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Basics ⬇

Outline

BASICS

Definition!!navigator!!

Maternal structural or functional defects that prevent:

  • The fertilized ovum from normal embryonic development
  • Transport of the embryo into the uterus by day 6 after ovulation
  • Embryonic survival until pregnancy is diagnosed by transrectal US ≥14 days after ovulation

Pathophysiology!!navigator!!

The normal rate of conception failure is ≈ 30% for young mares (based on day 14–16 US) but approaches 50–70% in older, subfertile mares.

Some of the specific causes of failure of conception are as follows:

  • Defective embryos
    • Old mares
    • Seasonal effects
    • Transferred embryos from older mares or embryos generated by IVF or other reproductive technologies
  • Unsuitable/hostile uterine environment
    • Endometritis can result in early CL regression and failure of maternal recognition of pregnancy
    • Endometrial periglandular fibrosis
    • Lymphatic cysts of sufficient size to impede embryonic mobility and failure of maternal recognition of pregnancy
    • Inadequate secretion of histotrophs
  • Xenobiotics
    • Equine fescue toxicosis and ergotism
    • Phytoestrogens, anecdotal
  • Oviductal disease
    • Unsuitable/hostile environment for embryonic development
    • Oviductal blockage
  • Endocrine disorders
    • Hypothyroidism—anecdotal
    • Luteal insufficiency—anecdotal
    • Endocrine disorders, such as PPID and EMS/IR
  • Maternal disease
    • Fever
    • Pain, such as that associated with severe laminitis—anecdotal

Depending on the specific infectious cause, the pathophysiologic mechanisms for conception failure can involve 1 or more of the following:

  • Defective embryo which cannot continue to develop
  • Unsuitable oviductal or uterine environment that prevents fertilization and/or embryonic development
  • Oviductal blockage or impaired function
  • Failure of maternal recognition of pregnancy
  • Early CL regression
  • Luteal insufficiency—anecdotal

Systems Affected!!navigator!!

Reproductive

Signs!!navigator!!

Historical Findings

1 or more of the following:
  • After appropriately timed breeding with semen of normal fertility:
    • Failure of pregnancy diagnosed by transrectal US at >14 days after ovulation
    • Failure of pregnancy diagnosed by TRP at >25 days after ovulation
    • Return, possibly early, to estrus
  • History of PMIE
  • Previous exposure to endophyte-infected fescue or ergotized grasses and grains
  • Geographic location, especially in relation to endophyte-infected fescue pastures/hay and/or ergotized grasses or grains
  • Recent systemic disease

Physical Examination Findings

  • Nonpregnant uterus, possibly with edema of endometrial folds or accumulation of intrauterine (luminal) fluid
  • Absence of a CL
  • Mucoid or mucopurulent vulvar discharge

Risk Factors!!navigator!!

  • Older mares >15 years of age, especially those with moderate/severe endometritis, periglandular fibrosis, and/or lymphatic cysts
  • Anatomical defects predisposing the genital tract to endometritis
  • Seasonal effects
  • Foal heat breeding—anecdotal and somewhat controversial
  • Inadequate nutrition
  • Exposure to xenobiotics—fescue toxicosis and ergotism
  • Some heterospecific matings, e.g. stallion crossed with jenny
  • Susceptibility to PMIE
  • Geographic location, especially in relation to endophyte-infected fescue pastures/hay and/or ergotized grasses or grains
  • Preexisting PPID and EMS/IR
  • Severe laminitis
  • Transfer of embryos from older mares or those generated using IVF or other reproductive technologies

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

Differential Diagnosis!!navigator!!

Mistiming of Insemination or Breeding

  • Monitor follicular development and ovulation by TRP or US
  • Appropriate timing of insemination or breeding
  • Ovulation induction to complement timing of insemination or breeding

EED

Transrectal US detects pregnancy at >14 days, but the pregnancy is absent on subsequent examination at <40 days of gestation.

Pregnancy Undetected by Transrectal US

Careful, systematic visualization of the horns, uterine body, including near cervix; a slow sweep, twice over the entire tract, to avoid missing an early vesicle (yolk sac) of pregnancy.

Ovulation Failure

  • TRP or US (preferred) to confirm ovulation and presence of a CL
  • Serum P4 level 6–7 days after ovulation or at end of estrus

Poor Semen Quality

Monitoring/examination of ejaculate for adequate number of spermatozoa with progressive motility and normal morphology.

Ejaculation Failure

  • Observation of flagging of stallion's tail
  • Palpation of ventral penile surface during live cover or collection of semen in an artificial vagina to confirm ejaculation was complete—6–10 pulses of the urethra
  • Examination of dismount semen sample for motile spermatozoa

Mishandling of Semen

Systematic review of all semen-handling procedures and equipment/supplies coming into contact with semen.

Impaired Spermatozoal Transport

  • Transrectal US to ensure absence of intrauterine fluid at insemination or breeding
  • Vaginal speculum and digital cervical examination to ensure cervical patency/rule out urovagina

Diagnostic Procedures!!navigator!!

  • CBC and serum biochemistry for inflammatory or stress leukocyte response, and/or other organ system involvement. Not indicated unless the mare has recently been ill
  • ELISA or radioimmunoassay analyses for maternal P4 useful at <80 days of gestation (normal levels vary from >1 to >4 ng/mL, depending on reference laboratory). Maternal estrogen concentrations can reflect fetal estrogen production and viability, especially conjugated estrogens, e.g. estrone sulfate
  • Anecdotal reports of lower triiodothyronine/thyroxine levels in mares with a history of conception failure, EED, or abortion (somewhat controversial)
  • Specialized testing for PPID or EMS/IR
  • Cytogenetic studies to detect chromosomal abnormalities
  • Endometrial biopsy procedures to assess endometrial inflammation and/or fibrosis
  • Vaginal speculum examination and hysteroscopy if structural abnormalities suspected in the cervix or uterus
  • Feed or environmental analyses for specific xenobiotics, including ergopeptine alkaloids, phytoestrogens, heavy metals
  • Transrectal US is essential to confirm ovulation and early pregnancy, and to detect intrauterine fluid and lymphatic cysts
  • A thorough reproductive evaluation prebreeding for individuals predisposed to conception failure, e.g. barren, old mares with a history of conception failure and/or endometritis
  • Transrectal US, vaginal speculum, endometrial cytology/culture, and endometrial biopsy to detect anatomic defects, endometritis, or fibrosis
  • Transrectal US, if performed earlier than normal, at 10 days post ovulation, may determine the presence of an embryo; however, there can be confusion between embryonic vesicles and lymphatic cysts
  • Embryo recovery, procedures as for ET, to detect embryonic transport into the oviduct or into the uterus (flushing procedure might be therapeutic as well)
  • Hysteroscopy of uterine lumen and uterotubal junctions
  • Oviductal patency can be assessed using a variety of procedures
  • Laparoscopy can be used to evaluate normal structure and function and ovarian–oviductal interactions

Pathologic Findings!!navigator!!

An endometrial biopsy can demonstrate the presence of moderate to severe chronic endometritis, endometrial periglandular fibrosis, and/or lymphatic lacunae.

Treatment ⬆ ⬇

Outline

TREATMENT

Appropriate Health Care!!navigator!!

  • Treat preexisting endometritis before insemination or breeding of mares during physiologic breeding season
  • Mares should have adequate body condition
  • Inseminate or breed foal heat mares if ovulation occurs >9–10 days postpartum and no intrauterine fluid is present
  • Uterine lavage 4–8 h post mating with administration of oxytocin and/or cloprostenol to treat PMIE
  • Progestin supplementation—somewhat controversial
  • Anecdotal reports of oviductal flushing to resolve oviductal occlusion
  • Depending on breed restrictions, various forms of advanced reproductive technologies (e.g. zygote or embryo retrieval from the oviduct or uterus for ET and oocyte retrieval and successful IVF with subsequent ET)
  • Primary, age-related (most are from aged mares) embryonic defects are refractory to treatment
  • Most cases of conception failure can be handled in an ambulatory situation
  • Increased frequency of US monitoring of follicular development and ovulation to permit insemination closer to ovulation, as well as more technical diagnostic procedures, may need to be performed in a hospital setting. Adequate restraint and optimal lighting might not be available in the field to permit quality US examination

Nursing Care!!navigator!!

  • Generally requires none
  • Minimal nursing care might be necessary after more invasive diagnostic and therapeutic procedures

Activity!!navigator!!

  • Generally no restriction of broodmare activity, unless contraindicated by concurrent maternal disease or diagnostic or therapeutic procedures
  • Preference may be to restrict activity of mares in competition because of the impact of stress on cyclicity and ovulation

Diet!!navigator!!

Generally no restriction, unless indicated by concurrent maternal disease (e.g. EMS) or nutritional problems (e.g. under- or overnourished).

Client Education!!navigator!!

  • Emphasize the aged mare's susceptibility to conception failure and her refractoriness to treatment
  • Discuss susceptibility of mares with preexisting systemic disease (e.g. PPID and EMS/IR) to EED
  • Inform clients regarding
    • the cause, diagnosis, and treatment of endometritis
    • the seasonal aspects and nutritional requirements of conception
    • the role that endophyte-infected fescue and certain heterospecific breedings might play in conception failure

Surgical Considerations!!navigator!!

  • Indicated for repair of anatomical defects predisposing mares to endometritis
  • Certain diagnostic and therapeutic procedures discussed above might also involve some surgical intervention

Medications ⬆ ⬇

Outline

MEDICATIONS

Drug(s) of Choice!!navigator!!

Altrenogest

  • Mares with a history of conception failure or moderate to severe endometritis (i.e. no active, infectious component) or fibrosis can be administered altrenogest (0.044–0.088 mg/kg PO once a day) beginning 2–3 days after ovulation or at diagnosis of pregnancy and continued until at least 90–100 days of gestation (taper daily dose over a 14 day period at the end of treatment)
  • Altrenogest administration can be started later during gestation, continued longer, or used for only short periods of time, depending on serum P4 levels during the first 80 days of gestation (>1 to >4 ng/mL depending on reference laboratory), clinical circumstances, risk factors, and clinician preference
  • If used near term, altrenogest frequently is discontinued 7–14 days before the expected foaling date, depending on the case, unless otherwise indicated by assessment of fetal maturity/viability or by questions regarding the accuracy of gestational length

Oxytocin

IM administration of 10–20 IU, 4–8 hours post mating for PMIE.

Cloprostenol

IM administration of 250 μg 12–24 hours post mating for PMIE.

Precautions, Possible Interactions!!navigator!!

  • Use altrenogest only to prevent conception failure of noninfectious endometritis
  • Care should be taken in the administration of cloprostenol or other prostaglandins following ovulation to prevent interference with CL formation and function
  • Iatrogenic administration of oxytocin and cloprostenol to pregnant mares. Use transrectal US to diagnose pregnancy at ≥14–16 days after ovulation to identify intrauterine fluid or pyometra early in the disease course for appropriate treatment
  • If pregnancy is diagnosed, frequent monitoring (weekly initially) may be indicated to detect EED
  • Altrenogest is absorbed through the skin, so persons handling this preparation should wear gloves and wash their hands
  • Cloprostenol can be absorbed through the skin, so persons handling this preparation should wear gloves and wash their hands after treating mares
  • Although supplemental progestins are commonly used to treat cases of conception failure, their efficacy is controversial
  • Primary, age-related, embryonic defects do not respond to supplemental progestins

Alternative Drugs!!navigator!!

  • Injectable P4 (150–500 mg/day, oil base) can be administered IM, once daily instead of the oral formulation. Variations, contraindications, and precautions are similar to those associated with altrenogest
  • Other injectable and implantable progestin preparations are available commercially for use in other species. Any use in horses of these products is off-label, and no scientific data are available regarding their efficacy
  • Newer, repository forms of P4 are occasionally introduced; however, some evidence of efficacy should be provided prior to use
  • Other prostaglandin products (e.g. prostaglandin F2α) have been used to prevent PMIE, but their efficacy has been suggested to be less than that of cloprostenol, with a greater risk for interference with subsequent CL formation and function
  • Thyroxine supplementation has been successful (anecdotally) for treating mares with histories of subfertility—controversial/considered deleterious by some clinicians
  • Appropriate medications for any other systemic diseases

Follow-up ⬆ ⬇

Outline

FOLLOW-UP

Patient Monitoring!!navigator!!

  • Accurate teasing records
  • Reexamination of mares treated for endometritis before breeding
  • Early examination for pregnancy by transrectal US
  • Monitor embryonic and fetal development with transrectal or transabdominal US

Prevention/Avoidance!!navigator!!

  • Recognition of at-risk mares
  • Management of endometritis before breeding
  • Removal of mares from fescue-infected pasture and ergotized grasses and grains after breeding and during early gestation
  • Prudent use of medications in bred mares
  • Exposure to known toxicants

Possible Complications!!navigator!!

  • Later EED
  • High-risk pregnancy
  • Abortion—infectious or noninfectious, depending on the circumstances

Expected Course and Prognosis!!navigator!!

  • Young mares with resolved cases of endometritis can have a fair to good prognosis for conception and completion of pregnancy
  • Older mares (>15 years of age) with a history of preexisting systemic disease, chronic, moderate to severe endometritis, endometrial periglandular fibrosis, and/or lymphatic cysts, as well as conception failure and/or EED generally have a guarded to poor prognosis for conception success, safe completion of pregnancy, and delivery of a healthy foal

Miscellaneous ⬆ ⬇

Outline

MISCELLANEOUS

Synonyms!!navigator!!

  • EED
  • Infertility
  • Subfertility

Abbreviations!!navigator!!

  • CL = corpus luteum
  • EED = early embryonic death
  • ELISA = enzyme-linked immunosorbent assay
  • EMS = equine metabolic syndrome
  • ET = embryo transfer
  • IR = insulin resistance
  • IVF = in vitro fertilization
  • P4 = progesterone
  • PMIE = post-mating-induced endometritis
  • PPID = pituitary pars intermedia dysfunction
  • TRP = transrectal palpation
  • US = ultrasonography, ultrasound

Suggested Reading ⬆ ⬇

Ball BA. Embryonic loss. In: McKinnon AO, Squires EL, Vaala WE, Varner DD, eds. Equine Reproduction, 2e. Ames, IA: Wiley Blackwell, 2011:2327–2338.

Author(s) ⬆

Author: Tim J. Evans

Consulting Editor: Carla L. Carleton