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Practice Patterns Among Board-Certified Reproductive Endocrinologists Regarding High-Order Multiple Gestations: A United States National Survey

From the Reproductive Medicine Associates of New Jersey, Somerset; and Division of Reproductive Endocrinology and Infertility, and Section of Epidemiology and Biostatistics, Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey.

Address reprint requests to: David B. Seifer, MD, UMDNJ-Robert Wood Johnson Medical School, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, 303 George Street, Suite 250, New Brunswick, NJ 08901; E-mail: seiferdb{at}umdnj.edu.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
OBJECTIVE: To assess current practice management, attitudes, and strategies of reproductive endocrinologists in the United States regarding high-order (at least three) multiple gestations.

METHODS: Questionnaires were mailed to 768 board-certified reproductive endocrinologists of whom 722 were eligible for the study. The questionnaires addressed topics such as practitioner demographics, management strategies, and attitudes regarding high-order multiple gestations.

RESULTS: The survey response rate was 52%. Most physicians performed 100–300 cycles of each ovulation induction with intrauterine insemination and in vitro fertilization in 1998 and 1999. The most commonly reported incidence of high-order multiple gestations resulting from each ovulation induction with intrauterine insemination and in vitro fertilization was 2–5% in 1998 and 1999. Strategies used to decrease the rate of high-order multiple gestations varied among practitioners. Informed consent regarding high-order multiple gestations was provided by 99.5% of practitioners. Information regarding selective reduction was provided by 98.3% of respondents. Over 90% of practitioners believed it is worthwhile to attempt to decrease the risk of high-order pregnancies at the risk of decreasing their group’s overall pregnancy rates.

CONCLUSION: Most reproductive endocrinologists reported concern over the rising risk of high-order multiple gestations resulting from therapies such as superovulation with intrauterine insemination or in vitro fertilization. However, the ways in which patients are counseled regarding such events, their sequelae, and methods to avoid them greatly differ among respondents. Given the inconsistent practice patterns, a multifaceted educational approach may provide an opportunity to reduce the incidence of high-order multiple gestations and their sequelae.

The incidence of multiple births, including high-order multiple gestations (at least three) has risen dramatically over the past several decades. Within the past decade alone, the percentage of high-order multiple gestations has increased from 0.7 per 1000 in 1990 to 1.7 per 1000 in 1997, a relative increase of 144%. Although some of the increase may be attributed to a rise in spontaneous high-order pregnancies, the majority has followed the Food and Drug Admnistration’s approval of ovulation-inducing medications in 1967 and 1970. The incidence of high-order multiple gestations has continuously increased and more than quadrupled since the introduction of assisted reproductive technology in 1980.¹ Nearly 80% of high-order multiple gestations are the result of ovulation-inducing medications and assisted reproductive technology.^1,2

High-order multiple gestations are at a greater risk than singleton gestations for preterm delivery, low (less than 2500 g) and very low (less than 1500 g) birth weight. Inherent in these situations are higher incidences of bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, fetal growth restriction, neurologic sequelae, and fetal death. There are also concerns with maternal morbidity from preeclampsia and gestational diabetes. These complications are associated with dramatic elevations in health care cost. The combined maternal and neonatal hospital charge for twin gestations is nearly four-fold that of singleton gestations, and that of triplet gestations is over ten-fold that of singleton gestations.³

Infertility programs are often judged by their pregnancy rate. Thus, there is a great deal of pressure to increase success rates. This is often accomplished by increasing the number of mature follicles that will ovulate during superovulation cycles and increasing the number of embryos transferred in in vitro fertilization (IVF) cycles. The benefit is achieving a greater number of pregnancies, but at the price of increasing the number of multiple gestations.

Various strategies have been used to decrease the risks. Selective fetal reduction has been used to reduce the number of fetuses carried; however, this method often introduces an ethical dilemma to many couples and is often not a feasible option. Furthermore, it is not without its own risk of pregnancy loss.^4,5 Recently, the focus has been directed to methods of prevention, including transferring fewer embryos, transferring embryos at the blastocyst stage of development, and more judicious use of ovulation induction medications combined with improved monitoring.^2,6

Initial data have been obtained regarding the use of informed consent for infertility treatment,⁷ but the opinions and management style of reproductive endocrinologists who use treatment that may result in high-order multiple gestations have not been addressed. We have noticed that variation exists within our own institution regarding the strategies used to decrease the incidence of high-order multiple gestations. Opinions of variables thought to be risk factors for these pregnancies, such as maximum estradiol level, number of mature follicles, and patient diagnosis are known to differ among physicians within the same practice or community. The use of interventions such as withholding human chorionic gonadotropin (hCG), withholding additional administration of gonadotropins before hCG (coasting), and cycle cancellation also varies.

As a first step toward reducing this rapidly growing concern, current practice management needs to be described. We designed this survey to assess the current strategies used by physicians who are board certified in reproductive endocrinology and infertility in the United States.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
Between September 2000 and January 2001, questionnaires (see Appendix A) were mailed to 768 reproductive endocrinologists who were certified by the American Board of Obstetrics and Gynecology (Dallas, TX). The Board provided a list of names and addresses, which were cross-referenced with recent editions of the ACOG directory of fellows and the American Society for Reproductive Medicine membership directory. The survey was sent in three separate mailings to maximize response. Each survey was accompanied by a self-addressed, stamped envelope and a cover letter explaining the objectives of the study. Physicians involved with industry or administration, currently retired, or who were no longer practicing within the field of reproductive endocrinology were considered ineligible (n = 46). These were excluded from the analysis, thereby resulting in 722 responses being eligible. Identification of survey respondents was removed before the statistical analysis to maintain anonymity.

The questionnaire was composed of 21 multiple-choice questions and was designed to take less than 10 minutes to complete. Many questions were designed to elicit more than one response. Physicians were queried as to their concern regarding high-order multiple gestations and the importance of reducing their own rates of these complications. They were also asked to identify patients considered to be most at risk, and the methods in which attempts are made to reduce the incidence of high-order multiple gestations (ie, cycle cancellation, withholding hCG, coasting, etc). Counseling regarding selective reduction and information regarding demographic characteristics such as practice location, city size, whether their practice was in a community or university setting, and number of partners were also ascertained.

Response rates, demographic information, methods used to decrease the incidence of high-order multiple gestations, informed consent, and general attitudes regarding high-order multiple gestations were calculated. Associations among demographic variables and practice management were evaluated using the ² analysis. P values < .05 were considered to indicate statistical significance, and all statistical tests were two-tailed. Statistical analysis was performed using the SAS System 8.2 (SAS Institute, Cary, NC) on the UNIX.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
The study was reviewed and approved by the University’s Institutional Review Board. A total of 375 questionnaires were returned, yielding a response rate of 52%. The number of responses from Puerto Rico and Canada were few (n = 6) and were therefore excluded from analyses involving geographic location. These surveys were, however, included in all other analyses. Most practitioners were located in the Northeast, practiced within relatively large (more than 500,000) populations in a community-based setting that consisted of two to four partners (Table 1). They performed 100–300 cycles of ovulation induction with intrauterine insemination and 100–300 cycles of IVF in 1998 and 1999. The most reported incidence of high-order multiple gestations resulting from each ovulation induction with intrauterine insemination and IVF was 2–5% in 1998 and 1999. Many different strategies are used to decrease the rate of high-order multiple gestations resulting from ovulation induction with intrauterine insemination, but most physicians included cycle cancellation, withholding hCG, and limiting the number of mature follicles as part of their management (Table 2). Among those who withheld hCG and intrauterine insemination, the individual threshold numbers of mature follicles and maximum estradiol levels ranged from 14 mm or more to 20 mm or more, and 1000 pg/mL or more to 2500 pg/mL or more, respectively (Table 3). Many patient factors were considered before cycle cancellation. These included the age of the patient, the number of previous ovulation induction cycles, the history of multiple gestation in the individual, the patient’s ovarian reserve, the diagnosis (ie, polycystic ovary syndrome), the number of mature follicles, the level of estradiol, and a history of ovarian hyperstimulation. The number of mature follicles was the most common factor considered (47%), whereas the number of previous ovulation induction cycles and the patient’s ovarian reserve were the least likely (4%) to be considered (Table 4). The specific strategies used to decrease the risk of multiple pregnancies in a superovulation cycle/intrauterine insemination also varied widely within each region. Among those respondents who withheld hCG and the intrauterine insemination, a mature follicle count of six or more and estradiol level of 2000 pg/mL or more were the most commonly reported thresholds despite geographic location. The number of mature follicles was the most important factor considered in deciding to withhold hCG/intrauterine insemination in all geographic locations.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

A decline in the incidence of high-order multiple gestations was reported in almost all regions for both ovulation induction with intrauterine insemination and IVF during the years 1998 and 1999. This decline may be reflective of a greater awareness regarding this complication and perhaps more prudent practice management including the use of blastocyst transfer.

The response rate of 52% of this survey is higher than the average received in mail-back questionnaires.^11,12 However, the possibility of selection bias still exists, as it is not possible to know that the opinions and practice management of the nonresponders are similar to those provided. Further, data collected from self-reported surveys may be limited in accuracy, but the conclusions are still valuable in explaining natural trends. This study provides a baseline for further evaluation regarding the approach by which physicians manage fertility treatment in those who are at greatest risk of having high-order multiple gestations.

Most respondents included selective reduction as an option for their patients to decrease the number of fetuses carried to term in an attempt to decrease the risk of maternal and perinatal morbidity and mortality. However, a discussion regarding selective reduction was often not reviewed with patients once gonadotropins had begun. The decision to reduce the number of fetuses may present a profound ethical and personal dilemma to the couple, which may be alleviated with more time to consider this option. Multifetal pregnancy reduction is associated with pregnancy loss and prematurity, but these complications have decreased as experience with the procedure has grown.¹³

Physicians will often try to decrease the risk of multiple gestations during ovulation induction with intrauterine insemination by using serum markers and transvaginal sonography. Unfortunately, most studies have demonstrated this technique to be ineffective.^14–16 A multicenter, randomized, clinical trial involving 1255 ovulation induction cycles withheld hCG if more than six follicles greater than 18 mm in diameter were present or if the estradiol level was greater than 3000 pg/mL. The multiple pregnancy rate was 30%.¹⁴ Another study evaluated 449 ovulation induction cycles where hCG was withheld if more than six follicles were present. The multiple pregnancy rate was 25.5%.¹⁵ Estradiol levels, number of follicles greater than 15 mm in diameter, and total number of follicles on the day of hCG administration were evaluated retrospectively in 3347 ovulation induction cycles. Although the risk of multiple gestation correlated with the extent of follicular response and estradiol levels, a group of patients at high risk for high-order multiple gestations could not be identified and the incidence of multiple gestations was not reduced.¹⁶ Currently, there is no consensus regarding specific ultrasound criteria or estradiol levels above which hCG should be withheld.¹⁷

The Society for Assisted Reproductive Technology/ Centers for Disease Control and Prevention National Registry included 360 fertility clinics in 1998. There were 61,650 embryo transfers reported, resulting in 19,891 live births and 28,500 infants.¹⁸ This volume has risen substantially from the initial national registry report in 1988. At that time, 30 clinics provided data for 2389 embryo transfers resulting in 337 clinical pregnancies.¹⁹ Such a rapid increase in the use of these procedures has been accompanied by an exponential increase in high-order multiple gestations, along with their medical and social consequences.

In an effort to decrease this trend, the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine published guidelines recommending limited numbers of embryos for transfer based on patient age and embryo quality.²⁰ Limiting the number of embryos transferred may indeed reduce the number of high-order multiple gestations encountered. However, for these guidelines to be implemented, physicians must deem it valuable to attempt to decrease the risk of high-order multiple gestations at the possible expense of also decreasing pregnancy rates. In this survey, over 90% of respondents believed it to be worthwhile, but only 74% were willing to decrease the high-order multiple gestation rate at the risk of reducing their twin pregnancy rate (P < .001). Patients often perceive a twin conception as a desirable event. Perhaps this misconception has influenced practitioners’ attitudes with regards to their own acceptance of twin gestations without regard to the increase in morbidity and mortality.

Improvements in technology such as better recognition of high-quality embryos, delaying transfer to the blastocyst stage, and advances in natural cycle IVF will help in using these guidelines. The most promising may be an improvement in blastocyst culture. This technique allows embryos of better quality to be selected. Recent modifications to embryo culture have allowed for the transfer of two blastocysts, while maintaining reasonable pregnancy rates and reducing the number of high-order multiple gestations.^21–23 Continued progress in identifying higher-quality embryos may lead to the ability to transfer only one embryo without a compromise in pregnancy rate, while nearly eliminating the multiple gestation rate.

This survey indicates that most physicians do recognize the challenges and increasing incidence of high-order multiple gestations, although practice management among them varies considerably. To achieve greater success in decreasing the incidence of high-order multiple gestations, a consensus as to which interventions lead to this goal and which do not needs to be more precisely established. Once this is accomplished, uniformity in practice management can be sought through education of both physicians and patients. A uniform approach as well as further advances in technology will hopefully lead to a significant reduction in multiple gestation rates in both ovulation induction with intrauterine insemination and IVF. Information provided by the Society for Assisted Reproductive Technology/Centers for Disease Control and Prevention has supplied us with extensive information regarding the number of assisted reproductive technology cycles performed and the number of cycles resulting in clinical pregnancies and deliveries. Clinic specific data concerning the number of high-order multiple pregnancies (ie, triplets, quadruplets, quintuplets, etc) would allow for a greater awareness among both physicians and patients. Patients seem to be well informed of success rates but would be better served by knowing the clinic’s specific rates of multiple gestations, particularly those of high order. The formation of a national registry of superovulation and intrauterine insemination would allow for a heightened awareness of the number of cycles performed as well as a more precise estimate of high-order multiple gestations. Recognition of these clinical parameters as well as an appreciation of the possible consequences resulting from such cases could have a greater impact in limiting this growing problem.

	APPENDIX A

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
Nondemographic Questions
What is the incidence of high-order multiple gestation (3) after gonadotropins and IUI in your group’s practice? (Please circle a response for each year)

For 1998 For 1999 a. <1% a. <1% b. 1–2% b. 1–2% c. 2–5% c. 2–5% d. 5–10% d. 5–10% e. 10–15% e. 10–15% f. >15% f. >15%

What is the risk of high-order multiple gestation (3) after IVF in your group’s practice? (Please circle a response for each year)

For 1998 For 1999 a. <1% a. <1% b. 1–2% b. 1–2% c. 2–5% c. 2–5% d. 5–10% d. 5–10% e. 10–15% e. 10–15% f. >15% f. >15%

How many cycles of ovulation induction (using gonadotropins) and IUI did your group perform? (Please circle a response for each year)

For 1998 For 1999 a. <100 a. <100 b. 100–300 b. 100–300 c. 300–500 c. 300–500 d. 500–700 d. 500–700 e. 700–900 e. 700–900 f. 1000 f. 1000 g. Other__ g. Other__

How many IVF retrievals did your group perform? (Please circle a response for each year)

For 1998 For 1999 a. <50 a. <50 b. 50–100 b. 50–100 c. 100–300 c. 100–300 d. 300–500 d. 300–500 e. 500–700 e. 500–700 f. 700–900 f. 700–900 g. 1000 g. 1000 h. Other__ h. Other__

What specific strategies have you used to decrease the risk of multiple pregnancies in a superovulation cycle/IUI cycle? (Circle all that apply)

1. Limit the number of mature follicles
   
2. Withhold hCG
   
3. Coasting
   
4. Cancel cycle
   
5. Convert to an IVF cycle
   
6. Other______________
   

What mean follicle diameter do you consider to be mature enough to trigger ovulation with hCG during a gonadotropin/IUI cycle?

1. 14 mm
   
2. 15 mm
   
3. 16 mm
   
4. 17 mm
   
5. 18 mm
   
6. 19 mm
   
7. 20 mm
   

When, if ever, do you withhold hCG and the IUI? (Circle one from each group)

Mature Follicles E2 (pg/mL) a. 4 a. E2 1000 b. 5 b. E2 1000–1500 c. 6 c. E2 1500–2000 d. 7 d. E2 2000 e. 8 e. E2 ____ f. ____

What patient factors do you consider in your decision to withhold hCG/IUI? Please rank in order of importance (1 = most important, 8 = least important)

____Number of previous OI cycles

____Age

____History of multiples

____Ovarian reserve

____Diagnosis (ie, PCOS)

____When there are "too many" mature follicles

____When the E2 is "too high"

____History of hyperstimulation

Which of the following is used to inform your patients receiving gonadotropins of the risk of high-order multiple gestations? (Circle all that apply)

1. Information provided by physician
   
2. Information provided by other office staff
   
3. None
   

In discussing the risk of high-order (3) multiple gestations, which of the following are reviewed with the patient? (Circle all that apply)

1. Risk of increased maternal morbidity (ie, preeclampsia, gestational diabetes)
   
2. Risk of preterm delivery
   
3. Risk of fetal growth retardation
   
4. Risk of neurologic sequelae
   
5. Risk of bronchopulmonary dysplasia
   
6. Risk of retinopathy of prematurity
   
7. Risk of fetal death
   
8. Social/economic concerns of high-order gestations
   

Is a discussion of selective reduction included in your conversation with your patient?

1. Yes
   
2. No
   

If yes, when is this information provided? (Circle all that apply)

1. Before beginning gonadotropins
   
2. Immediately before prescribing hCG
   
3. When more than a certain number of mature follicles are noted by ultrasound (What number is your threshold for counseling?____)
   
4. After a high-order multiple gestation is identified
   

If yes, how is this information provided? (Circle all that apply)

1. By physician
   
2. By other office staff
   

If yes, indicate which of the following are reviewed. (Circle all that apply)

1. Risk of continuing as a high-order multiple gestation to the fetuses/mother
   
2. Specific referrals to a center providing selective reduction
   
3. Risk of selective reduction to the pregnancy
   
4. Incidence of spontaneous reduction
   

Do you believe it is worthwhile to try to decrease the risk of high-order pregnancies (3) at the risk of decreasing your group’s overall pregnancy rate in ovulation induction/IUI or ART?

1. Yes
   
2. No
   

Do you believe it is worthwhile to try to decrease the risk of high-order pregnancies (3) at the risk of decreasing your group’s overall twin rate in ovulation induction/IUI or ART?

1. Yes
   
2. No
   

	Footnotes

 
Supported in part by a grant from National Institutes of Health, NIA AG15425 (to DBS).

PII S0029-7844(02)01950-6

Received August 23, 2001. Received in revised form January 2, 2002. Accepted January 17, 2002.

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TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
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2. Vidaeff AC, Racowsky C, Rayburn WF. Blastocyst transfer in human in vitro fertilization. A solution to the multiple pregnancy epidemic. J Reprod Med 2000;45:529–39.[Medline]

3. Callahan TL, Hall JE, Ettner SL, Christiansen CL, Greene MF, Crowley WF. The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence. N Engl J Med 1994;331:244–9.[Abstract/Free Full Text]

4. Wapner RJ, Davis GH, Johnson A. Selective reduction of multifetal pregnancies. Lancet 1990;335:90–3.[Medline]

5. Berkowitz RL, Lynch L, Lapinski R, Bergh P. First-trimester transabdominal multifetal pregnancy reduction: A report of two hundred completed cases. Am J Obstet Gynecol 1993;169:17–21.[Medline]

6. Nijis M, Geerts L, van Roosendaal E, Segal-Bertin G, Vanderzwalmen P, Schoysman R. Prevention of multiple pregnancies in an in vitro fertilization program. Fertil Steril 1993;159:1245–50.

7. Houmard BS, Seifer DB. Infertility treatment and informed consent: Current practices of reproductive endocrinologists. Obstet Gynecol 1999;93:252–7.[Abstract/Free Full Text]

8. Norwitz ER. Multiple pregnancy: Trends past, present, and future. Infertil Reprod Med Clin North Amer 1998;9: 351–69.

9. Seifer DB, Dodson WC, Reindollar RH, Santoro NF. Strategies to prevent multiple pregnancy during infertility treatment. Contemp Obstet Gynecol 2001;46:57–83.

10. National Center for Health Statistics. Trends in twin and triplet births: 1980–97. Natl Vital Stat Rep 1999;42: 1099–120.

11. Drane JW. Imputing nonresponses to mail-back questionnaires. Am J Epidemiol 1991;134:908–12.[Abstract/Free Full Text]

12. Sandlow JI, Kreder KJ. A change in practice: Current urologic practice in response to reports concerning vasectomy and prostate cancer. Fertil Steril 1996;66:281–4.[Medline]

13. Evans MI, Wapner R, Carpenter R, Goldberg J, Timor-Tritsch IE, Ayoub MA, et al. International collaboration on multifetal pregnancy reduction (MFPR): Dramatically improved outcomes with increased experience. Am J Obstet Gynecol 1999;180(Suppl. 1S-II):28S.

14. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, et al. Efficacy of super-ovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999;340:177–83.[Abstract/Free Full Text]

15. Ragni G, Maggioni P, Guermandi E, Testa A, Baroni E, Colombo M, et al. Efficacy of double intrauterine insemination in controlled ovarian hyperstimulation cycles. Fertil Steril 1999;72:619–22.[Medline]

16. Oleski DM, Tur-Kaspa I, Vidali A, Karande V, Gleicher N. Reducing the risk of high order multiple pregnancy after ovarian stimulation with gonadotropins. N Engl J Med 2000;343:2–7.[Abstract/Free Full Text]

17. American Society of Reproductive Medicine. Multiple pregnancy associated with infertility therapy. ASRM Practice Committee Report. Birmingham, Alabama: 2000.

18. Assisted reproductive technology success rates. National summary and fertility clinic reports. Atlanta, Georgia: Centers for Disease Control and Prevention; 2000:91.

19. In vitro fertilization/embryo transfer in the United States: 1985 and 1986 results from the National IVF/ET Registry. Fertil Steril 1988;49:212–5.[Medline]

20. American Society of Reproductive Medicine. Guidelines on number of embryos transferred. ASRM Practice Committee Report. 1999.

21. Gardner DK, Vella P, Lane M, Wagley L, Schlenker T, Schoolcraft WB. Culture and transfer of human blastocysts increases implantation rates and reduces the need for multiple embryo transfers. Fertil Steril 1998;69:84–8.[Medline]

22. Milki AA, Fisch JD, Behr B. Two-blastocyst transfer has similar pregnancy rates and a decreased multiple gestation rate compared with three-blastocyst transfer. Fertil Steril 1999;72:225–8.[Medline]

23. Marek D, Langley M, Gardner DK, Confer N, Doody KM, Doody KJ. Introduction of blastocyst culture and transfer for all patients in an in vitro fertilization program. Fertil Steril 1999;72:1035–40.[Medline]

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This Article Abstract Full Text (PDF) Correction (v99,p1136) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hock, D. L. Articles by Ananth, C. V. Search for Related Content PubMed PubMed Citation Articles by Hock, D. L. Articles by Ananth, C. V.