ECTOPIC PREGNANCY AND MATERNAL-FETAL INFECTIONS
| EVALUATION AND MANAGEMENT OF SUSPECTED ECTOPIC PREGNANCY— Julia Johnson, MD, Professor,
Department of Obstetrics and Gynecology, Vice Chair for Gynecology, and Director, Division of Reproductive Endocrinology
and Infertility, University of Vermont College of Medicine, Burlington
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| Introduction: ectopic pregnancy accounts for 2% of all pregnancies, and often ends in miscarriage; ≈70% of ectopic
pregnancies resolve spontaneously, suggesting incidence may be higher; accounts for 9% of pregnancy-related
deaths in the United States
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| Risk factors: history of ectopic pregnancy (risk 10% with one ectopic, 30% with two); history of surgery involving
reproductive organs; history of open abdominal surgery (risk ≈30%); history of pelvic inflammatory disease or
mild chlamydial infection; use of progestin contraceptive or intrauterine device (does not cause ectopic pregnancy,
but does not prevent ectopic pregnancy as effectively as intrauterine pregnancy); older maternal age
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| Clinical presentation: in women of reproductive age presenting with pain and bleeding, consider ectopic pregnancy
until proven otherwise; majority of women with ectopic pregnancy do not present with classic triad of pain,
bleeding, and adnexal mass; obtain pregnancy test
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| Early diagnosis: monitor beta-human chorionic gonadotropin ( β-hCG) levels—intrauterine pregnancy confirmed with
β-hCG >2000 mIU/mL; normal β-hCG increases 50% to 100% every 2 days early in pregnancy, increases more slowly
as pregnancy progresses, peaking in ≈8 wk at ≈100,000 mIU/mL; normal β-hCG increase does not ensure intrauterine
pregnancy (Barnhart showed normal β-hCG increase in 17% of ectopic pregnancies); obtain transvaginal ultrasonography
(US) once β-hCG >2000 mIU/mL—in normal uterus, gestational sac evident when β-hCG >2000 mIU/mL or at 5
wk plus 2 days gestation (excluding possible multiple gestation, uterine fibroids, or known uterine anomaly); pseudosac
in 5% to 15% of ectopic pregnancies; fetal heart tones within 1 wk of seeing gestational sac or β-hCG >10 800 mIU/mL
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| Value of transvaginal US: suspect ectopic pregnancy if transvaginal US does not show intrauterine gestational sac
and β-hCG level >2000 mIU/mL; look for free fluid in cul-de-sac; inspect adnexa (eg, look for double decidual sign,
double bleb sign, peritrophoblastic flow, or live embryo); active blood flow around adnexa (using US with Doppler
flow imaging) suggests ectopic pregnancy; most ectopic pregnancies nonviable, but look for fetal heart activity (presence
of viable intrauterine pregnancy in adnexa most likely reason for failed medical therapy for ectopic pregnancy)
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| Dilation and curettage (D and C): indicated to confirm absence of intrauterine pregnancy if β-hCG continues to
rise; presence of endometrial cells on D and C confirms ectopic pregnancy; if β-hCG level falling, follow levels until
undetectable; rising β-hCG, negative US, and absence of intrauterine chorionic villi confirm diagnosis of ectopic pregnancy
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| Methotrexate (MTX) treatment: folic acid antagonist; inhibits DNA synthesis and cell replication; targets early
placental cells, causing separation from fallopian tubes; University of Vermont study (1995)—success rate ≈85% (increase
to 92% over last 10 yr attributed to early diagnosis); patient instructed to discontinue prenatal vitamins and not
to drink alcohol or engage in sexual intercourse (may increase risk for rupture); moderate discomfort common after
treatment and presumed caused by bleeding from fallopian tube with separation of pregnancy (usually resolves
within 24-48 hr); side effects in ≈25% of patients (primarily mild gastric distress); dizziness reported (patients encouraged
to report because of risk for tubal rupture); severe side effects, eg, neutropenia, alopecia, and pneumonitis,
rare; potential candidates—patients diagnosed early with limited symptoms; patients desiring future fertility; patients
willing to return weekly for blood work; highest risk for rupture— β-hCG >10,000 mIU/mL, adnexal mass >3.5 cm,
and positive fetal heart activity on US; contraindications—breast-feeding woman not desiring to stop; worsening
pain or increasing fluid on US; coexisting condition for which MTX contraindicated; long distance from medical
care, or limited availability of transportation
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 | Single-dose regimen: 50 mg/m2 ; equal or greater success rate, compared to multidose regimen (at speaker’s institution);
obtain β-hCG levels on day medication given, and again on days 4 and 7 (expect 15% decline between
days 4 and 7); repeat MTX if β-hCG decline <15%; follow β-hCG until undectable; fewer office visits and fewer
injections with single regimen
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| Multidose regimen: 1 mg/kg every other day for 4 days; leucovorin (folinic acid) 0.1 mg/kg administered as “rescue”
medication on alternate days; monitor β-hCG routinely; follow β-hCG levels until undetectable; increased
effectiveness and slightly faster drop in β-hCG with multidose regimen
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| Surgical treatment options: laparoscopy preferred over laparotomy in nonemergency cases; laparotomy reserved
for hemodynamically unstable patients; risk for residual trophoblastic disease 10% if fallopian tube not removed;
cornual pregnancy requires laparotomy
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| Medical vs surgical treatment: equal success for subsequent intrauterine pregnancy; decreased cost and risk with
medical therapy; surgical therapy allows for permanent sterilization of patient not desiring future pregnancy;
speaker recommends salpingectomy in patient with history of 2 ectopic pregnancies
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| MATERNAL-FETAL INFECTIONS —Wendy Kinzler, MD, Associate Professor, Department of Obstetrics, Gynecology,
and Reproductive Sciences, and Director, Pregnancy Loss Evaluation Service, Division of Maternal Fetal
Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick
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| Toxoplasmosis: Toxoplasma gondii; intracellular parasite; cats primary hosts, humans secondary hosts; approximately
one-third seropositivity in United States; infection spread by consumption of cysts in undercooked meat
(accounts for ≈50% of infections), contact with oocyts in infected cat feces, or contact with infected materials in
soil; maternal infection—rate <1%; symptomatic in 10%; symptoms nonspecific, eg, lymphadenopathy (most common),
malaise, fever, myalgias; manifestations more severe in immunocompromised patients; congenital
infection—rate <0.1%; risk for vertical transmission 10% to 15% in first trimester (but greater severity of infection),
≈60% in third trimester; ≈25% of infants infected congenitally show signs on US; even though most infected
infants asymptomatic, 80% (if not more) develop sequelae, eg, eye findings, neurologic abnormalities; maternal
diagnosis—serologic testing not well standardized; false-positive rate high (5%- 10%); IgM levels can remain elevated
for 1 yr; send IgG and IgM antibodies in parallel 3 wk apart (draw blood on day zero and again 3 wk later;
laboratory tests at same time); send all suspicious titers to reference laboratory (see Editor’s note); reference laboratory
can perform avidity testing to determine whether IgG titer reflects chronic or acute infection; fetal
diagnosis—fetal blood sampling to detect toxo-specific IgM (feasible only in second half of pregnancy; false-negative
result possible if infection occurred at <20 wk gestation); amniotic fluid polymerase chain reaction (PCR)
testing used in confirmed maternal infection; confirmed maternal infection—spiramycin shown to reduce vertical
transmission rates ≈60%; available only through Food and Drug Administration (FDA); confirmed fetal infection—
multidrug regimen required; no proven treatment regimen eliminates transmission; prevention—instruct patient to
avoid outside cats, changing cat litter, undercooked meat, and gardening without gloves; sulfamethoxazole–trimethoprim
(SMZ-TMP; Bactrim) prophylaxis for immunocompromised patients with low CD4 counts; multiantigenic
vaccine in development
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| Varicella-zoster: DNA herpesvirus; highly contagious (attack rate 60%-90%); infectivity occurs before onset of rash;
transmission primarily by respiratory droplets; immunity life-long; rare in pregnancy (<1 per 1000 pregnancies); may
begin to see more adults develop infection as vaccine’s immunity wears off; maternal infection—diagnosed clinically;
infectivity highest during prodromal stage; generalized vesicular eruptions; secondary complications (eg, pneumonitis,
encephalitis) more common in adults (incidence of pneumonitis 10%-15%, with classic respiratory signs and diffuse
peribronchial infiltrates; mortality 25%); congenital infection—severe cutaneous scarring when limb buds forming can
result in limb-reduction defects; cortical atrophy, central nervous system (CNS) findings, microcephaly, and microophthalmia;
risk for congenital infection 1% to 2% if maternal infection acquired in first 20 wk of pregnancy (rare if maternal
infection acquired in second half of pregnancy); neonatal infection—maternal infection occurs within 3 wk of
delivery; most severe if onset of maternal disease within 5 days of delivery; presentation variable; mortality 20% to
30%; treatment—supportive care; parenteral acyclovir recommended for symptomatic neonatal infection and disseminated
maternal cases; contact isolation; prevention—avoid direct contact with skin lesions; breast-feeding should be
avoided only if lesions at area of suckling; varicella–zoster immune globulin (VZIG)—given to neonate if maternal
symptoms occur 5 days before or 2 days after delivery; reduces maternal infection rate by 70% in susceptible mother
(must be administered ≤96 hr after exposure), but does not reduce fetal exposure if mother already infected; live attenuated
virus, not recommended for use during pregnancy; duration of immunity unknown; no concerns with household
contacts (children of pregnant mother can receive vaccine); 70% of patients with uncertain immune status show signs of
previous exposure
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| Rubella: single-stranded RNA virus; humans only known natural host; one serotype; seronegativity rate <10% (ie,
most people not susceptible to infection); advancing age, Asian ethnicity, and nulliparity increase risk for seronegativity;
maternal infection—asymptomatic in approximately one-third of women; symptoms nonspecific until development
of maculopapular rash; tender lymphadenopathy (especially postauricular) classic finding; significant arthralgias
in ≈30% of women; congenital infection—rare; risk for congenital rubella syndrome ≈20% in presence of maternal
infection (significantly increased in first trimester, decreases as pregnancy progresses); no reports of malformations
after 16 wk gestation; no reports of congenital rubella syndrome due to vaccination; sequelae (deafness, mental retardation,
heart disease, cataracts, glaucoma) result of cytolysis and embolism (“blueberry muffin” skin lesions);
treatment—acetaminophen for symptoms; glucocorticoids and platelet transfusion; prognosis excellent; mortality
rare; prevention—vaccination key; in use since 1969; 95% effective after single dose; vaccination provides lifetime
immunity; virus may be shed from nasopharynx for several weeks, but not transmitted; arthralgias possible after vaccination;
elimination of rubella and congenital rubella syndrome national health objective; <25 cases annually in
United States since 2001 (majority of cases come from virus genotypes originating outside United States
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| Cytomegalovirus (CMV): double-stranded DNA herpesvirus; restricted to humans; many serotypes; reinfection possible;
long incubation period; IgM response generally disappears within 2 mo; highest rate of seroconversion between
ages 15 and 35 yr; seropositivity correlated with low socioeconomic status, multigravity, advanced maternal age, early
age at first pregnancy, and high number of sexual partners; transmission requires close contact; shed in body fluids; prolonged
viral excretion; prevalence during pregnancy 1% to 4% for primary infection and ≈10% to 15% for recurrent infection;
maternal infection—generally asymptomatic; symptoms nonspecific; at least 25% of patients with primary
CMV have negative IgM; ≈10% of patients with recurrent CMV have persistent IgM response (positive or negative
IgM does not identify whether infection primary or recurrent); diagnosis by seroconversion or ≥4-fold rise in parallel
IgG titers; congenital infection—most common congenital viral infection; occurs in 1% to 2% of all neonates; incidence
30% to 50% after primary maternal infection; 1% to 2% rate after recurrent infection; classic tetrad includes microcephaly,
intracranial calcifications, severe mental retardation, and chorioretinitis; of those with symptoms at birth
(10%), 90% have long-term neurologic sequelae; of those asymptomatic (90%), 10% have long-term neurologic sequelae;
diagnosis—US findings; fetal blood sampling (limited by time of exposure); amniotic fluid PCR with culture
excellent sensitivity (testing of choice); treatment—no recommendations (for maternal or fetal infection); ganciclovir
and foscarnet used (ganciclovir may reduce sensorineural hearing loss in newborns), but neither studied for antepartum
use or paternal use to reduce severity of fetal infection; counsel patients in high-risk work environment; strict hygiene
practices; recombinant vaccine in development; data on hyperimmune globulin for newborns encouraging (probably
limited use in pregnancy)
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| Herpes simplex virus (HSV): prevalent sexually transmitted disease; >500,000 new cases in United States annually;
first episode primary—first exposure to HSV (no previous exposure); first episode nonprimary—first exposure,
but patient has HSV-2 antibodies or vice versa; recurrent genital herpes—reactivation of HSV in patient who
has antibodies; fetal risk highest with first episode or first episode nonprimary; maternal infection—first episode
primary infection severe; lesions last several weeks; local tender regional lymphadenopathy; fever, malaise; first
episode nonprimary and recurrent herpes milder infections, and viral shedding shorter (<1 wk [2 to 3 wk with primary
infection]); congenital infection—correlated with trimester in which exposure occurred; first trimester primary
infection associated with spontaneous abortion; second and third trimester exposure increases risk for preterm
birth and low birth weight; greatest concern third trimester exposure and neonatal HSV; direct contact with vaginal
fluids cause of 90% of cases; <5% antepartum transmission; ≈5% postpartum transmissions; diagnosis made clinically
or by virus isolation; risk for congenital infection with first episode (primary or nonprimary) ≈50% if active
lesion present at time of delivery, ≈30% to 35% if patient asymptomatic; risk lower with recurrent HSV (3%-4% if
active lesion present, 0.04% if asymptomatic); three types of congenital infection—localized infection affecting
skin, eyes, and mouth; characterized by skin vesicles or scarring; chorioretinitis; mortality rate close to zero; approximately
two-thirds of patients presenting initially with localized cutaneous lesions develop CNS infections;
mortality 10% to 15%; increased risk for long-term morbidities; mortality high with disseminated disease; jaundice,
pneumonia, disseminated intravascular coagulation (DIC), seizures, and neurologic sequelae; treatment—
acyclovir (or similar antiretroviral) shown to decrease duration of symptoms and to decrease viral shedding; supportive
care; prevention—when herpetic lesions present at time of delivery, cesarean delivery reduces risk for congenital
infection by ≈85%; acyclovir shown to reduce chance of herpetic lesion at time of delivery; nonoxynol-9
may decrease sexual transmission; no vaccine currently available
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| Conclusions: routine screening not recommended for most fetal infections; maternal serology useful but confusing;
US findings confirmatory, but majority of infected fetuses do not show signs on US; amniotic fluid PCR inconclusive;
patient education paramount to prevention
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Suggested Reading
Barnhart K et al: The pharmacology of methotrexate. Expert Opin Pharmacother 2:409, 2001; Centers for Disease
Control and Prevention (CDC): Women with smallpox vaccine exposure during pregnancy reported to the
National Smallpox Vaccine in pregnancy Registry—United States, 2003; Gracia CR, Barnhart KT: Diagnosing
ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol 97:464, 2001; Barnhart K, et al: An
update on the medical treatment of ectopic pregnancy. Obstet Gynecol Clin North Am 27:653, 2000; Bixby S et al:
Presence of a yolk sac on transvaginal sonography is the most reliable predictor of single dose-methotrexate treatment
failure in ectopic pregnancy. J Ultrasound Med 24:591, 2005; Jamieson DJ et al: Emerging infections and
pregnancy. Emerg Infect Dis 12:1638, 2006; Stegmann BJ, Carey JC: TORCH infections. Toxoplasmosis, Other
(syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirs (CMV), and herpes infections. Curr Womans
Health Rep 2:253, 2002.
Educational Objectives
| The goal of this program is to improve the diagnosis and management of ectopic pregnancy and infectious diseases in
pregnancy. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Evaluate reproductive-age women, who are complaining of pelvic pain and vaginal bleeding, for ectopic pregnancy.
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| 2. Discuss the role of human chorionic gonadotropin, transvaginal ultrasonography, and dilation and curettage in
diagnosing ectopic pregnancy.
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| 3. Treat patients with confirmed ectopic pregnancy.
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| 4. Recognize common perinatal infections.
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| 5. Manage common infections associated with pregnancy.
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Editor’s Note
Toxoplasma Serology Laboratory of the Palo Alto Medical Foundation Research Institute—www.pamf.org/serology
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Johnson has received
research grant support from Wyeth, Berlex, Procter and Gamble, and Organon.
Acknowledgment
Dr. Johnson was recorded at Women’s Health Issues for Primary Care Providers sponsored by the University of Vermont
College of Medicine, held on May 9-11, 2007, in Burlington, VT. Dr. Kinzler was recorded at Issues & Controversies
2006 sponsored by the Robert Wood Johnson Medical School, held on November 9-11, 2006, in Lake Buena Vista,
FL. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this
program.
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