Multiple pregnancies: a call for action

Howard W. Jones, Jr., M.D., and John A. Schnorr, M.D.

The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, EasternVirginia Medical School, Norfolk, Virginia

The 1990s have been referred to as the “Technology Decade” because of the evolution ofthe Internet, exponential growth of .com companies, and soaring stock market. The Technol-ogy Decade has also had a profound impact on assisted reproductive technologies (ARTs)through scientific advances that have increased implantation rates, pregnancy rates, andunfortunately, multiple-pregnancy rates. In fact, between 1988 and 1997 (the most recentfigures available), the multiple-pregnancy rate increased faster than the NASDAQ Composite!We could only hope for a “correction” in the multiple pregnancy rates such as the NASDAQComposite experienced over the first part of the year 2000 (Figure 1; ref. 1–9).

The most recent statistics available from the US Department of Health and Human Services(published September 14, 1999) demonstrate an alarming trend in twin, triplet, and high-ordermultiple births. Between 1980 and 1997, the number of infants born in multiple deliveries hasrisen at a remarkable pace. Since 1980, twin births have risen 52% from 68,339 to 104,137births, and the number of triplet and higher order gestations has quadrupled, climbing from1,337 to 6,737 births. Within the category of triplet and higher order multiple births, tripletbirths have increased 142%, quadruplet pregnancies increased 123%, and quintuplet andhigher order births increased 98% between 1989 and 1997 (10).

The significant increase in multiple births appears to coincide with two overlapping andrelated trends. The first is the older age at childbearing, because within spontaneous concep-tions, older women are more likely to have a multiple birth. Second, there is an increase in theavailability and use of fertility-enhancing therapies, which typically result in a high percentageof multiple pregnancies. It has been estimated that approximately one third of the increase inmultiple births since the early 1980s has been attributed to a shift in maternal age distribution;the remaining two thirds is likely the result of ovulation induction, gamete intrafallopiantransfer (GIFT), and in vitro fertilization (IVF), the principal fertility-enhancing therapies(11–14). If these estimates are reliable, the fertility-enhancing therapies translate into morethan 225,0000 multiple births over the study period of 1980–1997 (10).

It is difficult to ascertain the impact of artificial ovulation induction alone with regard to themultiple pregnancy rates. Levene et al. studied 156 consecutive triplet and higher ordermultiple pregnancies and discovered that 32% of the triplet pregnancies were spontaneous,30% were from ovulation induction, and the remaining 36% were from IVF/GIFT (15).Ovulation induction resulted in the majority of quadruplet pregnancies: 66% vs. 33% werefrom IVF/GIFT. The impact of ovulation induction was further investigated by Derom et al.,who studied 458 twin and 78 triplet pregnancies resulting from ARTs. In 77% (351/458) of thetwin pregnancies and 72% (56/78) of the triplet pregnancies, artificial induction of ovulationalone was the only treatment (16). It is of significance that no official or unofficial body hasoffered any regulations or guidelines to avoid high-order multiple pregnancies due to ovulationinduction. This essay offers an approach to a solution for the multiple-pregnancy problems dueto IVF.

IVF allows more control over the multiple-pregnancy rates by allowing the patient andphysician to determine the optimum number of embryos to transfer. It is often a difficultdecision for the physician and patient because of the heavy focus on maximizing a woman’s

Received June 12, 2000;accepted June 12, 2000.Reprint requests: HowardW. Jones Jr., M.D., JonesInstitute for ReproductiveMedicine, 601 ColleyAvenue, Norfolk, Virginia23507 (FAX: 757-446-5905;E-mail: joneshw@evms.edu).

EDITOR’S CORNERFERTILITY AND STERILITY tVOL. 75, NO. 1, JANUARY 2001Copyright ©2001 American Society for Reproductive MedicinePublished by Elsevier Science Inc.Printed on acid-free paper in U.S.A.

The opinions andcommentary expressed inEditor’s Corner articles aresolely those of the author.Publication does not implyendorsement by the Editoror American Society forReproductive Medicine.

0015-0282/01/$20.00PII S0015-0282(00)01612-5

11

chance of becoming pregnant. One common practice formaximizing the chance of pregnancy is to transfer multipleembryos into the uterine cavity. As expected, this also resultsin a dramatic increase in the multiple-pregnancy rate, with-out a significant improvement in the overall pregnancy rate.

There has been a considerable international effort to solvethe IVF multiple-pregnancy rate problem. These efforts havetaken the form of guidelines or regulations by unofficial orofficial bodies, indicating a maximum number of pre-em-bryos considered allowable to transfer.

Under the aegis of the International Federation of FertilitySocieties (IFFS), a compilation of these guidelines, regula-tions, or the absence of either, was made for 38 nations.While this compilation concerned multiple aspects of ART,only the compilation in relation to the number of pre-em-bryos to transfer is pertinent to this discussion. The survey ofsovereign political entities, in other words, nations or states,fell into three categories: [1] those with legislation; [2] thosewith voluntary guidelines; and [3] those with neither. Amongthe 23 entities with legislation, there are nine entities thatlimit the number of embryos to be transferred, the numbervarying from two to a maximum of four. Regulations areoften rather specific, allowing no exceptions. The penaltiesfor violation are not trivial. For instance, a clinic’s license topractice might be withdrawn (United Kingdom), there couldbe a fine or imprisonment (Germany), imprisonment and afine of at least FS1000,000 (Switzerland), loss of license andprobably imprisonment (South Australia) and a fine (Germa-ny), or loss of license (Sweden). Interestingly enough, 14 ofthe nations operating with legislation do not indicate a limitto the number to be transferred.

Four of the 10-guideline countries specifically limit thenumber to transfer, although in the nature of the thing, thereis no enforcement mechanism. Six of the 10 guidelinescountries in the IFFS today do not have any specificationsabout the number to transfer.

One country (the United States), when surveyed, althoughnot specific in the number to be transferred, neverthelessburdened the individual programs with transferring no morethan will result in a 2% or less triplet rate among all preg-nancies. Since the survey, the United States has, through thepractice committee of the American Society for Reproduc-tive Medicine, issued guidelines specifying exact numbersthat are acceptable to transfer. None of the sovereign statesoperating without legislation or guidelines has a limit on thenumber of embryos to be transferred, as might be expected.

Effectiveness of SurveillanceIt seems clear that the voluntary guideline system in the

United States has not solved the problem of multiple gesta-tions. There are at least four aspects to an explanation of thefailure.

First, there is the intense desire of the patient to becomepregnant. When informed of the risks of multiples, manypatients are prepared to accept the risks. There is need formore education of the patient public. This would includematerials and their dissemination.

Second, there is need for backbone in the medical pro-fession. Although we are in an era of patient participation intherapy, it is inescapable that the physician should accept atleast equal responsibility for preventing untoward results.Unfortunately, the physician is many times prepared to be arisk taker for competitive reasons, of which more are listedlater in this article. At a minimum, the physician must besure that the informed consent signed by the patient is clearand detailed as to the multiple-pregnancy risk.

Third, there is the unfortunate aspect of competitionamong ART programs to achieve a high pregnancy rate. Thehigh pregnancy rate is considered desirable to ensure theprosperity of any program in question. Generally speaking,patients lack adequate medical sophistication to interpretprograms’ specific pregnancy rates. As they now exist, pro-gram-specific pregnancy rates do not give consideration tothe multiple variables involved in achieving a specific preg-nancy rate. Thus, specific pregnancy rates are misleading.Furthermore, in clinic-specific reporting, as it now exists, noconsideration is given to the prevalence of fetal reduction inthe calculation of multiple-pregnancy rates.

If these observations are correct, in our opinion, it wouldbe in the best interest of the patient to take whatever steps arenecessary to eliminate clinic-specific reporting as it now exists.The American Society of Reproductive Medicine bears aheavy responsibility in this regard.

Fourth, scientific advances, which we all cherish, haveinadvertently contributed to the problem. If any given pro-gram has adjusted the number to transfer to eliminate unde-sirable multiples, any improvement in the implantation ratewill pari passu reintroduce undesirable multiples.

The elimination of multiples because of scientific advance

F I G U R E 1

— Multiple pregnancy rate, – – Nasdaq composite.

Jones. Multiple pregnancies: a call for action. Fertil Steril 2001.

12 Jones and Schnorr Multiple pregnancies: a call for action Vol. 75, No. 1, January 2001

is difficult, to say the least. The best to be hoped for is a veryprompt adjustment of the number transferred when improve-ment in implantation rates is perceived. Patients need to bewarned of the down side of scientific advance, and indeed,some paragraph about this might be appropriate to include ininformed consent forms.

Surveillance in Millennium 2000 (United States)It seems inescapable that voluntary guidelines as they

now exist have failed to control the multiple-pregnancyproblems in IVF in the United States. There are severalconsiderations. There would probably be general agreementthat avoidance of federal regulations is a most desirable aim.Furthermore, there seems to be a constitutional requirementthat such regulation be assigned to states. Therefore, anyfederal action would likely take the form of a recommenda-tion to the states of a model law, which would have toadopted state by state. The attempt that is now in progress atsurveillance of embryological laboratories is an example ofthe compliance with this constitutional requirement.

Is There a Workable Voluntary Way? ThereMay Be

The Voluntary Licensing Authority of Great Britain canbe considered as an example. As a result of the study byDame Warnock in the United Kingdom, there was a recom-mendation for a licensing authority. In view of the antici-pated delay in action by the Parliament, the Royal College ofObstetricians and Gynecologists established a voluntary li-censing authority, the basis of which was the inspectionaccording to announced guidelines of the various programsand the issuance of a license to that program as havingfulfilled the requirements previously set forth by the College.In the event of violation of any of the requirements, thelicensing authority was authorized to withdraw the license.This seemed to work well. There was no official governmen-tal imposition, and the patient had the opportunity to be surethat the program in which she was being treated had indeedbeen licensed by the Authority. This gave considerable pa-tient assurance.

It is true that the Voluntary Licensing Authority has nowbecome official under the name of the Human Embryologyand Fertilization Authority and that it continues to operate byissuing licenses and the withdrawal of them for violations,but there is reason to argue that the authority was as effectiveon a voluntary basis as it is when it is official.

In the view of these authors, serious consideration shouldbe given in the United States to attempting to establish whatamounts to a voluntary licensing authority molded to theAmerican system. An attempt was made to do that previ-ously by the then American Fertility Society and the Amer-ican College of Obstetricians and Gynecologists in the es-tablishment of the National Advisory Board of Reproductive(NABER), but NABER did not seize the opportunity to

pursue this goal and rather concerned itself with reevaluatingthe ethical aspects of matters that had been considered by theEthics Committee of the American Fertility Society; indeed,it might update some of these requirements. This, in ouropinion, was unfortunate, and it might be that a new startneeds to be made. The ASRM and ACOG bear heavy re-sponsibility in this regard, and somehow or other, it isdevoutly hoped that this letter will call to the attention ofASRM and ACOG that it is necessary for them to take actionto establish a national body that would be willing to under-take the duties of voluntary licensing. This might very wellwork to overcome the problem of multiple pregnancies with-out governmental interference.

References1. In vitro fertilization-embryo transfer in the United States: 1988 results

from the IVF-ET Registry. Medical Research International. Society forAssisted Reproductive Technology. American Fertility Society. FertilSteril 1990;53:13–20.

2. In vitro fertilization-embryo transfer (IVF-ET) in the United States:1989 results from the IVF-ET Registry. Medical Research Interna-tional, Society for Assisted Reproductive Technology, The AmericanFertility Society. Fertil Steril 1991;55:14–22; discussion 22–3.

3. In vitro fertilization-embryo transfer (IVF-ET) in the United States:1990 results from the IVF-ET Registry. Medical Research Interna-tional. Society for Assisted Reproductive Technology (SART), TheAmerican Fertility Society (published erratum appears in Fertil Steril1993 Jan;59(1):250). Fertil Steril 1992;57:15–24.

4. Assisted reproductive technology in the United States and Canada:1991 results from the Society for Assisted Reproductive Technologygenerated from the American Fertility Society Registry. Fertil Steril1993;59:956–62.

5. Assisted reproductive technology in the United States and Canada:1992 results generated from the American Fertility Society/Society forAssisted Reproductive Technology Registry. Fertil Steril 1994;62:1121–8.

6. Assisted reproductive technology in the United States and Canada:1993 results generated from the American Society for ReproductiveMedicine/Society for Assisted Reproductive Technology Registry. Fer-til Steril 1995;64:13–21.

7. Assisted reproductive technology in the United States and Canada:1994 results generated from the American Society for ReproductiveMedicine/Society for Assisted Reproductive Technology Registry. Fer-til Steril 1996;66:697–705.

8. Assisted reproductive technology in the United States and Canada:1995 results generated from the American Society for ReproductiveMedicine/Society for Assisted Reproductive Technology Registry. Fer-til Steril 1998;69:389–98.

9. Assisted reproductive technology in the United States: 1996 resultsgenerated from the American Society for Reproductive Medicine/So-ciety for Assisted Reproductive Technology Registry. Fertil Steril1999;71:798–807.

10. US Department of Health and Human Services. Trends in twin andtriplet births: 1980–97. Washington, DC: Centers for Disease Controland Prevention, 1999.

11. Jewell SE, Yip R. Increasing trends in plural births in the United States.Obstet Gynecol 1995;85:229–32.

12. Martin JA, MacDorman MJ, Mathews TJ. Triplet births: trends andoutcomes, 1971–94. National Center for Health Statistics, 1997.

13. Wilcox LS, Kiely JL, Melvin CL, Martin MC. Assisted reproductivetechnologies: estimates of their contribution to multiple births andnewborn hospital days in the United States. Fertil Steril 1996;65:361–6.

14. Kiely JL, Kleinman JC, Kiely M. Triplets and higher-order multiplebirths. Time trends and infant mortality. Am J Dis Child 1992;146:862–8.

15. Levene MI, Wild J, Steer P. Higher multiple births and the modernmanagement of infertility in Britain. The British Association of Peri-natal Medicine. Br J Obstet Gynaecol 1992;99:607–13.

16. Derom C, Derom R, Vlietinck R, Maes H, Van den Berghe H. Iatro-genic multiple pregnancies in East Flanders, Belgium. Fertil Steril1993;60:493–6.

FERTILITY & STERILITY t 13