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Long-Term Prognosis of Pregnancies Complicated by Slow Embryonic Heart Rates in the Early First Trimester Peter M. Doubilet, MD, PhD, Carol B. Benson, MD, Jeanne S. Chow, MD Slow embryonic heart rates at gestational age 7 weeks or less are associated with high risk of first trimester death. Our goal was to determine the prognosis for those embryos with slow early heart rates who survive the first trimester. We prospectively recorded embryonic heart rates for all obstetrical sonograms obtained on singleton pregnancies at or before 7.0 weeks’ gestation since 1993. We collected information about pregnancy outcome, including date of live birth or in utero death and presence and nature of congenital anomalies. First trimester survival rate was 61.6% among 531 embryos with slow early heart rates (<100 bpm at ≤6.2 weeks, <120 bpm at 6.3 to 7.0 weeks), lower than the survival rate of 91.5% among 1501 embryos with normal heart rates (p < 10–8, Fisher’s exact test). Among 299 pregnancies in which the early heart rate was slow and the fetus was still alive at the end of the first trimester, 277 (92.6%) resulted in liveborn ABBREVIATIONS bpm, Beats per minute; SD, Standard deviation Received February 9, 1999, from the Department of Radiology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts. Revised manuscript accepted for publication May 11, 1999. Address correspondence and reprint requests to Peter M. Doubilet, MD, PhD, Department of Radiology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. infants without congenital anomalies, similar to the frequency of 95.1% in cases with normal early heart rates (p > 0.10, Fisher’s exact test). Structural and chromosomal anomalies, however, occurred more than twice as frequently in cases with slow early heart rates: 5.4% (16 of 299) of the first trimester survivors with slow early heart rates proved to have anomalies, as compared to 2.4% (31 of 1281) of cases with normal early heart rates (p < 0.05, Fisher’s exact test). In conclusion, a pregnancy in which the embryo has a slow heart rate at or before 7.0 weeks’ gestation and which continues beyond the first trimester has a high likelihood (>90%) of resulting in a liveborn neonate without congenital anomalies. Embryos with slow early heart rates do, however, have a greater risk of having anomalies than embryos with normal early heart rates. KEY WORDS: Embryo, heart rate; Pregnancy, outcome; Heart rate, embryonic. A slow embryonic heart rate in the early first trimester is associated with a poor short-term prognosis.1–7 In particular, rates below 100 bpm prior to 6.3 weeks’ gestation and below 120 bpm between 6.3 weeks and 7.0 weeks carry an elevated risk of death by the end of the first trimester. The risk of embryonic death is close to 100% when the rate is less than 80 bpm below 6.3 weeks or less than 100 bpm between 6.3 weeks and 7.0 weeks. The risk declines progressively with increasing heart rates until it plateaus for heart rates over 100 bpm at less than 6.3 weeks or 120 bpm between 6.3 weeks and 7.0 weeks.5 1999 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 18:537–541, 1999 • 0278-4297/99/$3.50 538 PROGNOSIS WITH SLOW EMBRYONIC HEART RATE Although the short-term prognosis for embryos with slow heartbeats in the early first trimester has been well documented, little is known about the long-term prognosis for those embryos who survive the first trimester. Most studies assessing the relationship between early embryonic heart rates and outcome have followed pregnancies only until the end of the first trimester. As a result, little or no data exist on the liveborn rate and frequency of congenital anomalies in first trimester survivors who had had slow early embryonic heart rates. We undertook a study to assess pregnancy outcome in such embryos. MATERIALS AND METHODS We prospectively recorded the results of all sonograms obtained at our institution between January 1993 and June 1998 demonstrating singleton pregnancies up to 7.0 weeks’ gestation with embryonic cardiac activity. When a woman underwent sonography more than once at or prior to 7.0 weeks, the earliest sonogram demonstrating cardiac activity was used in the study. Data recorded for each case included gestational age and heart rate (measured via M-mode) at the time of the study sonogram, and the results of any subsequent sonogram obtained during the pregnancy. Birth information was recorded, when available, including date of birth and neonatal discharge diagnoses. Embryonic heart rate was classified as “slow” if it was less than 100 bpm at 6.2 weeks or earlier or less than 120 bpm between 6.3 weeks and 7.0 weeks of gestation.5 A heart rate above these cutoff points was classified as normal. First trimester outcome was classified as “live” if a sonogram at or beyond 13 weeks’ gestation showed a live fetus or if the pregnancy resulted in a liveborn infant. It was classified as “dead” if, prior to 13 weeks, a sonogram showed no heartbeat or the patient miscarried. Final pregnancy outcome was classified as “liveborn with no anomaly” if a liveborn infant was delivered at or beyond 24 weeks’ gestation and no anomaly was diagnosed either prenatally or during the neonatal hospital stay. It was classified as “pregnancy loss with no anomaly” if delivery occurred prior to 24 weeks or in utero death occurred at any gestational age and no anomaly was diagnosed on prenatal ultrasonogram, at delivery, or via fetopsy. Pregnancy outcome was classified as “anomaly” if an anomaly was present at birth or fetopsy. Minor J Ultrasound Med 18:537–541, 1999 anomalies, such as hydrocele or pigmented skin lesions, were ignored (i.e., neonates with such findings were classified as having no anomaly). Cases lost to follow-up and those terminated electively (other than terminations performed because of fetal anomaly) were not assigned to any of these outcome classifications. RESULTS The study population included 1392 singleton pregnancies scanned prior to 6.3 weeks’ gestation and 1425 scanned between 6.3 weeks and 7.0 weeks. Mean heart rate (± SD) prior to 6.3 weeks was 109.2 ± 14.0 bpm and between 6.3 weeks and 7.0 weeks was 125.3 ± 15.9 bpm. First trimester survival rate was lower in pregnancies with slow early embryonic heart rates than in those with normal embryonic heart rates (Table 1). In pregnancies in which the patients were scanned prior to 6.3 weeks, the first trimester survival rate was 53.8% among cases with slow embryonic heart rates, significantly lower than the survival rate of 89.3% when the embryonic heart rate was normal (p < 10–8, Fisher’s exact test). The lower the heart rate, the lower the survival rate: 69.5% for heart rates of 90 to 99 bpm, 43.5% for rates of 80 to 89 bpm, and 8.8% for rates less than 80 bpm. A similar relationship between heart rate and survival was found in cases scanned between 6.3 weeks and 7.0 weeks: embryos with slow heart rates (less than 120 bpm) were less likely than those with normal heart rates to survive the first trimester (66.6% versus 93.8%; p < 10–8, Fisher’s exact test), and the survival rate was poorer with lower heart rates. Overall, cases with slow embryonic heart rates at 7.0 weeks’ gestation or less had a first trimester survival rate of 61.6%, lower than the survival rate of 91.5% in cases with normal embryonic heart rates (p < 10–8, Fisher’s exact test). In those pregnancies in which the fetus survived the first trimester, over 90% resulted in liveborn neonates without congenital anomalies, regardless of the early heart rate (Table 2). Among 299 pregnancies in which the early heart rate was slow and the fetus was still alive at the end of the first trimester, 277 (92.6%) resulted in normal liveborn infants (omitting cases with unknown outcome). This was similar to the frequency of 95.1% in cases with normal early heart rates (p > 0.10, Fisher’s exact test). Congenital anomalies, however, were more common in first trimester survivors with slow early heart rates than in those with normal heart rates (Table 2). Sixteen (5.4%) of the 299 first trimester survivors J Ultrasound Med 18:537–541, 1999 DOUBILET ET AL 539 Table 1: Relationship Between Embryonic Heart Rate and First Trimester Outcome First Trimester Outcome Embryonic Heart Rate Gestational age ≤6.2 weeks Slow <100 bpm <80 bpm 80–89 bpm 90–99 bpm Normal ≥100 bpm Gestational age 6.3 weeks to 7.0 weeks Slow <120 bpm <100 bpm 100–109 bpm 110–119 bpm Normal ≥120 bpm Total (gestational age ≤7.0 weeks) Slow Normal N Live Dead Survival Rate 208 34 46 128 774 112 3 20 89 691 96 31 26 39 83 53.8%* 8.8% 43.5% 69.5% 89.3%* 323 61 52 210 727 215 4 30 181 682 108 57 22 29 45 66.6%† 6.6% 57.7% 86.2% 93.8%† 531 1501 327 1373 204 128 61.6%‡ 91.5%‡ N, Number of cases with known first trimester outcome. *p < 10–8, Fisher’s exact test. †p < 10–8, Fisher’s exact test. ‡p < 10–8, Fisher’s exact test. with slow early heart rates proved to have anomalies, more than double the frequency of 2.4% (31 of 1281) in cases with normal early heart rates (p < 0.05, Fisher’s exact test). Cardiac, chromosomal, and other anomalies all occurred more frequently in fetuses whose early heart rates had been slow than in those with normal early heart rates (Table 3). In particular, the frequency of aneuploidy in fetuses who survived the first trimester was 1.3% among those whose early embryonic heart rates had been slow, significantly Table 2: Final Pregnancy Outcome Among First Trimester Survivors: Relationship to Embryonic Heart Rate Final Pregnancy Outcome Embryonic Heart Rate N Liveborn with No Anomaly Pregnancy Loss* with No Anomaly Anomaly Gestational age ≤6.2 weeks Slow <100 bpm <80 bpm 80–89 bpm 90–99 bpm Normal ≥100 bpm Gestational age 6.3 weeks to 7.0 weeks Slow <120 bpm <100 bpm 100–109 bpm 110–119 bpm Normal ≥120 bpm 98 3 18 77 639 91 (92.9%) 2 16 73 601 (94.1%) 2 (2.0%) 1 0 1 16 (2.5%) 5 (5.1%) 0 2 3 22 (3.4%) 201 4 29 168 642 186 (92.5%) 4 27 155 617 (96.1%) 4 (2.0%) 0 1 3 16 (2.5%) 11 (5.5%) 0 1 10 9 (1.4%) Total (gestational age ≤7.0 weeks) Slow Normal 299 1281 277 (92.6%)† 1218(95.1%)† 6 (2.0%) 32 (2.5%) 16 (5.4%)‡ 31 (2.4%)‡ N, Number of first trimester survivors with known final pregnancy outcome. *Includes in utero deaths and fetuses delivered prior to 24 weeks. †p > 0.10, Fisher’s exact test. ‡p < 0.05, Fisher’s exact test. 540 PROGNOSIS WITH SLOW EMBRYONIC HEART RATE J Ultrasound Med 18:537–541, 1999 Table 3: Anomalies Occurring in First Trimester Survivors: Relationship to Embryonic Heart Rate Early Heart Rate Type of Anomaly* Slow Normal Cardiac 3 cases (incidence† = 1.0%; 3/299): VSD and right aortic arch; transposition of great vessels; coarctation 9 cases (incidence = 0.7%; 9/1281): ventricular septal defect (3); transposition of great vessels; coarctation; DORV, TGV, HLV; hypoplastic left ventricle; atrial septal defect (2) Chromosomal 4 cases (incidence = 1.3%; 4/299): trisomy 21 (3); 47,XYY 4 cases (incidence = 0.3%; 4/1281): trisomy 21 (3); 48,XXYY Other 9 cases (incidence = 3.0%; 9/299): hydrocephalus; omphalocele; amniotic band syndrome; unilateral renal agenesis; VATER syndrome; GI malrotation and SBO; hemivertebrae; harlequin syndrome; hydrops 18 cases (incidence = 1.4%; 18/1281): hydrocephalus; anencephaly (3); DandyWalker malformation; omphalocele; unilateral renal agenesis (3); dysplastic left kidney; pulmonary sequestration; facial anomalies (2); polydactyly; Fanconi anemia; clubfoot; hydrops (2) Total (all anomalies) 16 cases (incidence = 5.4%; 16/299) 31 cases (incidence = 2.4%; 31/1281) *Each pregnancy with an anomalous fetus is listed only once in the table. In the case of fetuses with multiple anomalies, the most serious anomaly is listed. †Incidence among first trimester survivors with known final pregnancy outcome. VSD, Ventricular septal defect; DORV, double outlet right ventricle; TGV, transposition of the great vessels; HLV, hypoplastic left ventricle; GI, gastrointestinal; SBO, small bowel obstruction; VATER, vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia. greater than the 0.3% in those whose early heart rates had been normal (p < 0.05, Fisher’s exact test). Half of all aneuploid fetuses (three of six with trisomy 21, one of two with other chromosomal abnormalities) had slow early heart rates. Maternal age was 35 years or older in seven of the eight aneuploid fetuses, including all four whose early heart rates had been slow. DISCUSSION With transvaginal ultrasonography, the embryonic heartbeat can be visualized beginning at approximately 6.0 weeks’ gestation, and its rate can be measured via Mmode sonography. The mean heart rate in early pregnancy increases progressively from approximately 100–120 bpm at 6.0 weeks to between 145–170 bpm at 9.0 weeks, after which it declines slowly for the rest of the first trimester.7,12–15 The heart rate in an individual embryo or fetus of less than 10 weeks’ gestational age varies little from measurement to measurement, so that reliable information about heart rate can be obtained from a single measurement.16 Embryos with slow heart rates prior to 7.0 weeks have a poor short-term prognosis, with a high chance of death before the end of the first trimester.1–7 In particular, in comparison to embryos with normal heart rates, the likelihood that an embryo will survive the first trimester is lower when the heart rate is less than 100 bpm prior to 6.3 weeks or less than 120 bpm between 6.3 weeks and 7.0 weeks of gestation. Below these cutoffs points, the slower the heart rate the poorer the prognosis for first trimester survival.5 Our study confirms this relationship between a slow embryonic heart rate and poor first trimester outcome. When a slow early embryonic heart rate is found at sonography, the parents should be advised that the risk of miscarriage in the first trimester is high. If the fetus survives the first trimester, however, counseling the parents is difficult, because the existing literature provides little information about the long-term prognosis for these pregnancies. Our study addresses this issue. We assessed the final outcome in pregnancies that continue beyond the first trimester, comparing those with slow early embryonic heart rates to those with normal early embryonic heart rates. That is, we addressed the J Ultrasound Med 18:537–541, 1999 question, ”If an embryo with a slow early heart rate survives the first trimester, what is the likelihood that the pregnancy will result in a normal neonate?” Our study demonstrates that the prognosis for an embryo with a slow early heart rate who survives the first trimester is good, with a 92.6% likelihood that the pregnancy will result in birth of a normal neonate. This prognosis is similar to the 95.1% likelihood of a good outcome for an embryo whose early embryonic heart rate had been normal and who survives the first trimester. That is, death occurring after a slow embryonic heart rate at 7.0 weeks of gestation or less is likely to occur quickly—within the first trimester—or not at all. Our findings also indicate that a slow early embryonic heart rate is associated with an elevated risk of congenital anomalies. The frequencies of cardiac, chromosomal, and other anomalies are all increased when an embryo has a slow early heart rate. Overall, a pregnancy complicated by a slow heart rate at 7.0 weeks of gestation or less has at least twice the risk of anomalies than one with a normal early heart rate. Although the risk of aneuploidy is increased in fetuses with slow early heart rates, all aneuploid fetuses with slow early heart rates in our series were born of women over the age of 35 years. These women would have been offered amniocentesis based on maternal age, independent of the heart rate findings. On the basis of our results, we suggest the following approach when a slow embryonic heart rate is seen in the early first trimester. A 1–2 week follow-up sonogram should be obtained and, unless embryonic death is diagnosed, another scan should be performed in the late first trimester. If the fetus is still alive at this time, the parents should be told that the likelihood of subsequent death is now low, but that the risk of anomalies is elevated. In view of this risk, sonography should be performed at approximately 18 weeks to evaluate for fetal structural anomalies. Karyotype testing is probably not indicated in the absence of another risk factor for aneuploidy (e.g., maternal age of 35 years or greater, thickened nuchal lucency on the late first trimester sonogram). In summary, an embryo with a slow early heart rate has a markedly increased chance of dying within the first trimester. If it survives the first trimester, the likelihood of subsequent death is low, but the risk of anomalies is elevated. DOUBILET ET AL 541 REFERENCES 1. Laboda LA, Estroff JA, Benacerraf BR: First trimester bradycardia: A sign of impending fetal loss. J Ultrasound Med 8:561, 1989 2. May DA, Sturdevant NV: Embryonal heart rate as a predictor of pregnancy outcome: A prospective analysis. 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J Diagn Med Sonog 2:49, 1989 16. Montenegro N, Ramos C, Matias A, et al: Variation of embryonic/fetal heart rate at 6–13 weeks' gestation. Ultrasound Obstet Gynecol 11:274, 1998