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Idiopathic recurrent pregnancy loss recurs at similar gestational ages
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REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY
Idiopathic recurrent pregnancy loss recurs at similar gestational ages Cara Heuser, MD; Jess Dalton, MSPH; Cora Macpherson, PhD; D. Ware Branch, MD; T. Flint Porter, MD; Robert M. Silver, MD OBJECTIVE: To determine whether a correlation exists between gesta-
tional ages of idiopathic recurrent pregnancy loss (iRPL). STUDY DESIGN: Cohort of women with iRPL who had an initial loss
(qualifying pregnancy [QP]) with precise documentation of gestational age. Outcomes in the immediate next pregnancy (index pregnancy [IP]) were compared between preembryonic (group I), embryonic (group II), or fetal (group III) losses in the QP.
losses. Group II had 14% preembryonic, 53% embryonic, and 9% fetal losses. Group III had 19% preembryonic, 23% embroyonic, and 29% fetal loses. Correlation coefficient for type of loss among the QPs and IPs was 0.14, P ⫽ .009. CONCLUSIONS: Women with iRPL tend to have losses recur in the same gestational age period. Causes for RPL may be gestational age specific and should guide further investigations into causes.
RESULTS: Three hundred thirty-four women met inclusion criteria. In
their IP, group I had 41% preembryonic, 28% embryonic, and 10% fetal
Key words: embryonic, etiologies, miscarriage, preembryonic
Cite this article as: Heuser C, Dalton J, MacPherson C, et al. Idiopathic recurrent pregnancy loss recurs at similar gestational ages. Am J Obstet Gynecol 2010;203:343.e1-5.
H
uman reproduction is a remarkable but inefficient process. Maximally fertile couples have only an approximately 30% chance of conception in a given menstrual cycle,1 and average monthly fecundity is 20%.2 Successful conception does not guarantee a live birth. Instead, over 30% of conceptions are lost early in gestation.3 Many of these likely result from problems with implantation or very early conceptus development and may not be clinically apparent. However, 12% to 14% of conceptions result in clinically recognized pregnancy loss.4 The causes of clinical recognized pregnancy loss also are poorly understood in many cases. Recurrent pregnancy loss, often defined as greater than 2 or 3 consecutive From the Department of Obstetrics and Gynecology (Drs Heuser, Branch, Porter, and Silver and Mr Dalton), University of Utah School of Medicine, Salt Lake City, UT; and Social and Scientific Systems, Inc, Silver Spring, MD (Dr MacPherson). Received Nov. 4, 2009; revised Feb. 16, 2010; accepted May 6, 2010. Reprints not available from the authors. 0002-9378/$36.00 © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.05.010
losses with no more than 1 live birth, occurs in 1-3% of couples, a percentage that is greater than would be expected solely by chance. Purported causes of recurrent pregnancy loss include genetic abnormalities, uterine malformations, antiphospholipid syndrome, hormonal abnormalities, other immunologic disorders, and other causes.5 However, in 50% or more of cases, no single-cause etiology is found. These women are considered to have idiopathic recurrent pregnancy loss (iRPL). Little progress has been made over the years in regard to causes, treatments, and prognosis for patients with this devastating condition. It seems to us very likely that causes of pregnancy loss differ during the preembryonic, embryonic, and fetal periods. Furthermore, the timing of pregnancy loss may have prognostic implications for future pregnancies. We hypothesized that that in women with iRPL, losses recur at similar gestational ages. However, precise details regarding gestational age at the time of pregnancy loss are lacking from most published studies of recurrent pregnancy loss (RPL). Our purpose was to determine whether a correlation exists between gestational ages of recurrent losses in a cohort of pregnancies with precise gestational dating in women with iRPL.
M ATERIALS AND M ETHODS The study was approved by the University of Utah Institutional Review Board. Study participants were identified through a recurrent miscarriage database that includes patients referred to our practice for evaluation of recurrent pregnancy loss. Uniform data were ascertained regarding prior pregnancies, medical problems, and diagnostic evaluations of either individual or recurrent fetal losses. Testing for recognized causes of pregnancy loss was at the discretion of the primary physician. Inclusion criteria were as follows: a history of RPL, defined as 2 or more pregnancy losses, and inclusion in the aforementioned database from March 2001 through December 2006, at least 1 unexplained pregnancy loss with precise documentation of gestational age at the time of loss (qualifying pregnancy [QP]) and at least 1 pregnancy subsequent to the QP. The first pregnancy after the QP was termed the index pregnancy (IP). Medical and obstetric histories were abstracted by review of medical records and, in some cases, patient interview. Women with known causes of RPL were not included. IP that resulted in elective terminations or ectopic pregnancies also were excluded from analysis. Patients
OCTOBER 2010 American Journal of Obstetrics & Gynecology
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TABLE 1
Demographics and medical history data
Demographic
Group I Anembryonic loss (<6 wk) (n ⴝ 109)
Group II Embryonic loss (6.0-10.0 wk) (n ⴝ 131)
Group III Fetal loss (>10.0 wk) (n ⴝ 94) P value
Age at QP (mean)
27.3
28.5
28.0
.26
Age at IP (mean)
28.3
29.7
29.1
.23
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
⬎ .99
Diabetes, n (%)
1 (0.9)
1 (0.8)
0
HTN, n (%)
2 (1.8)
0
2 (2.1)
.19
Tobacco use, n %)
4 (3.7)
5 (3.8)
1 (1.1)
.47
Thyroid disease, n (%)
7 (6.4)
9 (6.9)
6 (6.4)
⬎ .99
Family history of RSAB, n (%)
6 (5.5)
16 (12.4)
8 (8.6)
.18
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
HTN, hypertension; IP, index pregnancy; QP, qualifying pregnancy; RSAB, RPL: ⱖ2 pregnancy losses, and inclusion in the aforementioned database from March 2001 through December 2006, at least 1 unexplained pregnancy loss with precise documentation of gestational age at the time of loss (QP) and at least 1 pregnancy subsequent to the qualifying pregnancy. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
who had suffered losses after either chorionic villus sampling or amniocentesis were not included. Pregnancy losses were characterized as precisely as possible with regard to gestational age, using sonographic measurements, evaluation of the delivered fetus, or both. Pregnancies were divided into the following groups: previous pregnancies, QP, IP, and subsequent pregnancies. Precise documentation of gestational age was considered present if a sonogram documented a crown rump length with no fetal cardiac activity or a FIGURE
The timing in gestation of all QPs in the cohort 120
Number of Losses
100 80 60 40 20 0 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Gestational Age (weeks)
The vast majority of losses occurred before 14 weeks’ gestation. Early fetal deaths (10-14 weeks’ gestation) and preembryonic losses (⬍6 weeks’ gestation) also were common. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
343.e2
gestational sac without an embryo or fetal pole. In cases with delivery of a formed fetus, fetal biometric measurements were considered indicative of gestational age. Patients were divided into 3 groups based on the timing of their first wellcharacterized pregnancy loss: group I: preembryonic (⬍6 weeks’ gestation); group II: embryonic (6 through 9 weeks and 6 days); and group III: Fetal (ⱖ10 weeks). Preembryonic pregnancy was defined as sonogram findings including: (1) Mean sac diameter ⬎20 mm with no embryo, (2) mean sac diameter ⬎8 mm without yolk sac, or (3) yolk sac ⬎6 mm with no embryo.5 Embryonic demise was defined as an embryo with crown-rump length ⬎5 mm, ⬍50 mm, and no cardiac activity. Fetal death was defined as the intrauterine demise of a fetus known to be alive at or beyond 10 completed weeks of gestation documented by (1) detection of fetal heart tones, (2) the ultrasonographic detection of a conceptus with biometric measurements indicating a gestational age at or beyond 10 weeks of gestation, or (3) the delivery of a dead conceptus whose size indicated a gestational age at or beyond 10 weeks’ gestation.6,7 Women with losses beyond 16-18 weeks were included in the cohort. Data were analyzed with SAS version 9.2 (SAS Institute, Inc., Cary, NC). Categorical outcomes were compared with the 2 or Fisher’s exact test. Continuous
American Journal of Obstetrics & Gynecology OCTOBER 2010
outcomes were measured using Spearman’s correlation coefficients and linear regression models. Data were analyzed using (1) the IP only and (2) all subsequent pregnancies.
R ESULTS Three hundred thirty-four women were identified that met inclusion criteria. One hundred nine women had a preembryonic loss, 131 had an embryonic demise, and 94 had fetal demise at the time of QP. Demographics and patient characteristics at the time of the QP are shown in Table 1. Groups were similar with regard to age, ethnicity, and medical history. The Figure illustrates the timing in gestation of all QPs in the cohort. The vast majority of losses occurred before 14 weeks’ gestation. Early fetal deaths (10-14 weeks’ gestation) and preembryonic losses (⬍6 weeks’ gestation) also were common. Noteworthy, is the striking mode at 4 weeks of gestation, which is generally consistent with previous studies.5 Obstetric outcomes before the QP and subsequent to the IP for the entire cohort are depicted in Table 2. There were a total of 516 previous pregnancies and 777 subsequent pregnancies. On average, patients had 1.5 pregnancies before the QP and 2.3 subsequent pregnancies. As expected in a cohort of women with RPL, there were high rates of losses in both prior and subsequent pregnancies. It is noteworthy that almost one-third of prior losses (for the most part occurring before the patient seeks specialized care) could be categorized by gestational age. Table 3 shows the pregnancy outcomes in the IP, stratified by timing in gestation. Patients in each group were most likely to have recurrent losses of the same type as their QP. The gestational age of the QP was significantly correlated with gestational age of the IP (correlation coefficient 0.24; P ⬍ .0001). Similarly, the gestational age of the QP was significantly associated with gestational age in the IP in a regression model. For each 1 week increase in the gestational age of the QP, there was a 0.5 week in-
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TABLE 2
Summary of overall prior and subsequent pregnancies for entire cohort Variable
Total
Term live births
Preterm live births
Neonatal demise
Pregnancies before QP
516
283
18
4
Anembryonic loss
Embryonic loss
0
Fetal loss
0
0
Unspecified loss
Other
167
44
....................................................................................................................................................................................................................................................................................
(55%)
(3%)
(0.8%)
(32%)
(8%)
186
26
5
107
167
131
142
13
(24%)
(3%)
(0.6%)
(14%)
(21%)
(17%)
(18%)
(1.7%)
................................................................................................................................................................................................................................................................................................................................................................................
Pregnancies subsequent to IP
777
....................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
IP, index pregnancy; QP, qualifying pregnancy. Reported as n and percent. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
crease in the gestational age of the IP (parameter estimate ⫽ 0.5; P ⫽ .009). Additional subsequent pregnancies are depicted in Table 4. The results are similar to those observed in the IPs. These data were not analyzed statistically because many women had more than 1 subsequent pregnancy and precise gestational dating was not available for all pregnancies.
C OMMENT In a population of women with recurrent pregnancy loss, losses are likely to recur at gestational ages similar to those previously documented. Thus, women with a history of preembryonic losses are more likely to have recurrent preembryonic losses, those with embryonic demises are more likely to have recurrent embryonic demises, and those with fetal demises are more likely to have recurrent fetal deaths, when compared with women with other types of pregnancy losses. These observations suggest the possibility of specific, but as yet undiscovered, causes of loss that influence the viability of pregnancy at precise gestational ages. Some recognized causes of pregnancy loss appear to be gestational-age specific. For example, preembryonic losses are more likely to be associated with fetal aneuploidy than losses occurring later in gestation.8 Indeed, chromosomal abnormalities are present in more than 90% of preembryonic abortus tissues,9 compared with only 6-12% of losses after 20 weeks’ gestation.10 Thrombophilias such as protein S deficiency are associated with fetal death but not earlier miscarriage.11 Fetal losses comprise a high proportion of pregnancy losses in women
with antiphospholipid syndrome.12,13 In women with septate uteruses, 25.5% have miscarriages less than 13 weeks; whereas, 6.2% have losses between 14 to 22 weeks’ gestation.14 It is possible that iRPLs at specific times in gestation may result from single mutations in genes critical to embryonic development, placental formation or growth, or angiogenesis. Many single gene mutations are embryo-lethal in transgenic mice, often leading to fetal death in midgestation associated with evidence of abnormal placentation or angiogenesis. These “knockout” mice typically undergo embryonic or fetal death at very precise times in gestation.15 Moreover, the timing in gestation of the losses varies from one transgenic model to another, suggesting very temporally specific and critical effects of the targeted genes on normal pregnancy. It is likely that human homologs account for some
causes of pregnancy loss in women, and our data are consistent with this hypothesis. Other studies have supported the concept that pregnancy loss follows specific gestational age patterns. In a study of serial transvaginal ultrasound in low-risk pregnancy, Goldstein16 found that 13.4% of 232 women had a pregnancy loss. Fully 87% of the losses, representing 12% of all pregnancies, occurred before 10 menstrual weeks’ gestation, and no embryos that were alive at 8.5 weeks’ gestation died before 14 weeks’ gestation. Thirteen percent of the losses, representing 1% to 2% of all pregnancies, occurred from 14 to 20 weeks’ gestation.16 Another study reported that only 3.2% of women with a live embryo seen at 8 weeks’ gestation eventually had a pregnancy loss, and all of these occurred between 10.5 and 16 weeks’ gestation. Thus, embryos surviving to 8 weeks’ ges-
TABLE 3
QP vs IP outcomes IP outcome
Timing of QP loss
<6 wk (n ⴝ 81)
6-10.0 wk (n ⴝ 122)
>10.0 wk, stillbirth (n ⴝ 50)
>10.0 wk, livebirth (n ⴝ 81)
Anembryonic loss (⬍6 wk)
45
30
11
23
(n ⫽ 109)
41.3%
27.5%
10.1%
21.1%
Embryonic loss (6-10.0 wk)
18
70
12
(n ⫽ 131)
13.7%
53.4%
Fetal loss (⬎10.0 wk)
18
22
27
27
(n ⫽ 94)
19.2%
23.4%
28.7%
28.7%
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
31
..............................................................................................................................................................................................................................................
9.2%
23.7%
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
IP, index pregnancy; QP, qualifying pregnancy. Reported as n and percent. Correlation coefficient 0.24; P ⬍ .001. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
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TABLE 4
Subsequent pregnancy outcomes, not including IP All subsequent pregnancy outcomes (n ⴝ 777)
Timing of QP loss Anembryonic loss (⬍6 wks)
Total number of subsequent pregnancies
Unspecified SAB (n ⴝ 145)
<6 wk (n ⴝ 107)
6-10.0 wk (n ⴝ 167)
>10.0 wk, stillbirth (n ⴝ 146)
>10.0 wk, livebirth (n ⴝ 212)
261
46 (18%)
60 (23%)
53 (20%)
36 (14%)
66 (25%)
................................................................................................................................................................................................................................................................................................................................................................................
Embryonic loss (6-10.0 wk)
273
49 (18%)
30 (11%)
85 (31%)
28 (10%)
81 (30%)
Fetal loss (⬎10.0 wk)
243
50 (21%)
17 (7%)
29 (12%)
82 (34%)
65 (27%)
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
IP, index pregnancy; QP, qualifying pregnancy; SAB, spontaneous abortion. Reported as n and percent. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
tation have a very low mortality rate during the next few weeks. The overall rate of pregnancy loss rises again in the early fetal period. The subsequent pregnancy loss rate is only 1% if a live fetus is seen at 14-16 weeks’ gestation.17 Frias et al7 reported on the timing of fetal death in a cohort of women with recurrent fetal death. Over two-thirds of the deaths occurred during the second trimester with the mode between 16 and 18 weeks’ gestation. This study has several limitations. The cohort includes individuals referred for recurrent pregnancy loss, many of whom were seeking specialized care. Accordingly, our results cannot be generalized to the overall obstetric population. It is likely that subsequent outcomes in all groups were worse than for women with sporadic pregnancy loss. However, these data are useful for patients with iRPL. Also, many women did not undergo complete evaluations for recognized causes of recurrent pregnancy loss and most losses did not have karyotypes assessed. Although these data would be of interest, it is not clinically or economically practical to perform all of these tests in all couples or losses. Our data reflect typical current care of women with pregnancy loss in the United States. Furthermore, although it is possible that pregnancy surveillance may have differed between the QP and subsequent pregnancies, we believe that this difference is unlikely to influence results significantly in that (1) in most patients, the QP and subsequent pregnancies were followed by the same practitioners, and (2) the patients included had documentation of gestational age not 343.e4
solely by clinical dating criteria but also by ultrasound and examination of the products of conception at the time of the loss in both the QP and subsequent pregnancies. Our study also has numerous strengths. First, this study addresses an important and understudied clinical question. To our knowledge, this is one of the few studies to include details regarding the specific gestational ages of recurrent pregnancy losses. Furthermore, patients were prospectively and consecutively identified, helping to limit bias. Data were verified with medical records, sonogram reports, and laboratory values abstracted by trained medical personnel. Finally, this study includes a large number of women with RPL that is comparable to previously performed studies that range in sample size from 50 to 500. In summary, subsequent pregnancy losses among women presenting with recurrent pregnancy loss are likely to occur at gestational ages similar to those documented in their prior pregnancies. This implies that causes for pregnancy loss may vary at different times in gestation and that the timing of prior pregnancy losses may have prognostic implications for subsequent pregnancies. Failure of growth and death of the conceptus commonly precede clinically evident abortion, often by several weeks. Thus, the gestational age at which the abortion is recognized does not necessarily indicate when pregnancy failure occurred. Clinicians, and especially researchers, are encouraged to ascertain precise data regarding the timing of pregnancy loss with an emphasis on sonographic and postmortem findings. Further investiga-
American Journal of Obstetrics & Gynecology OCTOBER 2010
tions should focus on gestational agespecific causes for recurrent pregnancy loss. f REFERENCES 1. Zinaman MJ, Clegg ED, Brown CC, O’Connor J, Selevan SG. Estimates of human fertility and pregnancy loss. Fertil Steril 1996; 65:503-9. 2. Evers JL. Female subfertility. Lancet 2002; 360:151-9. 3. Wilcox AJ, Weinberg CR, O’Connor JF, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189-94. 4. Boklage CE. Survival probability of human conceptions from fertilization to term. Int J Fertil 1990;35:75, 79-80, 81-94. 5. Silver RM, Branch DW. Sporadic and recurrent pregnancy loss. In: Reece E, Hobbins J, eds. Medicine of the fetus and mother. Philadelphia: JB Lippincott Company; 1999:195-216. 6. Branch DW, Silver RM. Criteria for antiphospholipid syndrome: early pregnancy loss, fetal loss, or recurrent pregnancy loss? Lupus 1996;5:409-13. 7. Frias AE Jr, Luikenaar RA, Sullivan AE, et al. Poor obstetric outcome in subsequent pregnancies in women with prior fetal death. Obstet Gynecol 2004;104:521-6. 8. Kline J, Stein Z. Epidemiology of chromosomal anomalies in spontaneous abortion: prevelence, manifestation, and determinants. In: Bennett M, Edmonds D, eds. Spontaneous and recurrent abortion. Oxford, UK: Blackwell Scientific Publications; 1987:29-50. 9. Fantel A, Shepard T. Morphologic analysis of spontaneous abortuses. In: Bennett M, Edmonds D, eds. Spontaneous and recurrent abortion. Oxford, UK: Blackwell Scientific Publications; 1987:8-28. 10. Wapner RJ, Lewis D. Genetics and metabolic causes of stillbirth. Semin Perinatol 2002;26:70-4. 11. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003;361:901-8.
www.AJOG.org 12. Branch DW. Thoughts on the mechanism of pregnancy loss associated with the antiphospholipid syndrome. Lupus 1994;3:275-80. 13. Oshiro BT, Silver RM, Scott JR, Yu H, Branch DW. Antiphospholipid antibodies and fetal death. Obstet Gynecol 1996;87:489-93.
Reproductive Endocrinology and Infertility 14. Raga F, Bauset C, Remohi J, et al. Reproductive impact of congenital Mullerian anomalies. Hum Reprod 1997;12:2277-81. 15. Rossant J, Cross JC. Placental development: lessons from mouse mutants. Nat Rev Genet 2001;2:538-48.
Research
16. Goldstein SR. Embryonic death in early pregnancy: a new look at the first trimester. Obstet Gynecol 1994;84:294-7. 17. Simpson JL, Mills JL, Holmes LB, et al. Low fetal loss rates after ultrasound proved viability in early pregnancy. JAMA 1987;258:2555-7.
OCTOBER 2010 American Journal of Obstetrics & Gynecology
343.e5
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REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY
Idiopathic recurrent pregnancy loss recurs at similar gestational ages Cara Heuser, MD; Jess Dalton, MSPH; Cora Macpherson, PhD; D. Ware Branch, MD; T. Flint Porter, MD; Robert M. Silver, MD OBJECTIVE: To determine whether a correlation exists between gesta-
tional ages of idiopathic recurrent pregnancy loss (iRPL). STUDY DESIGN: Cohort of women with iRPL who had an initial loss
(qualifying pregnancy [QP]) with precise documentation of gestational age. Outcomes in the immediate next pregnancy (index pregnancy [IP]) were compared between preembryonic (group I), embryonic (group II), or fetal (group III) losses in the QP.
losses. Group II had 14% preembryonic, 53% embryonic, and 9% fetal losses. Group III had 19% preembryonic, 23% embroyonic, and 29% fetal loses. Correlation coefficient for type of loss among the QPs and IPs was 0.14, P ⫽ .009. CONCLUSIONS: Women with iRPL tend to have losses recur in the same gestational age period. Causes for RPL may be gestational age specific and should guide further investigations into causes.
RESULTS: Three hundred thirty-four women met inclusion criteria. In
their IP, group I had 41% preembryonic, 28% embryonic, and 10% fetal
Key words: embryonic, etiologies, miscarriage, preembryonic
Cite this article as: Heuser C, Dalton J, MacPherson C, et al. Idiopathic recurrent pregnancy loss recurs at similar gestational ages. Am J Obstet Gynecol 2010;203:343.e1-5.
H
uman reproduction is a remarkable but inefficient process. Maximally fertile couples have only an approximately 30% chance of conception in a given menstrual cycle,1 and average monthly fecundity is 20%.2 Successful conception does not guarantee a live birth. Instead, over 30% of conceptions are lost early in gestation.3 Many of these likely result from problems with implantation or very early conceptus development and may not be clinically apparent. However, 12% to 14% of conceptions result in clinically recognized pregnancy loss.4 The causes of clinical recognized pregnancy loss also are poorly understood in many cases. Recurrent pregnancy loss, often defined as greater than 2 or 3 consecutive From the Department of Obstetrics and Gynecology (Drs Heuser, Branch, Porter, and Silver and Mr Dalton), University of Utah School of Medicine, Salt Lake City, UT; and Social and Scientific Systems, Inc, Silver Spring, MD (Dr MacPherson). Received Nov. 4, 2009; revised Feb. 16, 2010; accepted May 6, 2010. Reprints not available from the authors. 0002-9378/$36.00 © 2010 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.05.010
losses with no more than 1 live birth, occurs in 1-3% of couples, a percentage that is greater than would be expected solely by chance. Purported causes of recurrent pregnancy loss include genetic abnormalities, uterine malformations, antiphospholipid syndrome, hormonal abnormalities, other immunologic disorders, and other causes.5 However, in 50% or more of cases, no single-cause etiology is found. These women are considered to have idiopathic recurrent pregnancy loss (iRPL). Little progress has been made over the years in regard to causes, treatments, and prognosis for patients with this devastating condition. It seems to us very likely that causes of pregnancy loss differ during the preembryonic, embryonic, and fetal periods. Furthermore, the timing of pregnancy loss may have prognostic implications for future pregnancies. We hypothesized that that in women with iRPL, losses recur at similar gestational ages. However, precise details regarding gestational age at the time of pregnancy loss are lacking from most published studies of recurrent pregnancy loss (RPL). Our purpose was to determine whether a correlation exists between gestational ages of recurrent losses in a cohort of pregnancies with precise gestational dating in women with iRPL.
M ATERIALS AND M ETHODS The study was approved by the University of Utah Institutional Review Board. Study participants were identified through a recurrent miscarriage database that includes patients referred to our practice for evaluation of recurrent pregnancy loss. Uniform data were ascertained regarding prior pregnancies, medical problems, and diagnostic evaluations of either individual or recurrent fetal losses. Testing for recognized causes of pregnancy loss was at the discretion of the primary physician. Inclusion criteria were as follows: a history of RPL, defined as 2 or more pregnancy losses, and inclusion in the aforementioned database from March 2001 through December 2006, at least 1 unexplained pregnancy loss with precise documentation of gestational age at the time of loss (qualifying pregnancy [QP]) and at least 1 pregnancy subsequent to the QP. The first pregnancy after the QP was termed the index pregnancy (IP). Medical and obstetric histories were abstracted by review of medical records and, in some cases, patient interview. Women with known causes of RPL were not included. IP that resulted in elective terminations or ectopic pregnancies also were excluded from analysis. Patients
OCTOBER 2010 American Journal of Obstetrics & Gynecology
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TABLE 1
Demographics and medical history data
Demographic
Group I Anembryonic loss (<6 wk) (n ⴝ 109)
Group II Embryonic loss (6.0-10.0 wk) (n ⴝ 131)
Group III Fetal loss (>10.0 wk) (n ⴝ 94) P value
Age at QP (mean)
27.3
28.5
28.0
.26
Age at IP (mean)
28.3
29.7
29.1
.23
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
⬎ .99
Diabetes, n (%)
1 (0.9)
1 (0.8)
0
HTN, n (%)
2 (1.8)
0
2 (2.1)
.19
Tobacco use, n %)
4 (3.7)
5 (3.8)
1 (1.1)
.47
Thyroid disease, n (%)
7 (6.4)
9 (6.9)
6 (6.4)
⬎ .99
Family history of RSAB, n (%)
6 (5.5)
16 (12.4)
8 (8.6)
.18
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
HTN, hypertension; IP, index pregnancy; QP, qualifying pregnancy; RSAB, RPL: ⱖ2 pregnancy losses, and inclusion in the aforementioned database from March 2001 through December 2006, at least 1 unexplained pregnancy loss with precise documentation of gestational age at the time of loss (QP) and at least 1 pregnancy subsequent to the qualifying pregnancy. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
who had suffered losses after either chorionic villus sampling or amniocentesis were not included. Pregnancy losses were characterized as precisely as possible with regard to gestational age, using sonographic measurements, evaluation of the delivered fetus, or both. Pregnancies were divided into the following groups: previous pregnancies, QP, IP, and subsequent pregnancies. Precise documentation of gestational age was considered present if a sonogram documented a crown rump length with no fetal cardiac activity or a FIGURE
The timing in gestation of all QPs in the cohort 120
Number of Losses
100 80 60 40 20 0 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Gestational Age (weeks)
The vast majority of losses occurred before 14 weeks’ gestation. Early fetal deaths (10-14 weeks’ gestation) and preembryonic losses (⬍6 weeks’ gestation) also were common. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
343.e2
gestational sac without an embryo or fetal pole. In cases with delivery of a formed fetus, fetal biometric measurements were considered indicative of gestational age. Patients were divided into 3 groups based on the timing of their first wellcharacterized pregnancy loss: group I: preembryonic (⬍6 weeks’ gestation); group II: embryonic (6 through 9 weeks and 6 days); and group III: Fetal (ⱖ10 weeks). Preembryonic pregnancy was defined as sonogram findings including: (1) Mean sac diameter ⬎20 mm with no embryo, (2) mean sac diameter ⬎8 mm without yolk sac, or (3) yolk sac ⬎6 mm with no embryo.5 Embryonic demise was defined as an embryo with crown-rump length ⬎5 mm, ⬍50 mm, and no cardiac activity. Fetal death was defined as the intrauterine demise of a fetus known to be alive at or beyond 10 completed weeks of gestation documented by (1) detection of fetal heart tones, (2) the ultrasonographic detection of a conceptus with biometric measurements indicating a gestational age at or beyond 10 weeks of gestation, or (3) the delivery of a dead conceptus whose size indicated a gestational age at or beyond 10 weeks’ gestation.6,7 Women with losses beyond 16-18 weeks were included in the cohort. Data were analyzed with SAS version 9.2 (SAS Institute, Inc., Cary, NC). Categorical outcomes were compared with the 2 or Fisher’s exact test. Continuous
American Journal of Obstetrics & Gynecology OCTOBER 2010
outcomes were measured using Spearman’s correlation coefficients and linear regression models. Data were analyzed using (1) the IP only and (2) all subsequent pregnancies.
R ESULTS Three hundred thirty-four women were identified that met inclusion criteria. One hundred nine women had a preembryonic loss, 131 had an embryonic demise, and 94 had fetal demise at the time of QP. Demographics and patient characteristics at the time of the QP are shown in Table 1. Groups were similar with regard to age, ethnicity, and medical history. The Figure illustrates the timing in gestation of all QPs in the cohort. The vast majority of losses occurred before 14 weeks’ gestation. Early fetal deaths (10-14 weeks’ gestation) and preembryonic losses (⬍6 weeks’ gestation) also were common. Noteworthy, is the striking mode at 4 weeks of gestation, which is generally consistent with previous studies.5 Obstetric outcomes before the QP and subsequent to the IP for the entire cohort are depicted in Table 2. There were a total of 516 previous pregnancies and 777 subsequent pregnancies. On average, patients had 1.5 pregnancies before the QP and 2.3 subsequent pregnancies. As expected in a cohort of women with RPL, there were high rates of losses in both prior and subsequent pregnancies. It is noteworthy that almost one-third of prior losses (for the most part occurring before the patient seeks specialized care) could be categorized by gestational age. Table 3 shows the pregnancy outcomes in the IP, stratified by timing in gestation. Patients in each group were most likely to have recurrent losses of the same type as their QP. The gestational age of the QP was significantly correlated with gestational age of the IP (correlation coefficient 0.24; P ⬍ .0001). Similarly, the gestational age of the QP was significantly associated with gestational age in the IP in a regression model. For each 1 week increase in the gestational age of the QP, there was a 0.5 week in-
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TABLE 2
Summary of overall prior and subsequent pregnancies for entire cohort Variable
Total
Term live births
Preterm live births
Neonatal demise
Pregnancies before QP
516
283
18
4
Anembryonic loss
Embryonic loss
0
Fetal loss
0
0
Unspecified loss
Other
167
44
....................................................................................................................................................................................................................................................................................
(55%)
(3%)
(0.8%)
(32%)
(8%)
186
26
5
107
167
131
142
13
(24%)
(3%)
(0.6%)
(14%)
(21%)
(17%)
(18%)
(1.7%)
................................................................................................................................................................................................................................................................................................................................................................................
Pregnancies subsequent to IP
777
....................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
IP, index pregnancy; QP, qualifying pregnancy. Reported as n and percent. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
crease in the gestational age of the IP (parameter estimate ⫽ 0.5; P ⫽ .009). Additional subsequent pregnancies are depicted in Table 4. The results are similar to those observed in the IPs. These data were not analyzed statistically because many women had more than 1 subsequent pregnancy and precise gestational dating was not available for all pregnancies.
C OMMENT In a population of women with recurrent pregnancy loss, losses are likely to recur at gestational ages similar to those previously documented. Thus, women with a history of preembryonic losses are more likely to have recurrent preembryonic losses, those with embryonic demises are more likely to have recurrent embryonic demises, and those with fetal demises are more likely to have recurrent fetal deaths, when compared with women with other types of pregnancy losses. These observations suggest the possibility of specific, but as yet undiscovered, causes of loss that influence the viability of pregnancy at precise gestational ages. Some recognized causes of pregnancy loss appear to be gestational-age specific. For example, preembryonic losses are more likely to be associated with fetal aneuploidy than losses occurring later in gestation.8 Indeed, chromosomal abnormalities are present in more than 90% of preembryonic abortus tissues,9 compared with only 6-12% of losses after 20 weeks’ gestation.10 Thrombophilias such as protein S deficiency are associated with fetal death but not earlier miscarriage.11 Fetal losses comprise a high proportion of pregnancy losses in women
with antiphospholipid syndrome.12,13 In women with septate uteruses, 25.5% have miscarriages less than 13 weeks; whereas, 6.2% have losses between 14 to 22 weeks’ gestation.14 It is possible that iRPLs at specific times in gestation may result from single mutations in genes critical to embryonic development, placental formation or growth, or angiogenesis. Many single gene mutations are embryo-lethal in transgenic mice, often leading to fetal death in midgestation associated with evidence of abnormal placentation or angiogenesis. These “knockout” mice typically undergo embryonic or fetal death at very precise times in gestation.15 Moreover, the timing in gestation of the losses varies from one transgenic model to another, suggesting very temporally specific and critical effects of the targeted genes on normal pregnancy. It is likely that human homologs account for some
causes of pregnancy loss in women, and our data are consistent with this hypothesis. Other studies have supported the concept that pregnancy loss follows specific gestational age patterns. In a study of serial transvaginal ultrasound in low-risk pregnancy, Goldstein16 found that 13.4% of 232 women had a pregnancy loss. Fully 87% of the losses, representing 12% of all pregnancies, occurred before 10 menstrual weeks’ gestation, and no embryos that were alive at 8.5 weeks’ gestation died before 14 weeks’ gestation. Thirteen percent of the losses, representing 1% to 2% of all pregnancies, occurred from 14 to 20 weeks’ gestation.16 Another study reported that only 3.2% of women with a live embryo seen at 8 weeks’ gestation eventually had a pregnancy loss, and all of these occurred between 10.5 and 16 weeks’ gestation. Thus, embryos surviving to 8 weeks’ ges-
TABLE 3
QP vs IP outcomes IP outcome
Timing of QP loss
<6 wk (n ⴝ 81)
6-10.0 wk (n ⴝ 122)
>10.0 wk, stillbirth (n ⴝ 50)
>10.0 wk, livebirth (n ⴝ 81)
Anembryonic loss (⬍6 wk)
45
30
11
23
(n ⫽ 109)
41.3%
27.5%
10.1%
21.1%
Embryonic loss (6-10.0 wk)
18
70
12
(n ⫽ 131)
13.7%
53.4%
Fetal loss (⬎10.0 wk)
18
22
27
27
(n ⫽ 94)
19.2%
23.4%
28.7%
28.7%
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
31
..............................................................................................................................................................................................................................................
9.2%
23.7%
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
IP, index pregnancy; QP, qualifying pregnancy. Reported as n and percent. Correlation coefficient 0.24; P ⬍ .001. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
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343.e3
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TABLE 4
Subsequent pregnancy outcomes, not including IP All subsequent pregnancy outcomes (n ⴝ 777)
Timing of QP loss Anembryonic loss (⬍6 wks)
Total number of subsequent pregnancies
Unspecified SAB (n ⴝ 145)
<6 wk (n ⴝ 107)
6-10.0 wk (n ⴝ 167)
>10.0 wk, stillbirth (n ⴝ 146)
>10.0 wk, livebirth (n ⴝ 212)
261
46 (18%)
60 (23%)
53 (20%)
36 (14%)
66 (25%)
................................................................................................................................................................................................................................................................................................................................................................................
Embryonic loss (6-10.0 wk)
273
49 (18%)
30 (11%)
85 (31%)
28 (10%)
81 (30%)
Fetal loss (⬎10.0 wk)
243
50 (21%)
17 (7%)
29 (12%)
82 (34%)
65 (27%)
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
IP, index pregnancy; QP, qualifying pregnancy; SAB, spontaneous abortion. Reported as n and percent. Heuser. Gestational age of recurrent pregnancy loss. Am J Obstet Gynecol 2010.
tation have a very low mortality rate during the next few weeks. The overall rate of pregnancy loss rises again in the early fetal period. The subsequent pregnancy loss rate is only 1% if a live fetus is seen at 14-16 weeks’ gestation.17 Frias et al7 reported on the timing of fetal death in a cohort of women with recurrent fetal death. Over two-thirds of the deaths occurred during the second trimester with the mode between 16 and 18 weeks’ gestation. This study has several limitations. The cohort includes individuals referred for recurrent pregnancy loss, many of whom were seeking specialized care. Accordingly, our results cannot be generalized to the overall obstetric population. It is likely that subsequent outcomes in all groups were worse than for women with sporadic pregnancy loss. However, these data are useful for patients with iRPL. Also, many women did not undergo complete evaluations for recognized causes of recurrent pregnancy loss and most losses did not have karyotypes assessed. Although these data would be of interest, it is not clinically or economically practical to perform all of these tests in all couples or losses. Our data reflect typical current care of women with pregnancy loss in the United States. Furthermore, although it is possible that pregnancy surveillance may have differed between the QP and subsequent pregnancies, we believe that this difference is unlikely to influence results significantly in that (1) in most patients, the QP and subsequent pregnancies were followed by the same practitioners, and (2) the patients included had documentation of gestational age not 343.e4
solely by clinical dating criteria but also by ultrasound and examination of the products of conception at the time of the loss in both the QP and subsequent pregnancies. Our study also has numerous strengths. First, this study addresses an important and understudied clinical question. To our knowledge, this is one of the few studies to include details regarding the specific gestational ages of recurrent pregnancy losses. Furthermore, patients were prospectively and consecutively identified, helping to limit bias. Data were verified with medical records, sonogram reports, and laboratory values abstracted by trained medical personnel. Finally, this study includes a large number of women with RPL that is comparable to previously performed studies that range in sample size from 50 to 500. In summary, subsequent pregnancy losses among women presenting with recurrent pregnancy loss are likely to occur at gestational ages similar to those documented in their prior pregnancies. This implies that causes for pregnancy loss may vary at different times in gestation and that the timing of prior pregnancy losses may have prognostic implications for subsequent pregnancies. Failure of growth and death of the conceptus commonly precede clinically evident abortion, often by several weeks. Thus, the gestational age at which the abortion is recognized does not necessarily indicate when pregnancy failure occurred. Clinicians, and especially researchers, are encouraged to ascertain precise data regarding the timing of pregnancy loss with an emphasis on sonographic and postmortem findings. Further investiga-
American Journal of Obstetrics & Gynecology OCTOBER 2010
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