Spontaneous abortion_ Risk factors, etiology, clinical manifestations, and diagnostic evaluation - UpToDate.pdf

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Spontaneous ab abortio rtion n: Risk Risk facto ctors, etiolo iology gy, clin clinic ica al ma manife ifesta statio tions, and diagn iagno ostic stic evalua luation ion - UpT UpToDat Date

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Spontaneous abortion: Risk factors, etiology, clinical manifestations , and diagnostic evaluation  Authors: Togas Tulandi, MD, MHCM, MHCM , Haya M Al-Fozan, MD Section Editors: Deborah Levine, Levine, MD MD,, Robert L Barbieri, MD Deputy Depu ty Editor: Kristen Ec kler, MD, FACOG FACOG

 All topics are updated updated as new evidence becomes becomes available available and our peer review process is process  is complete. Literature re view current through: Jun through: Jun 2017. | This topi topic last updated: Jan updated: Jan 19, 2017. INTRODUCTION — INTRODUCTION — Spontaneous abortion, or miscarriage, is defined as a clinically recognized pregnancy loss before before the 20 20 th week of gestat gestation ion [1,2 [ 1,2]. ]. The World Health Organization (WHO) defines it as expulsion or  extraction of an embryo or fetus weighing 500 g or less. The term "fetus" will be used throughout this discussion, although the term "embryo" is the correct developmental term at ≤10 weeks of gestation. The etiology, risk factors, and diagnostic issues relating to spontaneous abortion are reviewed here. Recurrent abortion and management issues are discussed separately. (See "Evaluation of couples with recurrent pregnancy loss" and loss"  and "Spontaneous abortion: Management" .) TERMINOLOGY ● Intrauterine pregnancy of uncertain viability – viability  – Transvaginal ultrasonography shows an intrauterine gestational sac with no embryonic heartbeat (and no findings of definite pregnancy failure) [ 3]. ● Pregnancy of unknown location – location  – A urine or urine  or serum pregnancy test is pos itive and there is no intrauterine or ectopic pregnancy seen on transvaginal ultrasonography. ultrasonography. INCIDENCE — INCIDENCE — Spontaneous abortion is the most common complication of early pregnancy [ 1]. The frequency decreases with increasing gestational age. The incidence of spontaneous abortion (miscarriage) in clinically recognized pregnancies up to  20 gestational  20 gestational weeks is 8 to 20 percent. However, the incidence among women who have previously had a child is much lower (5 percent) [ 4,5 4,5]. ]. The overall risk r isk of spontaneous abortion after  15 weeks is low (about 0.6 percent) for chromosomally and structurally normal fetuses, but varies according to maternal age and ethnicity [ 6]. Loss of unrecognized unrecog nized or subcli subcl inical pregnancies pregnanci es is even higher, occurring in 13 to 26 percent of all pregnancies [4,5,7 [ 4,5,7]. ]. Early pregnancy losses are unlikely to be recognized unless daily pregnancy tests are performed. A study that compared women's bleeding following a pregnancy loss before 6 weeks of gestation with their typical menstruation found that mean bleeding length following a pregnancy loss was 0.4 days longer  than the woman's a verage menses and menses  and the amount of bleeding was light [ 8]. These data derive from studies such as the following representative examples: ● In a classic study in which daily urinary human chorionic gonadotropin (hCG) assays were performed, the total rate of pregnancy loss after implantation was 31 percent; 70 percent of losses (22 percent of all pregnancies) occurred before the pregnancy was detected clinically [ 4]. ● In another study, daily urinary hCG assays were performed on 518 nulliparous, newly married women aged 20 to 34 years who were attempting to conceive and had no known infertility factors [ 5]. Among 586 conceptions with a known outcome, 26 percent ended in preclinical loss, 8 percent ended in a clinically recognized loss, and 64 percent resulted in a live birth; the remaining 2 percent were induced abortions, ectopic pregnancies, molar pregnancies, and stillbirths.

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If preimplantation losses are considered, approximately 50 percent of fertilized oocytes do not result in a live birth [9 [9]. RISK FACTORS — FACTORS — Numerous risk factors are associated with an increased risk of pregnancy loss. The best documented risk factors for spontaneous abortion are advanced maternal age, previous spontaneous abortion, and maternal smoking. Maternal age  — Advancing maternal age is the most important risk factor for spontaneous miscarriage in healthy women. The effect of maternal age on pregnancy outcome was illustrated in a review of over 1 million pregnancies with known outcomes involving admission to a hospital [ 10 10]. ]. The overall rate r ate of spontaneous abortion was 11 percent and the approximate frequencies of clinically recognized miscarriage according to maternal maternal age were: were: age 20 to 30 years (9 ( 9 to 17 percent), age 35 years ( 20 percent), age 40 years (40 percent), and age 45 years (80 percent) [ 10 10]. ]. (See "Effects of advanced maternal age on pregnancy", section on 'Spontaneous abortion' .) Reproductive factors ● Previous spontaneous abortion — abortion  — Past obstetrical history is an important predictor of subsequent pregnancy outcome. The risk of miscarriage in future pregnancy is approximately 20 percent after one miscarriage, 28 percent after two consecutive miscarriages, and 43 percent after three or more consecutive miscarriages [1 [ 11]. By comparison, miscarriage occurred in only 5 percent of women in their  first pregnancy or in whom the previous pregnancy was successful. (See "Definition and etiology of  recurrent pregnancy loss", section on 'Previous pregnancy loss' .) ● Gravidity — Some studies have shown an increased risk of miscarriage with increasing gravidity [ 12 12], ], others have not [13,14 [ 13,14]. ]. Possible explanations for an association include (1) compensatory reproductive behavior (pregnancy failure is likely to be associated with repeated attempts at conception, resulting in higher gravidity) and (2) short interpregnancy intervals in multigravid women. (See "Interpregnancy interval and obstetrical complications" .) ● Prolonged ovulation to implantation implantation interv al — al — Early losses have been related to delayed implantation (ie, >10 days between ovulation and implantation), which might result from fertilization of an aging ovum, delayed tubal transport, or abnormal uterine receptivity [ 15 15]. ]. ● Prolonged time time to t o conception — conception  — Observational studies have suggested that prolonged time to achieving pregnancy correlates with an increased risk of miscarriage [ 16 16]. ]. Medications or substances Smoking — Smoking — Heavy smoking (greater than 10 cigarettes per day) is associated with an increased risk of  pregnancy loss (relative risk 1.2 to 3.4) [ 17-19 17-19]. ]. The association is stronger after controlling for other causes of pregnancy loss, such as limiting analysis to chromosomally normal abortuses [ 20 20]. ]. The mechanism responsible is unknown, but may relate to the vasoconstrictive and antimetabolic effects of tobacco smoke. Paternal smoking may also increase the risk of pregnancy loss [ 21 21], ], as may exposure to second hand smoke during childhood [22 [ 22]. ]. Smoking cessation should be recommended for its overall health benefits (see "Cigarette smoking: Impact on pregnancy and the neonate"  and "Overview of smoking cessation managem management ent in adults"). adults"). Alcohol — Alcohol — Observational studies have generally, but not consistently, found that moderate to high alcohol consumption increases the risk of spontaneous abortion [ 23-27 23-27]. ]. As an example, in one study, there was an increased risk of miscarriage in women who consumed more than 3 drinks per week during the first 12 weeks of pregnancy [23 [ 23]. ]. Interpretation of studies examining alcohol use in pregnancy is complicated by the difficulty of making accurate adjustments for the many confounding factors and underreporting of actual alcohol consumption. Women planning pregnancy should avoid alcohol consumption because alcohol is a known teratogen and a safe level https://w https://www ww.uptod .uptodate ate.com .com/conte /contents/spo nts/sponta ntane neous-abo ous-aborti rtion-ris on-ris k-factors- etiology-cli nical-ma nical- manifestat nifestations-and-diagnostic-eva ions-and-diagnostic-evaluation/ luation/print?sou print?source= rce=search_res… search_res…

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of alcohol intake has not been established for any stage of pregnancy. (See "Alcohol intake and pregnancy" and "Substance misuse in pregnant women" .) Cocaine — Use of cocaine is associated with preterm birth, and may also be a risk factor for spontaneous abortion [19]. In one study involving 400 women having had a spontaneous abortion and 570 controls who reached at least 22 weeks of gestation, the presence of cocaine in hair samples was independently associated with an increase in the prevalence of spontaneous abortion after adjustment for demographic and drug-use variables (OR 1.4; 95% CI 1.0-2.1) [ 19]. (See "Substance misuse in pregnant women" .) Nonsteroidal anti-inflammatory drugs — The use of nonsteroidal anti-inflammatory drugs (NSAIDs), but not acetaminophen, around the time of conception may be associated with an increased risk of miscarriage [28,29]. The postulated mechanism is that prostaglandin inhibitors interfere with the role prostaglandins play in implantation, thus potentially leading to abnormal implantation and pregnancy failure [ 30]. Although data are limited, it is reasonable to suggest that women trying to conceive should best avoid use of NSAIDS to minimize the risk of miscarriage, particularly when effective alternatives (eg, acetaminophen) are available. Caffeine — Based upon systematic reviews, it appears that caffeine intake is not associated with an increased risk of SAB, with the possible exception of intake of very high levels (ie, 1000 mg, or 10 cups of  coffee, over 8 to 10 hours). However, studies examining the question have methodologic limitations relating to selection and recall bias, confounding factors, the difficulty of quantifying caffeine consumption accurately (ie, variations in size of the cup, brand of coffee, and brewing method), and the failure to account for fetal karyotype, differences in caffeine metabolism, uncertainties in the time of fetal demise, and the possibility that any effect of caffeine may be gestational age-specific. The mechanism responsible for an association between high levels of caffeine intake and an increased risk of spontaneous abortion may relate to differences in maternal metabolism and clearance. This issue is discussed in detail separately. (See "The effects of caffeine on reproductive outcomes in women", section on 'Spontaneous abortion' .) Other factors ● Low folate level — Low plasma folate levels appear to be associated with spontaneous abortion only when the fetal karyotype is abnormal. A well-designed, population-based, case-control study observed that low plasma folate levels (≤2.19 ng/mL [4.9 nmol/L]) were associated with an increased risk of  spontaneous abortion at 6 to 12 weeks of gestation in pregnancies with abnormal fetal karyotype [ 31]. Low folate levels in pregnancies with normal fetal karyotype and high folate levels had no impact on rate of abortion. Of note, less than 5 percent of women received folate supplementation. Whether low folate levels increase the risk for embryo aneuploidy and subsequent abortion is under  investigation; some investigators have suggested that maternal polymorphisms in the methylenetetrahydrofolate reductase ( MTHFR ) and methionine synthase ( MTRR ) genes may increase the risk of meiotic nondisjunction. Whether or not MTHFR  polymorphisms independently increase the risk of  pregnancy loss is unclear [32,33]. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 21 (Down syndrome)'.) There is no evidence that vitamin supplementation prevents miscarriage [ 34]. There is no specific evidence that folate supplementation reduces the risk of miscarriage in women with hyperhomocysteinemia, although the possibility has been suggested [ 35]. However, folate supplements are routinely recommended for all pregnant women for prevention of neural tube defects. ● Extremes of maternal weight — Prepregnancy body mass index (BMI) less than 18.5 or above 25 kg/m2 has been associated with an increased risk of infertility and spontaneous abortion [ 36-40]. In a meta-analysis of 32 studies that included over 265,000 women, small but significantly increased risks of  miscarriage were reported for underweight (relative risk [RR] 1.08, 95% CI 1.05-1.11), overweight (RR 1.09, 95% CI 1.04-1.13), and obese women (RR 1.21, 95% CI 1.15-1.27) [ 41]. We encourage women who desire pregnancy to maintain a normal BMI to maximize their reproductive health. (See "Optimizing natural https://www.uptodate.com/contents/spontaneous-abortion-ris k-factors- etiology-cli nical-manifestations-and-diagnostic-evaluation/print?source=search_res…

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fertility in couples planning pregnancy"  and "Obesity in pregnancy: Complications and maternal management".) ● Fever — Fevers of 100°F (37.8°C) or more during pregnancy may increase the risk of miscarriage, but the only two large studies have yielded inconsistent and inconclusive results. • One study compared women having euploid abortions or aneuploid abortions to women delivering at 28 weeks of gestation or later (controls), reasoning that if fever was an antecedent (rather than a symptom) of spontaneous abortion, fever would be associated with euploid, but not aneuploid, abortions [42]. Results of the study were consistent with that hypothesis: fevers were significantly more prevalent among women having a euploid abortion than among controls (18 versus 7 percent), but not more prevalent among women with aneuploid abortions. Moreover, the risk of abortion related to the proximity of the febrile episode; the OR for abortion was 6.0 when fever occurred in the same calendar month, 3.3 when it occurred during the preceding month, and 1.4 when the febrile episode was two or more months before a euploid abortion. •  Another study analyzed data from more than 24,000 Danish women who were interviewed during the first 16 weeks of pregnancy to obtain information on the number of febrile episodes, the highest temperature, duration of fever, and gestational age at the time of the occurrence [ 43], which was subsequently linked with a pregnancy outcome registry. Fever occurred in 18.5 percent of  participants. There was no association between fever or any specific fever characteristic and first, second, or third trimester fetal death, before or after adjustment of risk factors. However, the low rate of first trimester pregnancy loss (2.3 percent) suggested that some women with spontaneous abortions were not included, potentially masking an effect of fever on early loss. ● Celiac disease  — Untreated celiac disease may be associated with a higher risk of spontaneous abortion. (See "Definition and etiology of recurrent pregnancy loss", section on 'Celiac disease' .) ETIOLOGY — Spontaneous abortion is most commonly caused by chromosomal abnormalities in the embryo or exposure to teratogens. It is often difficult to determine the cause of a spontaneous abortion in an individual case. In one-third occurring at 8 weeks of gestation or earlier, no embryo or yolk sac is observed in the gestational sac. In the remaining two-thirds of cases in which an embryo is identified, approximately half are abnormal, dysmorphic, stunted, or too macerated for examination [ 44]. Fetal factors Chromosomal abnormalities — Chromosomal abnormalities account for approximately 50 percent of all miscarriages [45]. Most such abnormalities are aneuploidies; structural abnormalities and mosaicism are responsible for a small proportion. As an example, cytogenetic abnormalities were found in 59 percent of 2389 post-miscarriage product-of-conception samples, analyzed using a high-resolution single-nucleotide polymorphism (SNP)-based microarray platform [ 46]. Abnormalities included: aneuploidy (85 percent); triploidy (10 percent); and tetraploidy (4.2 percent) Most such abnormalities are aneuploidies that occur with increasing frequency as maternal age increases. The earlier abortion occurs, the higher the incidence of cytogenetic defects [ 47,48]. In one study, for example, the prevalence of abnormal fetal karyotypes is 90 percent in empty sac pregnancies, 50 percent in abortions occurring at 8 to 11 weeks of gestation, and 30 percent in those occurring at 16 to 19 weeks [ 47]. Trisomy 16 is the most common autosomal trisomy and is always lethal. Most chromosomal abnormalities in the embryo arise de novo. Rarely, the abnormality is inherited from a parent who may have a balanced chromosomal translocation. (See "Definition and etiology of recurrent pregnancy loss", section on ' Genetic factors'.) Genetic abnormalities not detected by conventional cytogenetic analysis (G-banded karyotype) account for an undefined proportion of spontaneous abortions and include small deletions, duplications, and point mutations. https://www.uptodate.com/contents/spontaneous-abortion-ris k-factors- etiology-cli nical-manifestations-and-diagnostic-evaluation/print?source=search_res…

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Congenital anomalies — Congenital anomalies may be caused by chromosomal or other genetic abnormalities, by extrinsic factors (eg, amniotic bands), or by exposure to teratogens. Potential teratogens include maternal disorders (eg, diabetes mellitus with poor glycemic control), drugs (eg, isotretinoin), physical stresses (eg, fever), and environmental chemicals (eg, mercury). (See "Birth defects: Approach to evaluation" .) Trauma — Invasive intrauterine procedures such as chorionic villus sampling and amniocentesis, or trauma increase the risk of abortion. By contrast, during early pregnancy, the uterus is generally protected from blunt trauma to the maternal abdomen [ 49]. (See "Chorionic villus sampling" and "Diagnostic amniocentesis".) Maternal factors Uterine structural issues — Pregnancy loss may also be related to the host environment. As an example, congenital or acquired uterine abnormalities (eg, uterine septum, submucosal leiomyoma, intrauterine adhesions) can interfere with implantation and growth [ 50].  A few studies found that the only uterine anomaly that impairs reproductive outcome was a septate uterus. Removal of the septum significantly increased live birth rate and was associated with a high spontaneous conception rate in infertile women [ 51-53]. The effect of leiomyomas on the risk of spontaneous abortion is discussed in detail separately. (See "Reproductive issues in women with uterine leiomyomas (fibroids)" .) Maternal disease  — Acute maternal infection with any of a large variety of organisms (eg, Listeria monocytogenes, Toxoplasma gondii, parvovirus B19, rubella, herpes simplex, cytomegalovirus, lymphocytic choriomeningitis virus [54]) can result in abortion due to fetal or placental infection. At least one case report has linked Zika virus infection with first-trimester abortion [ 55]. The virus was isolated in the fetal tissue. Maternal endocrinopathies (eg, thyroid dysfunction, Cushing's syndrome, polycystic ovary syndrome) can also compromise the host environment. Since corpus luteum progesterone production is essential for the success of early pregnancy, it is plausible that early losses might result from corpus luteum dysfunction, but the concept is controversial. Some well-designed studies comparing maternal serum progesterone levels during the midluteal phase (when corpus luteum progesterone production is critical) found no difference between concentrations observed in continuing pregnancies and those that subsequently failed [ 56]. The use of  progesterone to distinguish between a nonviable (missed abortion or ectopic pregnancy) and a viable pregnancy when the location of the pregnancy is unknown is addressed separately. (See "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Progesterone' .) The effect of thyroid disease and thyroid peroxidase antibodies on abortion risk is also reviewed separately. (See "Overview of thyroid disease in pregnancy" .)  A hypercoagulable state due to an inherited or acquired thrombophilia and abnormalities of the immune system (eg, systemic lupus erythematosus, antiphospholipid syndrome) that may predispose to immunological rejection or placental damage are active areas of investigation. (See "Inherited thrombophilias in pregnancy" and "Pregnancy in women with antiphospholipid syndrome" .) Unexplained — The cause of abortions of chromosomally and structurally normal embryos/fetuses in apparently healthy women is unclear. As discussed above, genetic abnormalities not detected by a standard karyotype (small deletions, duplications, and point mutations) account for an undefined proportion of  spontaneous abortions. In a study where embryoscopy, embryo biopsy, and karyotype were performed in more than 200 patients with missed abortion, 18 percent of embryos having a normal karyotype exhibited grossly abnormal developmental morphology [ 57]. CLINICAL PRESENTATION — Spontaneous abortion usually presents as vaginal bleeding or pelvic pain or is an incidental finding on a pelvic ultrasound performed in an asymptomatic patient [ 58].

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Some women who present with spontaneous abortion have a previously unrecognized pregnancy. This is particularly likely for women with irregular menses or those who had another recent episode of vaginal bleeding that was interpreted as menses. Symptoms — The typical symptoms of a spontaneous abortion are vaginal bleeding or pelvic pain. Any bleeding or pelvic pain in a pregnant woman warrants further evaluation. (See 'Differential diagnosis' below.) Decreased fetal movement is only rarely a presentation of spontaneous abortion, since most abortions occur  before fetal movements are perceptible to the patient. Vaginal bleeding — The bleeding associated with spontaneous abortion ranges from scant brown spotting to heavy vaginal bleeding. The volume or pattern of bleeding does not predict a spontaneous abortion. Vaginal bleeding is common in the first trimester, occurring in 20 to 40 percent of pregnant women [ 59]. Even heavy, prolonged bleeding can be associated with a normal outcome. As an example, in a prospective study of over  4000 pregnant women, 12 percent of women with first trimester vaginal bleeding had a miscarriage, but miscarriage also occurred in 13 percent of women without bleeding [ 60]. In 90 to 96 percent of pregnancies in which vaginal bleeding occurs between 7 to 11 weeks of gestation and fetal cardiac activity is observed, pregnancy continues; success rates increase with gestational age when bleeding occurs [ 61]. (See 'Differential diagnosis' below and 'Threatened abortion'  below.) Vaginal bleeding may be accompanied by passage of fetal tissue, which typically is solid and has the appearance of a white mass covered with blood. Patients may mistake a blood clot for fetal tissue. Passage of  fetal tissue is usually accompanied by severe cramping. Pelvic pain — The pain that accompanies a spontaneous abortion is typically crampy or dull in character  and may be constant or intermittent. Incidental finding on ultrasound — Spontaneous abortion may be detected due to the absence of fetal cardiac activity on a hand-held Doppler or pelvic ultrasound examination. DIAGNOSTIC EVALUATION History — The gestational age should be calculated based on menstrual history or ultrasound assessment. (See "Prenatal assessment of gestational age and estimated date of delivery" .) The history should focus on the presence and characteristics of any vaginal bleeding and pelvic pain, and on the passage of fetal tissue. (See 'Symptoms' above.) Physical examination Hand-held Doppler device  — A hand-held Doppler ultrasound device may be used to detect fetal cardiac motion in the late first trimester. Loss of a previously detected fetal cardiac activity on such a device should raise suspicion for a missed abortion. However, because the failure to detect fetal cardiac activity with a handheld device may result merely from incorrect placement of the device, further evaluation with ultrasonography is required. (See "Clinical manifestations and diagnosis of early pregnancy", section on 'Findings on physical examination' .) Pelvic examination — A complete pelvic examination should be performed. The speculum examination is used to confirm that the uterus is the source of bleeding (rather than a cervical or vaginal lesion) and to assess the volume of bleeding. The most important component of the examination is to determine whether the cervix is dilated and whether products of conception are visible at the cervix or in the vagina. These features are used to classify the status of the spontaneous abortion, which impacts management. (See 'Post-diagnostic classification' below.)  A bimanual pelvic examination is performed to determine uterine size; an abdominal examination may also be useful when gestational age is greater than 12 weeks. In normal pregnancy, the size of the uterus should be https://www.uptodate.com/contents/spontaneous-abortion-ris k-factors- etiology-cli nical-manifestations-and-diagnostic-evaluation/print?source=search_res…

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consistent with gestational age. The uterus may be enlarged due to multiple gestation or the presence of  uterine leiomyomas. A small for gestational age uterus raises suspicion of a spontaneous abortion. (See "Clinical manifestations and diagnosis of early pregnancy", section on 'Findings on physical examination' .)  A purulent cervical discharge or uterine tenderness suggests a possible septic abortion, which also should be suspected in women who appear ill or are febrile. (See 'Septic abortion' below.) Pelvic ultrasound — Pelvic ultrasonography is the most useful test in the diagnostic evaluation of women with suspected spontaneous abortion [ 62]. The most important finding is fetal cardiac activity, which is typically first detected at 5.5 to 6 weeks. Other important findings are the size and contour of the gestational sac, the presence of a yolk sac, and the fetal heart rate. In general, these early pregnancy sonograms are performed transvaginally, as the gestational sac and its contents are best evaluated in early gestation through a transvaginal approach. (See "Clinical manifestations and diagnosis of early pregnancy", section on 'Ultrasound examination' .) Normal versus failed pre gnancy — The normal sequence of fetal development during very early pregnancy is summarized below and discussed in detail separately. (See "Ultrasonography of pregnancy of  unknown location".) ● Gestational sac – During embryologic development, the gestational sac develops, followed by the yolk sac, and then the embryo. The diagnostic criteria for a failed pregnancy are based upon the development of a yolk sac or embryo once the gestational sac has reached a size threshold. This size threshold used must have a high specificity, since a false positive diagnosis of spontaneous abortion may result in an intervention that harms a normal pregnancy. Early studies found that the absence of a yolk sac in a gestational sac >8 mm mean sac diameter (MSD) or the absence of an embryo in a gestational sac >16 mm suggested an abnormal pregnancy [ 63]. However, based upon data from a systematic review of eight observational studies and a large prospective study, the minimum threshold (to achieve a specificity of 95 percent for the diagnosis of a failed pregnancy) is a gestational sac ≥25 mm MSD without a yolk sac or  embryo [64,65]. American College of Radiology (ACR) and United Kingdom Royal College of Obstetricians and Gynaecologists (RCOG) guidelines use ≥25 mm gestational sac MSD as a criterion for the diagnosis of a failed pregnancy in the absence of a yolk sac or embryo [ 66-68]. ● Fetal cardiac activity – Fetal cardiac activity confirms a live pregnancy. The absence of cardiac activity in an embryo of any crown rump length (CRL) raises suspicion of an abnormal pregnancy. In a systemic review of eight observational studies, the minimum threshold to achieve a specificity of up to 100 percent for the diagnosis of a failed pregnancy was an embryo with no cardiac activity and a CRL of >5 to 6 mm [67]. However, for >6 mm, the lower limit of the confidence interval was a specificity of 87 percent, which would result in a false positive rate that is clinically unacceptable. Based upon these data and the presence of inter-operator variability in measurement, the ACR and the RCOG use ≥7 mm CRL as a criterion for the diagnosis of a failed pregnancy [ 66-68]. The finding of fetal cardiac activity does not exclude the possibility of a subsequent miscarriage. When fetal cardiac activity was detected at 5 to 6 weeks of gestation in women less than 36 years of age, the risk of subsequent spontaneous abortion was 4.5 percent. However, the risk of miscarriage despite previous detection of heart activity increased to 10 percent in women aged 36 to 39 years and 29 percent in women age 40 years or older [ 61]. In women with recurrent pregnancy loss, the risk of spontaneous pregnancy loss after observation of embryonic heart activity remains high, about 22 percent [ 69]. ● Growth rate – Slow growth of an early pregnancy is concerning, but there are insufficient data to establish a growth rate that is diagnostic of a failed pregnancy. Growth rates between healthy and abnormal pregnancies overlap and inter-observer variability is also a factor [ 70]. Potential predictors of failed pregnancy — The following ultrasound findings are predictive of  impending pregnancy loss. If any of these ominous findings are noted, a repeated ultrasound examination in https://www.uptodate.com/contents/spontaneous-abortion-ris k-factors- etiology-cli nical-manifestations-and-diagnostic-evaluation/print?source=search_res…

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approximately one week is indicated. When more than one concerning finding is present, the risk of  subsequent abortion increases several-fold [ 71]: ● Abnormal gestational sac – A gestational sac that is abnormally small or large in relation to the embryo within is associated with an increased risk of spontaneous abortion [ 72,73]. Small MSD is diagnosed when the difference between the MSD and CRL is less than 5 mm (MSD - CRL 35 percent is strongly predictive of  miscarriage. Results from different laboratories may vary and should not be used to demonstrate a decrease. In addition, in some cases, the hCG concentration may plateau. Blood type and antibody scree n — A Rh(D) typing and antibody screen should be drawn if not previously performed during the current pregnancy. Women with bleeding in pregnancy who are Rh(D)negative should be given anti-D immune globulin. (See "Prevention of Rhesus (D) alloimmunization in pregnancy", section on 'Prophylaxis after antepartum events associated with placental trauma or disruption of  the fetomaternal interface' .) Other testing — A serum progesterone of