Abstract  

Maternal age related and procedure-related fetal abortion rates were studied in 384 women aged 36 and over scheduled for transabdominal chorionic villus sampling (TA-CVS) at 12-14 weeks of gestation. The pre-TA-CVS abortion rate within 30 days of intake (at 6-10 weeks of gestation) rose from 1·9% at age 35-36 years to 10·9% at 40 years and older. Women entering in the 6th week of gestation had a greater probability of aborting before TA-CVS than women entering after day 48. 26 women aborted spontaneously before TA-CVS, the majority of abortions occuring at 10-12 weeks. TA-CVS was done in 346 women. 11 pregnancies were terminated because of genetic anomalies, and 8 women had spontaneous fetal loss. These findings justify delaying prenatal diagnosis in older pregnant women until 12 weeks of gestation

Cohen-Overbeek, T.E. (Titia)

Den Ouden, M.E.M.

Hop, W.C.J. (Wim)

Jahoda, M.G. (M.)

Pijpers, L. (Leendert)

Wladimiroff, J.W. (Juriy)

Erasmus University Digital Repository

27CLINICAL PRACTICESpontaneous abortion rate and advanced maternalage: consequences for prenatal diagnosisMaternal age related and procedure-related fetalabortion rates were studied in 384 women aged 36and over scheduled for transabdominal chorionicvillus sampling (TA-CVS) at 12-14 weeks ofgestation. The pre-TA-CVS abortion rate within 30days of intake (at 6-10 weeks of gestation) rosefrom 1&middot;9% at age 35-36 years to 10&middot;9% at 40 yearsand older. Women entering in the 6th week ofgestation had a greater probability of abortingbefore TA-CVS than women entering after day 48.26 women aborted spontaneously before TA-CVS,the majority of abortions occuring at 10-12 weeks.TA-CVS was done in 346 women. 11 pregnancieswere terminated because of genetic anomalies,and 8 women had spontaneous fetal loss. Thesefindings justify delaying prenatal diagnosis in olderpregnant women until 12 weeks of gestation.IntroductionThe primary indication for first-trimester prenatalchromosome analysis is advanced maternal age.12 Jahoda etaP found that transcervical chorionic villus sampling(TC-CVS) at 9-11 weeks of gestation was associated with asignificantly higher spontaneous abortion rate in womenaged 36 and older (7-2%) than in women aged under 36(2-6%). Whether this higher abortion rate is procedurerelated or due primarily to a higher baseline rate of fetal lossat advanced maternal age is uncertain. The objective of thepresent study was to determine maternal age related andprocedure related fetal abortion rates in older womenscheduled for transabdominal chorionic villus sampling(TA-CVS) at 12-14 weeks of gestation.Patients and methods384 pregnant women requesting first-trimester prenatal diagnosisbetween January and October, 1988, were included in the study.Admission critera were: (i) maternal age 36 years or older at 20weeks of gestation, (ii) a viable singleton pregnancy; (iii) gestationalage not beyond 76 days; (iv) no indication for prenatal diagnosisapart from advanced maternal age. TA-CVS was scheduled as anoutpatient procedure between 12 and 14 weeks of gestation.’ Afterreconfirmation of fetal viability by ultrasound, the skin wasdisinfected and a 20-gauge needle without stylet was introducedinto the chorion frondosum under continuous ultrasound guidance.No local anaesthetic was used. The needle was attached to a 20 mlsyringe filled with 5 ml saline. Chorionic tissue was obtained bymoving the needle under continuous suction in a vertical andoblique direction. During each procedure the number of attemptsand the amount of tissue collected were recorded. Non-attenderswere contacted personally in order to establish the reason for failingtheir appointment.In the event of a spontaneous abortion the gestational age atwhich this had occurred was documented. Continuing pregnancieswere followed up by means of a questionnaire about short-term andlong-term complications.StatisticsCumulative percentages of women having a spontaneousabortion while being scheduled for TA-CVS were calculated withlife-table methods.5 The log-rank test was used to comparepercentages between the different classes of gestational age andmaternal age. In this analysis, women were considered removedfrom the study as soon as TA-CVS had been completed.To assess the effect of the TA-CVS procedure on thespontaneous abortion rate, patients themselves partially served ascontrols. The composition of the control group depended on thevariable interval between intake and the TA-CVS procedure. Forexample, if 2 patients, matched for maternal and gestational age atintake, waited 15 and 20 days, respectively, then the intervalbetween day 16 and day 20 for patient 2 would serve as the controlperiod for patient 1, who by then had already undergone TA-CVS.Cox regressionb was used to compare abortion rates between thosestill waiting and those who had already undergone TA-CVS atvarious points of time. In this analysis the day of gestation at intakewas considered the day of entrance into the study. Relative (postversus pre TA-CVS) abortion rates, adjusted for maternal age, werecalculated? p values given are two-sided. The limit of statisticalsignificance was set at p < 0-05.ResultsMaternal age of the 384 women ranged from 35 to 49 years(median 37 years) and maternal parity from 0 to 6 (median1). Women were subdivided into five gestationalADDRESSES: Department of Obstetrics and Gynecology(T. E. Cohen-Overbeek, MD, M. den Ouden, MD, L. Pijpers, MD, M. G. J.Jahoda, MD, J. W. Wladimiroff, MD) and Department ofEpidemiology and Biostatistics (W C. J. Hop, MSC), ErasmusUniversity Medical School, Rotterdam, The Netherlands.Correspondence to Prof J W. Wladimiroff, Academic Hospital Dijkzigt,Erasmus University Medical School, Dr Molewaterplein 40, 3015 GDRotterdam, The Netherlands.28Cumulative percentages of women aborting spontaneouslywhile awaiting TA-CVS according to (A) maternal age and (B) )gestational age at intake.Numbers in parentheses denote number of women still being scheduledfor TA-CVS on days 0, 10, 20, and 30 after intake.age classes, 42-48 days (n = 10), 49-55 days (n = 68), 56-62days (n = 172), 63-70 days (n = 98), and 71-76 days (n = 36),and three maternal age classes, 35-36 years (n = 106), 37-39years (n = 213), and 40 years or older (n = 65). 5 womendecided against prenatal diagnosis and 7 women did notundergo TA-CVS for technical reasons (retrochorionichaematoma, posterior placenta in a retroverted uterus,vaginal blood loss, HB Ag positive). These womenremained in the study up to the moment of withdrawal orcancellation.There were 26 spontaneous abortions before TA-CVS.The percentage of women aborting while waiting forTA-CVS increased with advancing maternal age (figure, A).The percentage of women who aborted within 30 days afterintake rose from 1 -9% in the 35-36 years group to 10-9% inthe group aged 40 and older (trend test: p < 0-05). Womenentering the study between day 42 and 48 of gestation had agreater probability of aborting before TA-CVS than thoseentering beyond day 48 (p < 005; figure, B). The sameobservation was made when the comparison was adjustedfor maternal age (p<0-01). No correlation could beestablished between the incidence of spontaneous abortionand past reproductive performance.TA-CVS was carried out in 346 women, 6-54 days(median 26 days) after intake. Spontaneous abortionoccurred in 6 women between 15 and 29 days after TA-CVSand in 2 women at 66 and 81 days. 11 pregnancies wereterminated because of trisomy 21 (n = 6), trisomy 18 (n = 2),47, XXY (n = 2), or 47, XXX (n = 1). The remaining 327pregnancies progressed uneventfully up to 28 weeks.CUMULATED NO OF DAYS PATIENTS WERE FOLLOWED AND NOOF ABORTIONS BEFOREAND AFTER TA-CVS FOR EACH WEEK OFGESTATIONR = Total no of days patients were monitored dunng a particular week of gestation.A=no of abortions*Induced abortions after TA-CVSSubsequently, 1 woman suffered unexplained intrauterinedeath near term and 2 women were lost to follow-up.The table shows the numbers of spontaneous and inducedabortions before and after TA-CVS for each week ofgestation in relation to maternal age. The women appearedto have a smaller risk of spontaneous abortion after thanbefore TA-CVS, resulting in a maternal-age-adjustedrelative abortion rate (post versus pre TA-CVS) of 0-10.This result, however, is severely biased because of theremoval from the study of all chromosomally abnormalfetuses after TA-CVS. If all 19 abortions after TA-CVS areconsidered to have occurred spontaneously, the procedureled to a maternal-age-adjusted relative abortion rate of 1-66(not statistically significant). Additional adjustment forgestational age at intake resulted in a relative abortion rate of156.Chorionic villus tissue was obtained after one samplingattempt in 307 women, including the 8 with spontaneousabortion after TA-CVS. In 1 woman the procedure wasabandoned after one attempt, and a successful amniocentesiswas carried out at 16 weeks. Two samplings were carried outin the remaining 38 women.DiscussionThe safety of first-trimester invasive procedures has beenasssessed against the background risk of spontaneousabortion. Incidences of 2.1% and 3-3% have beenreported. S,9 However, the percentage of women of advancedmaternal age in these studies was always less than 9%.Maternal age groups were differentiated in one study,9 butthe number of older women (over 40 years) was too small toallow any definite conclusions. The increase inchromosomal anomalies with advancing maternal age ismore pronounced in populations undergoing CVS than in29populations referred for atimiocentesis.10 This stronglysuggests a maternal age dependent rise in fetal loss ratebetween 9 and 16 weeks of gestation. Moreover, theincidence of chromosomally normal abortions also rises withadvancing maternal age, with a steep increase after 36years."The present study confirms that there is a steady increasein early loss of a previously viable pregnancy with advancingmaternal age. This must be taken into consideration whenplanning first-trimester chorionic villus sampling in olderwomen. Our study suggests that at advanced maternal agethe risk of spontaneous abortion of a previously viable fetusin the first 12 weeks of gestation is greater than the chance oflive birth of an infant with a chromosomal anomaly.The decline in abortion rate is more pronounced between6 and 7 weeks of gestation than later. The increased abortionrisk for women entering the study in week 6 could beexplained by the apparently high initial abortion risk forthese women during weeks 7 and 8. At that time the abortionrate was 0 024 (3/124) abortions per day, whereas during thesame period the abortion rate for women entering the studyduring week 7-8 was 0-001 (2/1509) abortions per day. Thisreduction in abortion rate is probably influenced by theultrasound examination carried out at the intake visit. Theexclusion, at that stage, of all non-viable pregnancies wouldexplain the low abortion rate in patients entering duringweek 7-8.A relation between gestational age at intake and abortionrate has also been observed in other studies in which earlyfetal viability was documented by ultrasound.12,13 The onlymaternal age dependent data on fetal loss rates at givengestational periods presented in life-table style14 were basedon a cross-sectional study design and are therefore difficultto apply to a cohort under observation at a given stage ofpregnancy. Moreover, in that study fetal viability was notverified by ultrasound. From the present study it has alsobecome evident that a considerable number of pregnancylosses before TA-CVS occurred at 10-12 weeks of gestation.This coincides with the period surrounding the TC-CVSprocedure and explains the relatively high spontaneous fetalloss rate after TC-CVS in the advanced maternal agegroup. 3In contrast to Regan,15 we were unable to establish anyrelation between spontaneous abortion rate and pastreproductive performance. This may be because non-viablepregnancies were disregarded in the present study: 50% ofthe spontaneous abortions in Regan’s study would havefallen into this category.We found no evidence for any adverse effect of TA-CVSon the abortion rate. The abortion rate after TA-CVS wasnot significantly higher than that before the procedure, evenif it is assumed that all abortions would have occurredspontaneously. However, when all diagnosed chromosomalanomalies were excluded, the spontaneous abortion ratebefore TA-CVS was considerably higher than that observedafter the procedure.We suggest that these findings justify late first-trimesterchorionic villus sampling in women of advanced maternalage because the spontaneous abortion rate and theprocedure related abortion risk do not exceed the risk of fetalchromosomal abnormality. At 12 weeks of gestationtermination is still feasible as an outpatient procedure. Thisapproach will also be more cost effective, since a number ofaffected fetuses diagnosed early in the first trimester mostlikely would have aborted spontaneously by this time.We thank the Clinical Genetics Foundation, Rotterdam, for financialsupport.REFERENCES1. Brambati B, Lanzani A, Oldrini A. Transabdominal chorionic villussampling. Clinical experience of 1159 cases. Prenatal Diagnosis 1988; 8:609-17.2. Sachs ES, Jahoda MGJ, Kleyer WJ, Pijpers L, Galjaard H. Impact offirst trimester chromosome, DNA and metabolic studies onpregnancies at high genetic risk: experience with 1000 cases. Am J MedGenet 1988; 29: 293-303.3. Jahoda MGJ, Pijpers L, Vosters RPL, Wladimiroff JW, Reuss A, SachsES. Role of maternal age in assessment of risk of abortion after prenataldiagnosis during first trimester. Br Med J 1987; 295: 1237.4. Pijpers L, Johoda MGJ, Reuss A, Wladimiroff JW, Sachs ES.Transabdominal chorionic villus biopsy in second and third trimestersof pregnancy to determine fetal karyotype. Br Med J 1988; 297: 822-23.5. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomizedclinical trials requiring prolonged observation of each patient (part II:analysis and examples). Br J Cancer 1977; 35: 1-39.6. Cox DR. Regression models and life-tables. J R Statist Soc 1972; B34:187-220.7. Hop WCJ, van Buuren HR. A method to evaluate changes in prognosticstatus during follow-up, illustrated by an assessment of the effect of arebleed in patients with oesophageal variceal bleeding. Comput BiolMed 1989; 19: 181-88.8. Christiaens GCML, Stoutenbeek PH. Spontaneous abortion in provenintact pregnancies. Lancet 1984; ii: 571-72.9. Gilmore DH, McNay MB. Spontaneous fetal loss rate in early pregnancy.Lancet 1985; i: 107.10. Hook EB, Cross PhK, Jackson L, Pergament E, Brambati B. Maternalage-specific rates of 47,+21 and other cytogenetic abnormalitiesdiagnosed in the first trimester of pregnancy in chorionic villus biopsyspecimens: Comparison with rates expected from observations atamniocentesis. Am J Hum Genet 1988; 42: 797-807.11. Stein ZA. A woman’s age: childbearing and child rearing Am J Epidemiol1985; 121: 327-40.12. Liu DTY, Jeavons B, Preston C, Pearson D. A prospective study ofspontaneous miscarriage in ultrasonically normal pregnancies andrelevance to chorion villus sampling. Prenatal Diagnosis 1987; 7:223-27.13. Steer C, Campbell S, Davies M, Mason B, Collins W. Spontaneousabortion rates after natural and assisted conception. Br Med J 1989;299: 1317-18.14. Gustavii B. Chorionic biopsy and miscarriage in first trimester. Lancet1984; i: 562.15. Regan L, Braude PR, Trembath PL. Influence of past reproductiveperformance on risk of spontaneous abortion. Br Med J 1989; 299:541-45.From The LancetHealth service reformsAmongst the numerous evils which have been engendered by theAct of 1815, not the least obnoxious is the unnatural connectionthereby formed between the science of medicine and the trade of theshopkeeper. It may, possibly, have been intended by the framers ofthat Act, that the apothecary who keeps an open shop shouldconfine himself to the sale of medicines and other appurtenances ofhis art; but, as the Apothecaries’ Company was founded on aradically false principle, so has every one of its acts, and all theconsequences, tended to nothing less than the degradation and ruinof the profession. The occupation of the medical man should simplyconsist in the exercise of knowledge, and the administration ofremedies. The instant that he encroaches on the domain of others,by keeping an open shop, for the sale of goods, he loses a greatportion of the respect which naturally attaches to his profession, andis led, by the force of circumstances, to the committal of various actsthat are totally inconsistent with the dignity of his calling. We wouldcite numerous examples of this fact, were it not too disagreeable asubject to dwell on.(January 11, 1840)

Spontaneous abortion rate and advanced maternal age: Consequences for prenatal diagnosis

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Spontaneous abortion rate and advanced maternal age: Consequences for prenatal diagnosis

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