Early Pregnancy Loss and Stillbirth

Key Points

About 50% to 70% of conceptions are lost, most in the first trimester. Losses in preimplantation embryos are especially high: 25% to 50% of morphologically normal and 50% to 75% of morphologically abnormal embryos.
Sporadic pregnancy loss is age dependent, and 40-year-old women have twice the loss rate of 20-year-old women. Most of these pregnancies are lost before 8 weeks’ gestation.
At least 50% of clinically recognized pregnancy losses show a chromosomal abnormality, and those in miscarriages differ from those found in liveborn infants, although autosomal trisomies still account for 50% of abnormalities.
A balanced translocation is present in 5% of couples with REPL. Many nongenetic causes of REPL have been proposed, but very few are proven. Efficacy of treatment in these cases often remains uncertain.
Uterine anomalies are accepted causes of second-trimester losses, but their role in first-trimester losses is less clear. Couples who experience a second-trimester loss may benefit from metroplasty or hysteroscopic resection of a uterine septum.
Drugs, toxins, and physical agents are uncommon causes of early pregnancy loss, especially repetitive loss. It should not be assumed that exposures to toxicants explain repetitive losses. Passive and active smoking and illicit drug use are associated with higher rates of both early pregnancy loss and stillbirth.
Antiphospholipid syndrome (antibodies to lupus anticoagulant, antiphospholipid, and anti–β ₂ -glycoprotein) is an accepted cause of second-trimester losses but its role in first-trimester losses is arguable. Strict ACOG criteria exist for applying the diagnosis of antiphospholipid syndrome to a woman who had had repeated first-trimester REPL.
In REPL, the overall prognosis is good even without therapy. The live birth rate is 60% to 70% even with up to four losses and no prior liveborn infants. Women who have had more than four losses are less likely to have a cytogenetic explanation and may have a different prognosis.
An efficacious therapeutic regimen for REPL should show success rates greater than these expected background rates.
The frequency of chromosomal abnormalities and nonchromosomal genetic factors (e.g., syndromes) in stillbirths (losses after 20 weeks’ gestation or weighing at least 350 g) is underevaluated. Cultures initiated from postdelivery products (placenta or fetal skin) often lead to unsuccessful culture and thus tissue for cytogenetic studies should be obtained by amniocentesis or chorionic villus sampling when possible.
A major effort should be exerted to obtain full autopsy and imaging on all stillbirths because findings can alter management in future pregnancies. If a couple declines an autopsy, whole-body radiographs, magnetic resonance imaging, and other noninvasive imaging should be pursued.
Adverse first-trimester events or complications in a current or previous pregnancy may interfere with normal placentation and increases the risks for placental-related obstetric complications such as preeclampsia and/or inrauterine growth restriction.

Introduction

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About 50% to 70% of spontaneous conceptions are lost before completion of the first trimester, most before implantation or during the first month after the last menstrual period. These very early losses are often not recognized as conceptions. Of clinically recognized pregnancies, 10% to 15% are lost.

Frequency and Timing of Pregnancy Loss

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Fewer than half of preimplantation embryos persist, as witnessed by assisted reproductive technology success rates rarely exceeding 30% to 40% of cycles initiated. Even immediately after implantation, judged preclinical or chemical by the presence of β-human chorionic gonadotropin (β-hCG) in maternal serum, about 30% of pregnancies are lost. After clinical recognition, 10% to 12% are lost. Most clinical early pregnancy loss (EPL) occurs before 8 weeks.
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After the first trimester, pregnancy losses occur at a slower rate. Loss rates are only 1% in women confirmed by ultrasound to have viable pregnancies at 16 weeks.
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Maternal age is positively correlated with pregnancy loss rates at any gestational age. Prior pregnancy loss also increases loss rates, but far less than once believed.
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The clinical consequence of the above epidemiology facts is that in order to be judged efficacious in preventing recurrent early pregnancy loss (REPL), therapeutic regimens must show success rates substantially greater than 70%. Essentially no therapeutic regimen can make this claim.

Placental Anatomic Characteristics of Successful and Unsuccessful Pregnancies

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As judged by adult tissue criteria, the human fetus develops in a low-oxygen environment.
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Toward the end of the first trimester, the intrauterine environment undergoes radical transformation in association with onset of the maternal arterial circulation and the switch to hemotrophic nutrition (see Chapter 1 ).
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In about two-thirds of EPL, anatomic evidence of defective placentation is apparent.
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In about 80% of missed miscarriages, the onset of the maternal placental circulation is both precocious and generalized throughout the placenta.

Numerical Chromosomal Abnormalities: Most Frequent Cause of Early Pregnancy Loss

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Chromosomal abnormalities are the main cause of both preimplantation and clinically recognized pregnancy loss. At least 50% of clinically recognized pregnancy losses result from a chromosomal abnormality.

Types of Numerical Chromosomal Abnormalities

Autosomal Trisomy

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Autosomal trisomies represent the largest single class (about 50%) of chromosomal complements in cytogenetically abnormal early pregnancy failure.
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Aneuploidy usually results from errors at maternal meiosis I, and these are associated with advanced maternal age.
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Errors in paternal meiosis account for 10% of acrocentric (13, 14, 15, 21, and 22) trisomies.

Polyploidy

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Nonmosaic triploidy (3n = 69) and tetraploidy (4n = 92) are common in EPL. Tetraploidy is uncommon, rarely progressing beyond 2 to 3 weeks of embryonic life.
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An association exists between diandric (paternally inherited) triploidy and partial hydatidiform mole. This chromosomal abnormality can also be associated with persistent trophoblastic disease and thus needs to be identified in order to offer hCG follow-up.

Sex Chromosome Polysomy (X or Y)

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The complements 47,XXY and 47,XYY each occur in about 1 per 800 live-born male births; 47,XXX occurs in 1 per 800 female births but is increased in pregnancies conceived by intracytoplasmic sperm injection.

Monosomy X

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Monosomy X is the single most common chromosomal abnormality among early pregnancy failure, accounting for 15% to 20% of abnormal specimens ( Table 27.1 ).

TABLE 27.1

Chromosomal Completion in Spontaneous Abortions Recognized Clinically in the First Trimester

Data from Simpson JL, Bombard AT. Chromosomal abnormalities in spontaneous abortion: frequency, pathology and genetic counseling. In: Edmonds K (ed). Spontaneous Abortion . London: Blackwell; 1987.

Chromosomal Complement	Frequency	Percent
Normal 46,XX or 46,XY		54.1
Triploidy:		7.7
69,XXX	2.7
69,XYX	0.2
69,XXY	4.0
Other	0.8
Tetraploidy:		2.6
92,XXX	1.5
92,XXYY	0.55
Not stated	0.55
Monosomy X		18.6
Structural abnormalities		1.5
Sex chromosome polysomy:		0.2
47,XXX	0.05
47,XXY	0.15
Autosomal monosomy (G)		0.1
Autosomal trisomy for chromosomes:		22.3
1	0
2	1.11
3	0.25
4	0.64
5	0.04
6	0.14
7	0.89
8	0.79
9	0.72
10	0.36
11	0.04
12	0.18
13	1.07
14	0.82
15	1.68
16	7.27
17	0.18
18	1.15
19	0.01
20	0.61
21	2.11
22	2.26
Double trisomy		0.7
Mosaic trisomy		1.3
Other abnormalities or not specified		0.9
		100.0

Relationship Between Recurrent Losses and Numerical Chromosomal Abnormalities

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In a given family, successive EPL is likely to be either recurrently normal or recurrently abnormal.

Genetic Counseling and Management for Recurrent Aneuploidy

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Couples predisposed to recurrent aneuploidy are at increased risk not only for aneuploid EPL but also for aneuploid liveborn neonates.
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If the complement of the first miscarriage is abnormal, recurrence usually involves aneuploidy, although not necessarily of the same chromosome.
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Selective transfer of euploid embryos following preimplantation genetic diagnosis decreases the rate of clinical miscarriages in couples with REPL and live-born trisomies.

Chromosomal Rearrangements

Translocations

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Translocations are the most common structural rearrangement and are found in about 5% of couples who experience REPL.
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Individuals with balanced translocations are phenotypically normal, but their offspring may show chromosomal duplications or deficiencies as result of normal meiotic segregation.
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Women are about twice as likely as men to carry a balanced translocation.
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Reciprocal translocations involve not centromeric fusion but rather interchanges between two or more chromosomes. Overall, the risk is 12% for offspring of either female heterozygotes or male heterozygotes.
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Detecting a chromosomal rearrangement thus profoundly affects subsequent pregnancy management. Antenatal cytogenetic studies should be offered.
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Preimplantation genetic diagnosis of embryos from couples who have a balanced translocation reveals that most embryos are unbalanced: 58% in robertsonian translocations and 76% in reciprocal translocations.

Inversions

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Inversions are uncommon parental chromosomal rearrangements where the order of the genes is reversed but are responsible for REPL at a rate similar to translocations.
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Women with a pericentric inversion have a 7% risk for abnormal liveborn infants, whereas men carry a 5% risk.

Mosaics

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Mosaicism may be restricted to the placenta, the fetus per se being normal. This phenomenon is termed confined placental mosaicism.

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