pathology on maternal plasma progestagen and mam- pregnancy. Curr Opin Obstet Gynecol 2005;17:598–600. mary secretion calcium concentrations and on neonatal 27. Da Fonseca EB, Bittar RE, Carvalho MHB, et al. Prophy- adrenocortical function in the horse. J Reprod Fertil 1991; lactic administration of progesterone by vaginal suppository 44(Suppl):579–590. to reduce the incidence of spontaneous preterm birth in 7. Lofgren M, Backstrom T, Joelsson I. Decline in serum con- women at increased risk: a randomized placebo-controlled centration of 5␣-pregnane-3,20-dione prior to spontaneous double-blinded study. Am J Obstet Gynecol 2003;188:419. labor. Acta Obstet Gynecol Scand 1988;67:467–470. 28. Cross DL. Fescue toxicosis in horses. In: Bacon CW, 8. Brendemeuhl JP, Williams MA, Boosinger TR, et al. Hill NS, eds. Neotyphodium/grass interactions. New York: Plasma progestagens, triiodothyronine and cortisol con- Plenum Press, 1997;289–309. centrations in post date gestation foals exposed in utero to 29. Pashen RL, Allen WR. The role of the fetal gonads and tall fescue endophyte Acremonium coenophialum. Biol placenta in steroid production, maintenance of pregnancy Reprod Monogr 1995;1:53–59. and parturition in the mare. J Reprod Fertil 1979; 9. Evans TJ, Constantinescu GM, Ganjam VK. Clinical re- 27(Suppl):499. productive anatomy and physiology of the mare. In: 30. Silver M. Prenatal maturation, the timing of birth and Youngquist RS, ed. Current therapy in large animal the- how it may be regulated in domestic animals. Exp Physiol riogenology. Philadelphia: W.B. Saunders Co., 1997; 1990;75:285–307. 43–70. 31. Garfield RE, Kannan MS, Daniel ME. Gap junction forma- 10. LeBlanc MM, Macpherson M, Sheerin P. Ascending pla- tion in the myometrium: control by estrogens, progester- centitis: what we know about pathophysiology, diagnosis one and prostaglandins. Am J Physiol 1980;238:C81. and treatment, in Proceedings. Am Assoc Equine Pract 32. Madej A, Kindahl H, Mydahl C, et al. Hormonal changes 2004;50:127–143. associated with induced late abortions in the mare. J Re- 11. Ousey JC, Forhead AJ, Rossdale PD, et al. The ontogeny of prod Fertil 1987;35(Suppl):479. uteroplacental progestagen production in pregnant mares 33. Klonisch T, Mathias S, Cambridge G, et al. Placental lo- during the second half of gestation. Reproduction 2003;69: 540–548. calization of relaxin in the pregnant mare. Placenta 1997; 12. Lofgren M, Host J, Backstrom T. Effects in vitro of proges- 18:121–128. terone and two 5␣-reduced progestins, 5␣-pregnan,3,20-di- 34. Stewart DR, Addiego LA, Pascoe DR, et al. Breed differ- one and 5␣-pregnan-3a-ol-20-one, on contracting human ences in circulating equine relaxin. Biol Reprod 1992;46: myometrium at term. Acta Obstet Gynecol Scand 1992:71: 648–652. 28–33. 35. Ryan PL, Vaala WE, Bagnell C. Relaxin as an indicator of 13. Chavatte-Palmer P, Duchamp G, Palmer E, et al. Proges- placental insufficiency, in Proceedings. Am Assoc Equine terone, oestrogen and glucocorticoid receptors in the uterus Pract 1998;44:62–63. and mammary glands for mares from mid- to late- gestation. 36. Ryan PL, Bennet-Wimbush K, Vaala WE, et al. Systemic J Reprod Fertil 2000;56(Suppl):661–672. relaxin in pregnant pony mares grazed on endophyte-in- 14. Mason JI, Hinshelwood MM, Murray BA, et al. Tissue- fected fescue: effects of fluphenazine treatment. Theriog- specific expression of steroid 17 ␣-hydroxylase/C-17,20 enology 2001;56:471–483. lyase, 3␤-hydroxysteroid dehydrogenase and aromatase in 37. Neumann JL, Lazaris A, Huang XJ, et al. Production and the fetal horse, in Proceedings. Society for Gynecological characterization of recombinant equine prorelaxin. Do- Investigation Meeting 1993;357. mest Anim Endocrinol 2006;2:178–185. 15. Santschi EM, LeBlanc MM, Weston PG. Progestogen, oes- 38. Brendemeuhl JP. Reproductive aspects of fescue toxicosis. trogen sulphate and cortisol concentrations in pregnant In: Robinson NE, ed. Current therapy in equine medicine 4. mares during medical and surgical disease. J Reprod Fer- Philadelphia: W.B. Saunders Co., 1997;571–573. til 1991;44(Suppl):627–634. 39. Evans TJ, Rottinghaus GE, Casteel SW. Ergopeptine al- 16. Macpherson ML. Diagnosis and treatment of equine pla- kaloid toxicoses in horses. In: Robinson NE, ed. Current centitis. Vet Clin North Am [Equine Pract] 2006;22:763– therapy in equine medicine 5. Philadelphia: W.B. Saun- 776. ders Co. 796–798.

290 2007 ր Vol. 53 ր AAEP PROCEEDINGS IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE

40. Green EM, Raisbeck MF. Fescue toxicosis. In: Robin- 62. Schulman H, Fleischer A, Stern W, et al. Umbilical veloc- son NE, ed. Current therapy in equine medicine 4. Phila- ity wave ratios in human pregnancy. Am J Obstet Gynecol delphia: W.B. Saunders Co., 1997;670–673. 1984;148:985. 41. Ryan PL, Bennet-Wimbush K, Vaala WE, et al. Systemic 63. Ghosh G, Bregorowicz A, Brasert M, et al. Evaluation of relaxin in pregnant pony mares grazed on endophyte-in- third trimester uterine artery flow velocity indices in rela- fected fescue: effects of fluphenazine treatment. Theriog- tionship to perinatal complications. J Matern Fetal Neona- enology 2001;56:471–483. tal Med 2006;19:551–555. 42. Messer NT, Riddle T, Traub-Dargatz JL, et al. Thyroid 64. Gudmundsson S, Korszum P, Olofsson P, et al. New score hormone levels in Thoroughbred mares and their foals at indicating placental vascular resistance. Acta Obstet Gy- parturition, in Proceedings. Am Assoc Equine Pract 1998; necol Scand 2003;82:807–812. 44:248–251. 65. Fowden AL, Forhead AJ. Endocrine mechanisms of intra- 43. Boosinger TR, Brendemeuhl JP, Bransby DL, et al. Pro- uterine programming. Reproduction 2004;127:515–526. longed gestation, decreased tri-iodothyronine concentration 66. Allen WR, Wilsher S, Turnbull C, et al. Influence of ma- and thryoid gland histomorphologic features in newborn ternal size on placental, fetal and postnatal growth in the foals of mares grazing Acremonium coenophialum infected horse. In: Development in utero reproduction. 2002; fescue. Am J Vet Res 1995;56:66–69. 454–465. 44. Evans TJ, Youngquist RS, Loch WE, et al. A comparison of 67. Wooding FBD, Fowden AL. Nutrient transfer across the the relative efficacies of domperidone and reserpine in treat- equine placenta: correlation of structure and function. ing equine “fescue toxicosis,” in Proceedings. Am Assoc Equine Vet J 2006;38:175–183. Equine Pract 1999;45:207–209. 68. Silver M, Comline RS. Transfer of gases and metabolites in 45. Redmond LM, Cross DL, Strickland JR, et al. Efficacy of the equine placenta: a comparison with other species. J domperidone and sulpiride as treatments for fescue toxicosis Reprod Fertil 1975;23(Suppl):589–594.

in horses. Am J Vet Res 1995;55:722–729. 69. Comline RS, Silver M. PO2 levels in the placental circula- 46. Daels PF, Duchamp G, Porter D. Induction of lactation and tion of the mare and ewe. Nature 1968;217:76–77. adoption of foals by non-parturient mares, in Proceedings. 70. Silver M, Fowden AL. Uterine prostaglandin F metabolite Am Assoc Equine Pract 2002;48:68–71. production related to glucose availability in late pregnancy 47. Vanderplassche M. Obstetrician’s view of the physiology of and a possible influence of diet on time of delivery in the equine parturition and dystocia. Equine Vet J 1980;12:45– mare. J Reprod Fertil 1982;32(Suppl):511–519. 49. 71. Wilkins PA. High-risk pregnancy. In: Paradis MR, ed. 48. Rossdale PD, Ricketts SW. The practice of equine stud Equine neonatal medicine. Philadelphia: Elsevier Saun- medicine. Baltimore: Williams and Wilkins, 1980. ders, 2006;13–29. 49. Ginther OJ. Reproductive biology of the mare—basic and 72. Wilkins PA, Seahorn TL. Intranasal oxygen therapy in applied aspects. Cross Plains, WI: Ginther, 1979. adult horses. J Vet Emerg Crit Care 2000;10:221. 50. Bosh K, Fallon L. Characteristics of the equine placenta. 73. Jeffcott LB, Rossdale PD. A radiographic study of the fetus Equine Dis Q 2005;14. in late pregnancy and during foaling. J Reprod Fertil 1979; 51. Allen AL, Doige CE, Fretz PB, et al. Congenital hypothy- 27(Suppl):563–569. roidism, dysmaturity and musculoskeletal lesions in west- 74. Jeffcott LB, Rossdale PD. A critical review of methods for ern Canadian foals, in Proceedings. Am Assoc Equine induction of parturition in the mare. Equine Vet J 1977;9: Pract 1993;39:207–208. 208–215. 52. McLaughlin BG, Doige CE. Congenital musculoskeletal le- 75. Rossdale PD, Jeffcott LB. Problems encountered during sions and hyperplastic goitre in foals. Can Vet J 1981;22: induced foaling in Pony mares. Vet Rec 1975;97:371–372. 130–133. 76. Macpherson ML, Chaffin MK, Carroll GL, et al. Three 53. O’Grady JP, Veille J-C. Obstetric management of multiple methods of oxytocin-induced parturition and their effects on pregnancy and postmaturity. In: Fanaroff AA, Martin foals. J Am Vet Med Assoc 1997;210:799–803. RJ, eds. Neonatal-perinatal medicine: diseases of the fe- 77. Paschen RL. Low doses of oxytocin can induce foaling at tus and infant. St Louis, MO: CV Mosby Co., 1987;149– term. Equine Vet J 1980;12:85–87. 155. 78. Ley WB, Holyoak GR. Normal prefoaling mammary secre- 54. Dasari P, Niveditta G, Raghavan S. The maximal vertical tions. In: Samper LC, Pycock JF, McKinnon AO, eds. pocket and amniotic fluid index in predicting fetal distress Current therapy in equine reproduction. St. Louis, MO: in prolonged pregnancy. Int J Gyneacol Obstet 2007;96: W.B. Saunders Co., 2007;446–451. 89–93. 79. Ley WM. Pre-foaling management of the mare and induc- 55. Neilson JP. Induction of labour for improving birth out- tion of parturition. In: Robinson NE, ed. Current therapy comes for women beyond term. Obstet Gynecol 2007;109: in equine medicine, 3rd ed. Philadelphia: W.B. Saunders 753–754. Co., 1992;664–667. 56. Graves TK, Hansel W, Krook L. Prolonged gestation in a 80. Ousey JC, Dudan F, Rossdale PD. Preliminary studies of Holstein cow: adenohypophyseal aplasia and skeletal pa- mammary secretions in the mare to assess foetal readiness thology in the offspring. Cornell Vet 1991;81:277–294. for birth. Equine Vet J 1984;16:259–263. 57. Stabenfeldt GH, Edqvist L, Drost M. Endocrine changes 81. LeBlanc MM. Induction of parturition in the mare: as- during normal and prolonged bovine pregnancy. Acta En- sessment of readiness for birth. In: Koterba AM, Drum- docr 1975;199(Suppl):385. mond WH, Kosch PC, eds. Equine clinical 58. Macpherson ML. Identification and management of the neonatology. Philadelphia: Lea and Febiger, 1990;34–39. high risk pregnant mare, in Proceedings. Am Assoc 82. Rossdale PD, Ousey JC, Cottrill CM, et al. Effects of pla- Equine Pract 2007;53:293–304. cental pathology on maternal plasma progestagen and mam- 59. Bucca S. Diagnosis of compromised equine pregnancy. mary secretion calcium concentrations and on neonatal Vet Clin North Am [Equine Pract] 2006;22:749–761. adrenocortical function in the horse. J Reprod Fertil 1991; 60. Reef VB. Late term pregnancy monitoring. In: Samper 44(Suppl):579. JC, Pycock JF, McKinnon AO, eds. Current therapy in 83. Camillo F, Marmorini P, Romagnoli S, et al. Clinical stud- equine reproduction. Philadelphia: Saunders Elsevier, ies on daily low dose oxytocin in mares at term. Equine Vet 2007;410–416. J 2000;32:307–310. 61. McGladdery AL, Ousey JC, Rossdale PD. Serial Doppler 84. Jackson GM, Sharp HT, Varner MW. Cervical ripening ultrasound studies of the umbilical artery during equine before induction of labor: a randomized trial of prostaglan- pregnancy, in Proceedings. 3rd Conference of the Interna- din E2 gel versus low-dose oxytocin. Am J Obstet Gynecol tional Veterinary Perinatology Society 1993;37. 1994;171:1092–1096.

AAEP PROCEEDINGS ր Vol. 53 ր 2007 291 IN-DEPTH: PERINATOLOGY—END OF PREGNANCY THROUGH BEGINNING OF LIFE

85. Rigby S, Love C, Carpenter K, et al. Use of prostaglandin 105. Sellon DC. Foal with failure of passive transfer. In: E2 to ripen the cervix of the mare prior to induction of Paradis MR, ed. Equine neonatal medicine. Philadelphia: parturition. Theriogenology 1998;50:897–904. Elsevier Saunders, 2006;31–39. 86. Silver M. Prenatal maturation, the timing of birth and 106. Davis R, Giguere S. Evaluation of ﬁve commercially avail- how it may be regulated in domestic animals. Exp Physiol able assays and measurements of serum total protein con- 1990;75:285–307. centration via refractometry for the diagnosis of failure of 87. Ousey JC, Rossdale PD, Dudan FE, et al. The effects of passive transfer of immunity in foals. J Am Vet Med Assoc intrafetal ACTH administration on the outcome of preg- 2005;227:1640–1645. nancy in the mare. Reprod Fertil Dev 1998;10:359–367. 107. Rebello SA, Macpherson ML, LeBlanc MM, et al. The de- 88. Ousey JC, Rossdale PD, Palmer L, et al. Effects of mater- tection of placental drug transfer in equine allantoic ﬂuid. nally administered Depot ACTH 1–24 on fetal maturation Theriogenology 2005;64:776–777. and the timing of partuition n the mare. Equine Vet J 108. Rebello SA, Macpherson ML, Murchie TA, et al. Placental 2000;32:489–496. transfer of trimethoprim sulfamethoxazole and pentoxifyl- 89. Alm CC, Sullivan JJ, First NL. The effect of a corticoste- line in pony mares. Anim Reprod Sci 2006;94:432–433. roid (dexamethasone), progesterone, oestrogen and prosta- 109. Sertich PL, Vaala WE. Concentrations of antibiotics in

glandin F2␣ on gestation length in normal and mares, foals and fetal fluids after antibiotic administration ovariectomized mares. J Rerpod Fertil 1975;23(Suppl): in late pregnancy, in Proceedings. Am Assoc Equine Pract 637–640. 1992;38:727–736. 90. Ousey JC, Kolling, Allen WR. The effects of maternal 110. Graczyk J, Macpherson ML, Pozor MA, et al. Treatment dexamethasone treatment on gestation length and foal mat- efficacy of trimethoprim sulfamethoxazole and pentoxifyl- uration in Thoroughbred mares. Anim Reprod Sci 2006;94: line in equine placentitis. Anim Reprod Sci 2006;94:434– 436–438. 435. 91. Schlafer DH. Postmortem examination of the equine pla- 111. Murchie TA, Macpherson ML, LeBlanc MM, et al. A mi- centa, fetus and neonate: methods and interpretation of crodialysis model to detect drugs in the allantois fluid of findings, in Proceedings. Am Assoc Equine Pract 2004;50: pregnant pony mares, in Proceedings. Am Assoc Equine 144–161. Pract 2003;49:118–119. 92. Schlafer DH. The equine placenta before and after birth: 112. Santschi EM, Papich MG. Pharmacokinetics of gentamicin recognition of normal features and appreciation of lesions of in mares in late pregnancy and early lactation. J Vet Phar- clinical importance, in Proceedings. Mare Reproduction macol Ther 2000;23:359–363. Symposium 1996;122–137. 113. Harkens JD, Mundy GD, Stanley S, et al. Absence of de- 93. Whitwell KE, Jeffcott LB. Morphological studies on the tectable pharmacological effects after oral administration of fetal membranes of the normal singleton foal at term. Res isoxsuprine. Equine Vet J 1998;30:294–299. Vet Sci 1975;19:44–55. 114. Lauterbach R, Zembala M. Pentoxifylline reduces plasma 94. Whitwell KE. Morphology and pathology of the equine um- tumour necrosis factor—aopha concentration in premature bilical cord. J Reprod Fertil 1975;23(Suppl):599–603. infants with sepsis. Eur J Pediatr 1996;155:404–409. 95. Whitehead AE, Chenier TS, Foster RA. Placental charac- 115. Card CR, Wood MR. Effects of acute administration of teristics of Standardbred mares, in Proceedings. Am Assoc clenbuterol on uterine tone and equine fetal and maternal Equine Pract 2005;51:215–220. heart rates. Biol Reprod 1995;1:7–11. 96. Vandeplassche M, Lauwers H. The twisted umbilical cord: 116. Palmer E, Chavette-Palmer P, Duchamp G, et al. Lack of an expression of kinesis of the equine fetus? Anim Reprod effect for clenbuterol for delaying parturition in late preg- Sci 1986;10:163–175. nant mares. Theriogenology 2002;58:797–799. 97. Smith KC, Blundun AS, Whitwell KE, et al. A survey of 117. Barton MH, Moore JN, Norton N. Effects of pentoxifylline equine abortion, stillbirth and neonatal death in the UK infusion on response in horses to in vivo challenge exposure from 1988–1997. Equine Vet J 2003;35:496–501. with endotoxin. Am J Vet Res 1997;58:1300–1307. 98. Jan CL. Cellular components of mammary secretions and 118. Drury EM, Whitaker TC, Palmer L. Oral water soluble neonatal immunity: a review. Vet Res 1996;27:403. vitamin E levels in the mare in late gestation, its effects on 99. Zou S, Brady HA, Hurley WL. Protective factors in mam- serum vitamin E levels in the pre- and post-partum mare mary gland secretions during the periparturient period in and the neonate: a preliminary investigation, in Proceed- the mare. J Equine Vet Sci 1998;18:184. ings. Equine Nutrition Conference for Feed Manufactur- 100. Pearson RC, Hallowell AL, Bayly WM, et al. Times of ers. 2004;137. appearance and disappearance of colostral IgG in the mare. Am J Vet Res 1984;45:186. 101. Jeffcott LB. Duration of permeability of the intestine to aRegumate, Intervet, Millsboro, DE 19966. macromolecules in the newly-born foal. Vet Rec 1971;88: bOsterreider K. Personal communication. 2005. 340. cFoalWatch test kit, CHEMetrics, Calverton, VA 20138. 102. Morris DD, Meirs DA, Merryman GS. Passive transfer dPredict-a-Foal, Animal Healthcare Products, Vernon, CA failure in horses: incidence and causative factors on a 90054. breeding farm. Am J Vet Res 1985;46:2294. eWilson WD. Personal communication. 2006. 103. McGuire TC, Crawford TB. Passive immunity in the foal: fEquine Colostrometer, Jorgenson Laboratories, Loveland, CO measurement of immunoglobulin classes and specific anti- 80231. body. J Am Vet Res 1973;34:1299. gBRIX sugar refractomer, Total Reproduction, Victoria, Austra- 104. Giguere S, Polkes A. Immunologic disorders in neonatal lia. foals. Vet Clin North Am [Equine Pract] 2005;21:241–272. hSNAP Foal, IDEXX Laboratories, Portland, ME 04102.

292 2007 ր Vol. 53 ր AAEP PROCEEDINGS