RECURRENT PREGNANCY LOSS AND FIRST TRIMESTER BLEEDING
| RECURRENT PREGNANCY LOSS—Heather Gibson Huddleston, MD, Assistant Adjunct Professor of Obstetrics,
Gynecology, and Reproductive Sciences, University of California, San Francisco, School of Medicine
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| General considerations: definition—3 consecutive pregnancy losses <24 wk (2 losses used in some publications);
rate of sporadic miscarriage—50% of all conceptions; 12% to 15% of clinically recognized pregnancies; causes—
aneuploidy 50% to 70% (applies to patients with recurrent pregnancy loss [RPL] and to sporadic miscarriage); age
and miscarriage—aneuploidy in conceptus increases with age; data show risk for pregnancy loss in women 30 to
34 yr of age, 15%; risk in women >40 yr of age, 50%; risk for sporadic miscarriage 25% to 50%; RPL occurs in ≈1%
of couples (expected rate by chance alone [no underlying contributing factors] 0.34%); characteristics of patients
with RPL—conception delays (32%), late miscarriage (22%), stillbirths (6%), pregnancy with prematurity or intrauterine
growth restriction (IUGR; 20%); prognosis—longitudinal study of 325 patients with idiopathic recurrent miscarriage
(most evaluated after 3 losses, excluded if clear cause of pregnancy loss [eg, antiphospholipid antibody
syndrome]); data show 70% of patients conceived, with 75% success rate (average age 32 yr); chance of future success
in subsequent pregnancy—in patient 30 yr of age with 3 miscarriages, 80% (60%-65% for patient 40 yr of
age); data show patient 30 yr of age with 5 miscarriages had 70% chance of success
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| RPL and aneuploidy: incidence of aneuploidy high, whether person has sporadic or RPL; Stephenson et al showed
among patients 36 to 39 yr of age, 60% of RPL due to aneuploidy (similar incidence for sporadic-loss group); in
younger population, patients with RPL had lower rate of aneuploid loss than patients experiencing sporadic loss; karyotyping
of pregnancy loss tissue may provide useful information and prevent expensive and unnecessary work-up;
younger patients have proportionately more euploid losses (may be group to focus on in looking for cause)
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| Parental translocation: affects ≈4% of couples with RPL; detected by karyotyping both parents; can present as either
balanced reciprocal (exchange of genetic material across 2 chromosomes) or Robertsonian translocations (fusion
of 2 long arms at acrosome); may result in normal, abnormal balanced, or abnormal and unbalanced offspring;
typical patient has history of miscarriages, live births, or child with abnormalities; karyotyping of both parents necessary
for diagnosis; refer to genetic counselor if abnormality detected (translocations have different outcomes);
risk for unbalanced offspring depends on sex of carrier, type of rearrangement, and method of ascertainment;
Stephenson et al looked at 1893 couples with RPL; 51 structural chromosome rearrangements (2.7% of population)
identified; 58 monitored pregnancies, with live birth rate 71% (no report of abnormality in offspring); Goddijn et al
looked at 1234 couples; 41 identified as carrying translocation; 43 pregnancies in 25 couples followed; live birth
rate 70%; no report of abnormal unbalanced offspring after detection of structural chromosome abnormality; preimplantation
genetic diagnosis—multicenter retrospective study by Verlinsky et al found take-home baby rate
23% per cycle and 34% per transfer; may reduce chance for miscarriage; does not appear to increase live birth rate;
summary—parental translocation small (but important) cause of RPL; consider karyotyping both parents; important
to refer patient with multiple unexplained losses to genetic counselor; live birth rate may depend on particular
translocation; although more data needed, preimplantation genetic diagnosis may lower risk for miscarriage and
risk for unbalanced offspring
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| Anatomic causes: account for ≈15% of RPL; septate or bicornuate uterus, fibroids, adhesions, and polyps; uterine
cavity can be evaluated using hysterosalpingography, saline sonography, or hysteroscopy; Salim et al found uterine
malformation more prevalent in women with RPL (23.8% vs 5.3% in controls); septum can be removed with hysteroscopic
resection or hysteroscopic metroplasty; data suggest live birth rate ≈85% in patients who undergo resection;
surgical intervention not indicated for bicornuate and unicornuate uterus (no clear evidence surgery improves outcome);
no strong randomized data on impact of intracavitary fibroids, polyps, or adhesion on miscarriage; some data
suggest submucosal fibroids and polyps may be factor; hysteroscopic removal of submucosal polyp, fibroids, or adhesions
indicated (low-risk procedure); advise patient this may not be cause of problem
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| Antiphospholipid antibody syndrome: diagnosis requires clinical and laboratory parameters; clinical criteria—
thrombosis or pregnancy complications (eg, ≥3 spontaneous pregnancy losses at <10 wk); laboratory criteria—
positive plasma levels of lupus anticoagulant or anticardiolipin antibodies (IgG or IgM isotype); laboratory tests
must be repeated on 2 separate occasions, 6 wk apart (not uncommon to see nonspecific elevation of anticardiolipin
antibodies; persistent elevation needed for diagnosis); data show live birth rate ≈10% if left untreated, 42% to 44%
with low-dose aspirin, and 72% to 80% with low-dose aspirin and unfractionated heparin (some studies show similar
efficacy with low molecular weight heparin); important to identify patient having RPL because effective treatments
available
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| Endocrine causes: check thyroid, prolactin, and day 3 follicle-stimulating hormone (FSH) levels (elevated day 3
FSH increases chance for released egg to have fetal aneuploidy); check for uncontrolled diabetes; impact of
metformin—retrospective study by Jakubowitz et al of 96 nondiabetic women with polycystic ovary syndrome
(PCOS) who became pregnant; investigators found lower rate of miscarriage in women receiving metformin; prospective,
parallel randomized, double-blind, double placebo, controlled trial on nonobese anovulatory women with
PCOS suggested women receiving metformin had better cumulative pregnancy rate (>6 mo); pregnancy losses
lower in metformin group (9.7% vs 37% in controls); metformin discontinued once pregnancy diagnosed by ultrasonography
(US); metformin may have some benefit in women with PCOS (especially if obese) and RPL; more
data needed to support effectiveness in preventing pregnancy loss; counseling patients—50% of RPL unexplained;
testing may elevate patient expectations of receiving answers; important to inform patients early that no
cause of RPL may be found
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| Thrombophilias: thrombophilic mutations predominantly autosomal dominant; factor V Leiden mutation present in
≈5% of white population (much lower in other ethnic groups); prothrombin mutation found in ≈2% of white population;
factor V Leiden—3- to 5-fold increase in thrombotic risk, 80-fold increase in homozygous carriers; mutation occurs
in factor V gene; meta-analysis by Rey et al showed small association between factor V Lieden and RPL <13 wk
(odds ratio [OR] 2.01); higher association seen in loss >19 wk (OR 3.2); prothrombin gene mutation—meta-analysis
of 4 studies of RPL <13 wk found OR 2.32; methylene tetrahydrofolate reductase (MTHFR) gene mutation—C677T
or A1298C mutation; common in white population; low dietary folate, vitamins B6 and B12 may lead to elevated homocysteine;
no strong evidence linking MTHFR mutation with RPL; slight increased risk in patients with elevated homocysteine
levels; consider obtaining homocysteine level if work-up negative (less expensive than doing gene mutation
analysis); summary—possibly small association between RPL and factor V Leiden and prothrombin gene mutation;
lack of treatment strategies for thrombophilias makes aggressive work-up unwarranted; elevated homocysteine may
have small association; easy to treat with folic acid and vitamin B supplementation (speaker uses Folgard [folic acid, vitamins
B6 and B12 ]); small association precludes screening for MTHFR
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| EVALUATION AND MANAGEMENT OF FIRST TRIMESTER BLEEDING—Linda A. Hunter, MS, CNM, Clinical Instructor
of Obstetrics and Gynecology, Department of Nursing, the University of Vermont, College of Medicine, and Coordinator,
Claire M. Lintihac Nurse-Midwifery Service, Fletcher Allen Health Care, Burlington, VT
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| Introduction: 20% to 25% of pregnant women experience bleeding in first trimester (some sources quote 15% to
20%); ≈50% of these have miscarriage; bleeding in pregnancy source of anxiety; important to reassure patient bleeding
unlikely to lead to miscarriage, or ectopic or molar pregnancy
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 | Cervical ectropion: inversion of inner columnar cells of cervix visible on surface; greater incidence in women using
oral contraceptives or having loop electrocautery excision procedure; surface blood vessels source of bleeding;
high estrogen state in pregnancy makes ectropion more visible and sensitive; progesterone causes tissue engorgement
and congestion in cervix and uterus; if Papanicolaou (Pap) test performed, reassure patient blood on cytology
brush normal; speaker counsels patient to refrain from sexual intercourse (vaginal rest)
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| Sources of inflammation: lesions (eg, polyps, herpes simplex virus (HSV)–related, ruptured cysts, or glands)—polyps
generally not removed during pregnancy (because of excessive bleeding); counsel patient about amount of
spotting to expect and to seek care from health care provider when necessary; cellular changes on cervix [eg,
HSV, cervical intraepithelial neoplasia (CIN)]; sebaceous cyst from shaving labia (can rupture); cervicitis; inflammation
from Chlamydia or gonorrhea; vaginitis (trichomoniasis and bacterial vaginosis; treatment with metronidazole
not recommended in first trimester); progesterone vaginal gel (eg, Crinone)—no data supporting
spontaneous bleeding with use, but speaker reports cases of cervical friability and inflammation
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| Uterine causes: implantation bleeding—study of 151 women; 14 had some degree of bleeding in first trimester; 2
had missed abortion or miscarriage; 12 women had different patterns of bleeding; much higher incidence of bleeding
occurring near time when period expected, and none had bleeding near time of implantation; implantation
bleeding may not be actual phenomenon, but may be occurring near time of missed period; low-lying placenta or
placenta previa; subchorionic hematoma—no correlation between size of hematoma and pregnancy outcome;
missed abortion; ectopic pregnancy; molar pregnancy—often presents with bleeding after first trimester; suspect
if fetal heart rate cannot be detected at 11 or 12 wk, size greater than dates, markedly elevated levels of human
chorionic gonadotropin (hCG; eg, 100,000 mIU/mL), and significant nausea and vomiting
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| Other causes: postcoital spotting (patient may be reluctant to admit cause of spotting); rectal bleeding (eg, hemorrhoids,
fissures, constipation); cystitis (often asymptomatic during pregnancy); urethral diverticulum; perineal
skin lesions and fissures
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| Assessment: verify pregnancy and how far along (was pregnancy test done? was patient seen in office? has patient
been to emergency department?); ask direct questions (patients often do not reveal important information); establish
amount of bleeding (patient’s perception may be distorted); ask about presence of discharge; possible association
with intercourse, straining with bowel movement, exercise; presence of cramping, nausea, vomiting or syncope
(red flag); review other medical, obstetric and gynecologic history (eg, history of miscarriage, abnormal uterus);
evidence of domestic violence; urgent evaluation rarely needed; heavy bleeding, severe cramping, pain, or syncope
warrant immediate evaluation; be familiar with availability of resources
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| Physical examination: check temperature, heart rate, and blood pressure (orthostatic, if concerned about ectopic
pregnancy); determine thyroid hormone level; assess abdomen (mass felt on palpation red flag for further evaluation;
possibility of molar pregnancy or missed abortion of twin); inspect perineum, perirectal area, vagina, and cervix;
perform bimanual examination to ensure uterus size correlates with dating; wet mount if discharge present; check fetal
heart rate with Doppler (can be source of anxiety for patient if not readily available); obtain complete blood cell
count (CBC), blood type, and Rh status; quantitative β-hCG level; perform urinalysis and tests to rule out infection
(if suspected)
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| Ultrasonography: no absolute rule on whether US obtained first or quantitative β-hCG (depends on availability);
generally wait until serum β-hCG level ≥2000 mIU/mL; should see gestational sac by 5 wk plus 2 days (with good
menstrual dating) or with hCG level >2000 mIU/mL; once sac seen, should see fetal heart within 1 wk and hCG
level >10 800 mIU/mL
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| Management: viable pregnancy confirmed—any abnormal US findings (eg, subchorionic hematoma, low-lying
placenta, resolving twin gestation); treat underlying causes (eg, gonorrhea and Chlamydia); reassure patient (5%
risk for miscarriage once viable intrauterine pregnancy established); follow with repeat US, tests of cure, and referrals;
equivocal findings— β-hCG <2000 or US not conclusive for viable intrauterine pregnancy; repeat beta hCG
in 48 hr; US when β-hCG levels high enough; continue to rule out ectopic pregnancy; bed rest—studies show bed
rest not effective in preventing miscarriage (may make patient feel better); vaginal rest when appropriate
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| Expectant management of missed abortion: Butler et al found expectant management successful in 80% of patients
in process of miscarrying and 70% of patients with diagnosis of missed abortion; Nanda et al compared safety
and efficacy of expectant management to surgical treatment and found no clear superiority with either approach;
recommend patient’s preference be taken into consideration; misoprostol—Food and Drug Administration-approved
for treatment of ulcers since 1985; widely recommended for treatment of missed or incomplete miscarriage;
not approved for use in pregnancy; studies support use in treating missed abortion or incomplete miscarriage; can be
administered orally, vaginally, or rectally; diarrhea and shivering side effects; inclusion criteria for misoprostol therapy
at speaker’s institution—documented nonviable pregnancy <12 wk, fully informed consent; motivated compliant
patient, available for follow-up management with access to medical care (recommend taking medication first
thing in morning); ectopic pregnancy and viability must be ruled out; patient cannot have active vaginal bleeding;
contraindications—surgery broaching endometrial cavity (except for transverse cesarean delivery); sac size or crown
rump length >12 wk; protocol—misoprostol 800 µg per insertion; may repeat dose once after 24 hr; patient may insert
at home, as long as she has access to care and someone to drive her to hospital; follow-up in 24 to 48 hr if no miscarriage
occurs; follow up with US and quantitative β-hCG; emotional issues—history of bleeding heightens anxiety
in pregnant patients; empathy and patience paramount, even when clinician not alarmed; reassure patient baby fine;
bereavement and grieving can be significant and overwhelming
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Suggested Reading
Brigham SA et al: A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod
14:2868, 1999; Demetroulis C et al: A prospective randomized control trial comparing medical and surgical
treatment for early pregnancy failure. Hum Reprod 16:365, 2001; Gracia CR et al: Risk factors for spontaneous
abortion in early symptomatic first-trimester pregnancies. Obstet Gynecol 106(5 Pt 1):993, 2005; Goddijn M et al:
Clinical relevance of diagnosing structural chromosome abnormalities in couples with repeated miscarriage. Hum Reprod
19:1013, 2004; Grimbizis GF et al: Clinical implications of uterine malformations and hysteroscopic treatment
results. Hum Reprod 7:161, 2001; Nanda K et al: Expectant care versus surgical treatment for miscarriage.
Cochrane Database Syst Rev 12:CD003518, 2006; Nybo Andersen AM: Maternal age and fetal loss: population
based register linkage study. BMJ 320:1708, 2000; Salim R et al: A comparative study of the morphology of congenital
uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum Reprod
18:162, 2003; Say L et al: Medical versus surgical methods for first trimester termination of pregnancy. Cochrane
Database Syst Rev 25:CD003037, 2005; Stephenson MD et al: Reproductive outcomes in recurrent pregnancy loss
associated with a parental carrier of a structural chromosome rearrangement. Hum Reprod 21:1076, 2006; Verlinsky
Y et al: Over a decade of experience with preimplantation genetic diagnosis: a multicenter report. Fertil Steril 82:292,
2004.
Educational Objectives
The goal of this program is to improve the management of recurrent pregnancy loss and first trimester bleeding. After
hearing and assimilating this program, the clinician will be better able to:
| Define and recognize the primary cause of recurrent pregnancy loss.
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| Counsel patients after pregnancy loss about the likelihood of having a subsequent successful pregnancy.
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| Manage patients having recurrent pregnancy loss.
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| Triage pregnant patients experiencing first trimester bleeding.
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| Discuss the use of misoprostol in patients having a missed abortion.
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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 faculty reported nothing to disclose.
Acknowledgements
Dr. Huddleston was recorded at Obstetrics and Gynecology Update: What Does The Evidence Tell Us? sponsored by
the University of California, San Francisco, School of Medicine, and held October 11-13, 2006, in San Francisco.
Ms. Hunter 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.
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