British Journal of Obstetrics and Gynaecology September 1992, Vol. 99, pp. 741-744

FETAL A N D NEONATAL M E D I C I N E

Fetal heart rate in early pregnancy and chromosomal disorders J . M. M. VAN L I T H G . H . A. VISSER A. M A N T I N G H J . R. B E E K H U I S Department of Obstetrics and Gynaecology Oostersingel 59,97 13 EZ University Hospital Groningen Groningen, The Netherlands

ABSTRACT Objective To investigate normal fetal heart rate in early pregnancy and assess the hypothesis that abnormal fetal heart rate is associated with fetal chromosomal abnormalities. Design Prospective descriptive cross-sectional study. Setting Antenatal clinic associated to the University Clinic of Obstetrics, University Hospital Groningen, The Netherlands. Subjects 424 pregnant women who attended for prenatal counselling. Interventions Measurements of fetal heart rate from 6-16 weeks gestation, crosssectional study. Main outcome measures Fetal heart rate expressed as beats/min. Results Karyotyping showed a normal chromosomal pattern in 414 fetuses. The median fetal heart rate increased from 138 beats/min at 6 weeks to 177 beats/min at 9 weeks, thereafter, fetal heart rate gradually decreased to 150 beats/min at 16 weeks. Karyotyping showed 10 abnormalities: five trisomies 21, three trisomies 18, and two mosaic patterns in chorionic villi. Fetal heart rate of the trisomic fetuses was distributed around the median with that of all Down’s syndrome fetuses within the normal range. In one fetus with trisomy 18, the heart rate exceeded the 90th centile, in another it fell under the 10th centile. The two fetuses with a mosaic pattern in chorionic villi had heart rates outside the normal range. Conclusion Fetal heart rate in chromosomally abnormal fetuses in early pregnancy do not appear to be consistently different from that in normal fetuses. The use of a single measurement of fetal heart rate is not valuable for screening purposes. Chromosomal mosaicism in chorionic villi may be associated with abnormal fetal heart rate.

Fetal cardiac activity can be detected from approximately 40 days postmenstrual age onwards (Cadkin & McAlpin 1984; Schats et al. 1990a; Cacciatore et al. 1990). Heart rate is initially low, increases to a peak value of about 170 beats/min at 9 weeks and gradually decreases thereafter (Robinson & Shaw-Dunn 1973). In the pregnancies followed longitudinally that ended in an early miscarriage low fetal heart rates have been found and some of the fetuses have been chromosomally abnormal (Laboda et al. 1989; Schats et al. 1990a). In a fetus with Down’s syndrome the heart rate was consistently low and it has been suggested that an early abnormal heart rate might be an indication for chorionic villus sampling or amniocentesis (Schats et al. 1990b). To test the hypothesis that abnormal heart rate is associated with chromosomal abnormalities, we measured embryonic or fetal heart rate in pregnant women who were referred for prenatal counselling. Correspondence: A. Mantingh.

Subjects and methods We measured fetal heart rate in 424 women, who we saw for prenatal counselling, using an abdominal ultrasound scan (AcusonTMsectorscanner) and pulsed Doppler. In our centre, prenatal counselling precedes prenatal diagnosis by 1-5 weeks. Most of the women (95%) were 36 years or older. In each, blood flow velocity waveforms were obtained from the fetal heart and printed on-line using a strip chart recorder. Ten consecutive signals of good quality were selected and the time between the first and the 10th peak was measured. We expressed fetal heart rate as beats/min. Data were restricted to ten cycles since longer recordings are technically difficult at very early gestation. Moreover, before 16 weeks fetal heart rate accelerations or decelerations are not likely to occur (Wladimiroff 1972). The crown-rump length (CRL) or the biparietal diameter (BPD) was measured during the same session. Ultrasound age was calculated from the reference curves of Robinson (CRL) and of Campbell (BPD). The women selected for this study all had a reliable menstrual history, with a menstrual cycle length between 25 and 35 days. Gestational age was cal-

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J. M . M . V A N L I T H E T A L .

culated in days from the time since the first day of the last menstrual period (LMP). We performed chorionic villus sampling at 9-10 weeks or amniocentesis at 15-16 weeks gestation. We compared the heart rates of chromosomally abnormal fetuses with those with normal karyotypes. We made reference ranges for fetal heart rate according to gestational age by the LMP and by ultrasound measurements. This was done as fetuses with chromosomal abnormalities might be small because of slow growth (Fitzsimmons et al. 1990).

Results Prenatal diagnosis showed a normal karyotype in 414 fetuses. Figures 1 and 2 show heart rate of these fetuses, according to LMP and ultrasound. From these data medians and loth, 25th, 75th and 90th centiles were calculated (Table 1 and Figs 3 and 4). Median fetal heart rate increased from 138 beats/rnin at 6 weeks to a peak value of 177 beats/min at 9 weeks. At 16 weeks fetal heart rate had fallen to approximately 150 beats/min. Fetal karyotyping detected eight autosomal trisomies: five with trisorny 2 I and three with trisomy 18 (Table 2). The heart rate of these 8 fetuses was distributed around the median, with no difference between data analysed according to LMP or ultrasound. The fetal heart rate of all Down's syndrome fetuses fell within the normal range (Figs 3 and 4). Two of the three fetuses with trisomy 18 had a fetal heart rate outside the normal range, in one this exceeded the 90th centile ( I 77 beats/min at week 12) and the other was below the 10th centile (142 beats/ min at week 7) (Figs 3 and 4). In two pregnancies mosaic patterns in the chorionic villi were found. In both, a subsequent amniocentesis revealed a normal fetal karyotype (Table 2). The heart rate of both fetuses was, surprisingly, outside the normal range (158 beats/min at week 9 and 185 beats/min at week 10. (Figs. 3 and 4)).

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With vaginal ultrasound, fetal activity can be detected at about 40 days after the LMP (Timor-Tritsch eta/. 1988). The time of the first appearance of cardiac activity varies considerably (4 to 5 days) in pregnancies in which the ovulation is exactly known (Cadkin & McAlpin 1984; Schats et al. 1990a; Cacciatore et a/. 1990). A delayed appearance of cardiac activity and an early fetal bradycardia are related to early miscarriage (Laboda et a/. 1989; Schats et al. 1990a). This suggests that an abnormality might result in a delay in early functional development as well as in morphological development. In fetuses with chromosomal abnormalities there are often signs of early developmental disorders. This is reflected by the high rate of miscarriage, by the delay in morphological growth (weight, femur length) and also by fetal and placental biochemical factors in maternal serum (e.g., alpha-fetoprotein, human chorionic gonadotropin, unconjugated oestriol) (Fitzsimmons et al. 1990; Benacerraf et al. 1987; Merkatz et al. 1984; Bogart et a / . 1987; Canick et al. 1988). These findings have led to the hypothesis of a delayed developmental pattern, either morphological, functional or both in chromosomally abnormal fetuses (Cuckle et al. 1986; Seller 1990; Kronquist et al. 1990). However, abnormal biochemical factors may also be an expression of abnormal placental rather than abnormal fetal development (Van Lith et al. 1991). Disturbed development of the conceptus may be expressed by a delayed onset of fetal cardiac activity. Data on the emergence of cardiac activity in chromosomally abnormal fetuses are restricted to one case report (Schats et al. 1990b). In this case heart activity could first be detected at 28 days after follicle aspiration. This is slightly later than observed in normal pregnancy after follicle aspiration (26 to 27 days), but still within the normal range. 200

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Fig. 2. Heart rate of 414 fetuses with a normal karyotype according to gestational age based on ultrasound measurement (US).

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FETAL HEART RATE I N EARLY P R E G N A N C Y

Table 1. Heart rate in 414 chromosomally normal fetuses expressed as 25th median and 75th centile according to gestational age in completed weeks based on both last menstrual period (LMP) and ultrasound age. Fetal heart rate (beatdmin) According to LMP Gestational age (weeks) 6 7 8 9 10

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129.5 148.2 167.2 170.5 166.7 163.9 157.9 152.3 148.5 149.3 149.3

139.5 158.7 173.1 177.9 172.4 166.7 163.9 158.7 152.9 154.6 150.2

145.6 167.0 177.0 179.6 176.5 172.4 167.6 163.6 157.9 158.7 158.2

6 33 94 61 39 18 23 31 52 38 19

127.7 152.3 167.7 170.5 166.7 164.8 155.6 152.7 150.8 147.8 148.9

138.9 163.0 173.4 175.4 172.2 167.6 162.9 157.9 1546 152.2 150.0

143.5 172.4 1773 180.5 175.4 174.4 166.7 161.5 158.7 157.1 160.4

Another reflection of abnormal development might be an unusual heart rate in early pregnancy. This hypothesis was tested in this study. The reference ranges for fetal heart rate in early pregnancy that we obtained were similar to those that have been described (Robinson & Shaw-Dunn 1973; Hertzberg et al. 1988; Schats et al. 1990a). In our study the heart rate in the eight fetuses with chromosomal disorders did not differ from that in normal fetuses. The use of fetal heart rate for screening is, therefore, not valuable and our findings do not support the suggestion that prenatal diagnosis should be offered whenever an abnormal fetal

heart rate is detected early in pregnancy. An abnormal fetal heart rate might be more a marker for a forthcoming miscarriage rather than an indicator for a chromosomal abnormality. Invasive diagnostic procedures should be withheld. The finding of abnormal heart rates in the two fetuses with a mosaic pattern in chorionic villi is remarkable. Chromosomal mosaicism found in chorionic villi is almost always restricted to the extra-embryonic tissues and the fetus usually has a normal karyotype (Breed et al. 1990). However, with a mosaic pattern in the chorionic villi miscarriage and intrauterine growth retardation are more frequent (Johnson et al. 1990).

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Fig. 3. Heart rate of 10 fetuses with abnormal findings after prenatal diagnosis according to gestational age based on last menstrual period (LMP) (trisomy 21 = 0,trisomy 18 = 0, mosaicism in CVS = +). Normal fetal heart rate values are expressed as median and 10th and 90th centile.

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Fig. 4. Heart rate of 10 fetuses with abnormal findings after prenatal diagnosis according to gestational age based on ultrasound measurement (US) (trisomy 21 = 0,trisomy 18 = 0,mosaicism in CVS = +). Normal fetal heart rate values are expressed as median and 10th and 90th centile.

744

J . M . M . V A N L I T H ET A L .

Table 2. Heart rate of 10 fetuses with abnormal findings after prenatal diagnosis. Gestational age Chromosomal disorder

us LMP (daystweek) (daystweek)

47,XY,+21 47,XX,+21 47,XY,+21 47,XY,+2 1 47,XX,+21 47,XY,+18 47,XX,+18 47,XX,+18 46,XX/47,XX,+11 46,XY/47,XY,+I 8

521 7 531 7 7911 1 86112 94/13 551 7 88/12 108/15 651 9 70110

511 7 541 7 75/10 87/12 89/12 521 7 83111 107115 641 9 75/10

Fetal heart rate (beatslmin) 156.3 153.8 176.3 153.9 163.6 142.1 176.5 159.6 157.9 185.2

LMP = last menstrual period US = ultrasound measurement.

The abnormal fetal heart rate observed in the two pregnancies with chromosomal mosaicism in chorionic villi supports the concept of disturbed development, though the aetiology of the abnormal heart rate is obscure. In conclusion, although the number of abnormal chromosomes is small, the heart rates of chromosomally abnormal fetuses in early pregnancy do not appear to be consistently different from those of normal fetuses. A single measurement of fetal heart rate cannot be used as a screening method for identifying fetuses at risk for chromosomal abnormalities. Chromosomal mosaicism in chorionic villi may be associated with abnormal fetal heart rate.

Acknowledgment The authors wish to thank M. Kreytz and Mrs A. Woltjer for their excellent technical assistance. This study was financially supported by the Stichting voor Erfelijkheidsvoorlichting Groningen.

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