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Intrafollicular hemodynamics before the administration of human chorionic gonadotropin in women at risk of the ovarian hyperstimulation syndrome
FERTILITY AND STERILITY Copyright
1996 American Society for Reproductive Medicine
Vol. 65, No.4, April 1996
Printed on acid·free paper in U. S. A.
Intrafollicular hemodynamics before the administration of human chorionic gonadotropin in women at risk of the ovarian hyperstimulation syndrome
Olufunso A. Oyesanya, M.D.* John R. Parsons, M.D. William P. Collins, D.Sc. Stuart Campbell, M.D. Academic Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry, London, United Kingdom
Objective: To test the hypothesis that alteration of intrafollicular hemodynamics precedes the ovarian hyperstimulation syndrome (ORSS). Design: A prospective study. Setting: The IVF unit and the Doppler imaging laboratory of King's College Rospital, London. Patients: Twenty-four women undergoing IVF and considered to have an exaggerated response to ovarian stimulation and hence at risk of ORSS. Interventions: Transvaginal Doppler imaging ofthe intrafollicular blood flow was performed before hCG administration to determine the indexes of intrafollicular hemodynamics. Main Outcome Measures: Moderate or severe ORSS. Results: There was no statistically significant difference in mean age (32.63 ±: 1.77 versus 31.48 ±: 3.87), duration of infertility (6.00 ±: 2.19 versus 5.29 ±: 2.73), maximum peak systolic velocity (0.25 ±: 0.16 versus 0.26 ±: 0.21 m/s), mean of six maximal peak systolic velocity (0.15 ±: 0.04 versus 0.21 ±: 0.10), minimum pulsatility index (0.76 ±: 0.26 versus 0.59 ±: 0.23), mean of six minimal pulsatility indexes (0.89 ±: 0.30 versus 0.79 ±: 0.14), minimum resistance index (0.47 ±: 0.06 versus 0.41 ±: 0.10), and mean of six minimal resistance indexes (0.56 ±: 0.05 versus 0.53 ±: 0.06) of intrafollicular blood flow between the women who developed moderate or severe ORSS and matched controls. Conclusion: Measurement of intrafollicular hemodynamics before hCG administration does not predict the development of the ORSS. Fertil Steril 1996; 65:874-6 Key Words: Doppler, ORSS, prediction, pulsatility index, resistance index, velocity, hemodynamics, vascular permeability, IVF, superovulation
The exact pathogenesis ofthe ovarian hyperstimulation syndrome (OHSS) remains unknown. However, it generally is agreed that increased capillary permeability occurs and contributes to the syndrome (1). Alteration of intravascular hemodynamics is known to affect capillary permeability (2). We therefore hypothesized that an alteration of intrafollicular hemodynamics precedes OHSS and therefore its detection with Doppler imaging before hCG administration may be useful in predicting the syndrome
Received April 24, 1995; revised and accepted August 30, 1995. * Reprint request: Olufunso A. Oyesanya, M.D., Academic Department of Obstetrics and Gynaecology, King's College Hospital, Denmark Hill, London SE5:8RX, United Kingdom.
874
Oyesanya et al. Communications-in-brief
before hCG administration for IVF. We are not aware of any previous study of intrafollicular hemodynamics before the administration of hCG in women at risk of OHSS. MATERIALS AND METHODS
Approval of the local research ethics committee was obtained before starting the study. All volunteers to the study gave prior informed consent. Our IVF protocol has been described in detail elsewhere (3). During the study period, women with two ovaries undergoing IVF and considered to have an exaggerated response to stimulation (>20 follicles in total) were offered Doppler ultrasound imaging. Before the administration ofhCG, transvaginal Doppler ulFertility and Sterility
Table 1 Hemodynamic Parameters, Clinical Relevance, and Methods Parameter
Clinical relevance
How measured
Maximum peak systolic velocity (m/s) Mean of six maximal peak systolic velocities (m/s) Minimum pulsatility index Mean of six minimal pulsatility indexes (PI) Minimum resistance index Mean of six minimal resistance indexes (RI)
Maximum blood flow during peak systole
Peak systolic frequency shift
Mean blood flow during peak systole Minimum impedance to blood flow Mean minimal impedance Minimum resistance to blood flow Mean minimal resistance
Mean of six peak frequency shifts A - Bfmean PIl + PI2 + PI3 ± PI4 + PI5 ± PI6f6* A - BfA RIl + RI2 + RI3 + RI4 + RI5 + RI6f6*
* PI, pulsatility index; RI, resistance index.
trasound imaging was performed using a 5-MHz probe (Acuson EV519; Acuson Ltd., Uxbridge, United Kingdom) and a computed sonographic imaging system (Acuson 128XP10; Acuson Ltd.). Three follicles demonstrating maximal pulsatile flow were sampled from each ovary, noting the maximum peak systolic velocity in meters per second (m/s), the mean of six maximal peak systolic velocities, minimum pulsatility index, mean of six minimal pulsatility indexes, minimum resistance index, and mean of six minimal resistance indexes. At the same time, the number and size of the follicles (mean diameter in mm) were noted. All the scans were performed by the same operator (O.A.O.). The intraobserver variability for all the measurements was < 10%. All the women had oocyte retrieval and ET by an experienced operator using the same methods as described previously (3). Ovarian hyperstimulation syndrome was graded using standard criteria as described previously (4). For the purpose of analysis, for each woman who was admitted for moderate or severe OHSS and did not conceive (group 1, n = 8 cases), we chose two women with similar number offollicles, age (within 5-year age group), and duration ofinfertility who had their hCG, oocyte retrieval, and ET during the same period and neither had developed OHSS nor conceived to act as controls (group 2; n = 16 controls). Continuous data were expressed as means ± SD and were assessed for normality by using Shapiro and Francia's W' test. Comparison was performed by using either Student's t-test or Mann Whitney test as appropriate. P < 0.05 was considered as an indication of a significant difference. RESULTS
The mean age (32.63 ± 1.77 versus 31.48 ± 3.87 years), duration of infertility (6.00 ± 2.19 versus 5.29 ± 2.73 years), number of follicles (37.37 ± 12.55 versus 32.90 ± 8.09 mm), and maximum follicular diameter (22.00 ± 0.01 versus 22.23 ± 2.00 mm) were similar in the two groups (P > 0.05; not significant [NS]). There was no statistically significant differVol. 65, No.4, April 1996
ence in the mean peak systolic velocity (0.25 ± 0.16 versus 0.26 ± 0.21 m/s), mean of six maximal peak systolic velocities (0.15 ± 0.04 versus 0.21 ± 0.10 m/s), mean minimal pulsatility index (0.76 ± 0.26 versus 0.59 ± 0.23 ), mean of six minimal pulsatility indexes (0.89 ± 0.30 versus 0.79 ± 0.14 m/s), mean minimal resistance index (0.47 ± 0.06 versus 0.41 ± 0.10), and mean of six minimal resistance indexes (0.56 ± 0.05 versus 0.53 ± 0.06) between the two groups (P > 0.05; NS) (Table 1). Thus, the velocity and measures of impedance to blood flow were similar in those who progressed to OHSS and those who did not. DISCUSSION
The occurrence ofincreased capillary permeability is central to the etiopathogenesis of OHSS (4). We therefore hypothesized that because intravascular hemodynamics are known to alter capillary permeability, any method that measures the indexes of hemodynamics could be used to predict OHSS. In view of the small number of cases of moderate-severe OHSS, we were keen to eliminate other possible confounding variables and therefore matched for number of follicles, age, indication and duration of infertility, and absence of pregnancy. We controlled for pregnancy because endogenous hCG production by the successfully implanted embryos occurs in pregnant women and contributes to the worsening of a primary and the development of a secondary OHSS (5) and would have introduced an additional confounding variable. One previous study has shown a dramatic increase in peak systolic velocities of intrafollicular blood flow around the time of the LH surge (6). We therefore expected such dramatic increase in peak systolic velocities to occur before hCG administration in women prone to OHSS. We chose three follicles with maximal flow velocities in each ovary as we felt it was the practical approach and such follicles would be representative of the ovaries to which they belong. It is possible, but we believe it is unlikely, that other follicles not sampled could contribute to OHSS. We were surprised that the Oyesanya et al. Communications-in-brief
875
peak systolic velocity, pulsatility index, and resistance index were similar in the two study groups. It is possible that there are other intraovarian factors that affect capillary permeability in women at risk ofOHSS (1). Further studies are required to identify such factors so that the pathogenesis of OHSS becomes clearer.
4.
REFERENCES
5.
1. Goldsman MP, Pedram A, Dominguez CE, Ciuffardi I, Levin E, Asch RH. Increased capillary permeability induced by human follicular fluid: a hypothesis for an ovarian origin of the hyperstimulation syndrome. Fertil Steril 1995;63:268-72. 2. Fadnes HO, Oian P. Transcapillary fluid balance and plasma
6.
876
Oyesanya et al.
Communications· in-brief
3.
volume regulation: a review. Obstet Gynecol Surv 1989;44: 769-73. Oyesanya OA, Teo SK, Quah E, Abdurazak N, Lee FY, Cheng WC. Pituitary down regulation prior to in-vitro fertilization and embryo transfer: a comparison between a single dose of Zoladex depot and multiple daily doses of Suprefact. Hum Reprod 1995; 10: 5:1042-4. Golan A, Ron-EI R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989;44:430-40. Dahl Lyons CA, Wheeler CA, Frishman GN, Hackett RJ, Seifer D B, Haning RV. Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors. Hum Reprod 1994;9:792-9. Campbell S, Bourne TH, Waterstone J, Reynolds KM, Crayford TJB, Jurkovic D. Transvaginal color blood flow imaging of the periovulatory follicle. Fertil Steril 1993;60:433-8.
Fertility and Sterility
1996 American Society for Reproductive Medicine
Vol. 65, No.4, April 1996
Printed on acid·free paper in U. S. A.
Intrafollicular hemodynamics before the administration of human chorionic gonadotropin in women at risk of the ovarian hyperstimulation syndrome
Olufunso A. Oyesanya, M.D.* John R. Parsons, M.D. William P. Collins, D.Sc. Stuart Campbell, M.D. Academic Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry, London, United Kingdom
Objective: To test the hypothesis that alteration of intrafollicular hemodynamics precedes the ovarian hyperstimulation syndrome (ORSS). Design: A prospective study. Setting: The IVF unit and the Doppler imaging laboratory of King's College Rospital, London. Patients: Twenty-four women undergoing IVF and considered to have an exaggerated response to ovarian stimulation and hence at risk of ORSS. Interventions: Transvaginal Doppler imaging ofthe intrafollicular blood flow was performed before hCG administration to determine the indexes of intrafollicular hemodynamics. Main Outcome Measures: Moderate or severe ORSS. Results: There was no statistically significant difference in mean age (32.63 ±: 1.77 versus 31.48 ±: 3.87), duration of infertility (6.00 ±: 2.19 versus 5.29 ±: 2.73), maximum peak systolic velocity (0.25 ±: 0.16 versus 0.26 ±: 0.21 m/s), mean of six maximal peak systolic velocity (0.15 ±: 0.04 versus 0.21 ±: 0.10), minimum pulsatility index (0.76 ±: 0.26 versus 0.59 ±: 0.23), mean of six minimal pulsatility indexes (0.89 ±: 0.30 versus 0.79 ±: 0.14), minimum resistance index (0.47 ±: 0.06 versus 0.41 ±: 0.10), and mean of six minimal resistance indexes (0.56 ±: 0.05 versus 0.53 ±: 0.06) of intrafollicular blood flow between the women who developed moderate or severe ORSS and matched controls. Conclusion: Measurement of intrafollicular hemodynamics before hCG administration does not predict the development of the ORSS. Fertil Steril 1996; 65:874-6 Key Words: Doppler, ORSS, prediction, pulsatility index, resistance index, velocity, hemodynamics, vascular permeability, IVF, superovulation
The exact pathogenesis ofthe ovarian hyperstimulation syndrome (OHSS) remains unknown. However, it generally is agreed that increased capillary permeability occurs and contributes to the syndrome (1). Alteration of intravascular hemodynamics is known to affect capillary permeability (2). We therefore hypothesized that an alteration of intrafollicular hemodynamics precedes OHSS and therefore its detection with Doppler imaging before hCG administration may be useful in predicting the syndrome
Received April 24, 1995; revised and accepted August 30, 1995. * Reprint request: Olufunso A. Oyesanya, M.D., Academic Department of Obstetrics and Gynaecology, King's College Hospital, Denmark Hill, London SE5:8RX, United Kingdom.
874
Oyesanya et al. Communications-in-brief
before hCG administration for IVF. We are not aware of any previous study of intrafollicular hemodynamics before the administration of hCG in women at risk of OHSS. MATERIALS AND METHODS
Approval of the local research ethics committee was obtained before starting the study. All volunteers to the study gave prior informed consent. Our IVF protocol has been described in detail elsewhere (3). During the study period, women with two ovaries undergoing IVF and considered to have an exaggerated response to stimulation (>20 follicles in total) were offered Doppler ultrasound imaging. Before the administration ofhCG, transvaginal Doppler ulFertility and Sterility
Table 1 Hemodynamic Parameters, Clinical Relevance, and Methods Parameter
Clinical relevance
How measured
Maximum peak systolic velocity (m/s) Mean of six maximal peak systolic velocities (m/s) Minimum pulsatility index Mean of six minimal pulsatility indexes (PI) Minimum resistance index Mean of six minimal resistance indexes (RI)
Maximum blood flow during peak systole
Peak systolic frequency shift
Mean blood flow during peak systole Minimum impedance to blood flow Mean minimal impedance Minimum resistance to blood flow Mean minimal resistance
Mean of six peak frequency shifts A - Bfmean PIl + PI2 + PI3 ± PI4 + PI5 ± PI6f6* A - BfA RIl + RI2 + RI3 + RI4 + RI5 + RI6f6*
* PI, pulsatility index; RI, resistance index.
trasound imaging was performed using a 5-MHz probe (Acuson EV519; Acuson Ltd., Uxbridge, United Kingdom) and a computed sonographic imaging system (Acuson 128XP10; Acuson Ltd.). Three follicles demonstrating maximal pulsatile flow were sampled from each ovary, noting the maximum peak systolic velocity in meters per second (m/s), the mean of six maximal peak systolic velocities, minimum pulsatility index, mean of six minimal pulsatility indexes, minimum resistance index, and mean of six minimal resistance indexes. At the same time, the number and size of the follicles (mean diameter in mm) were noted. All the scans were performed by the same operator (O.A.O.). The intraobserver variability for all the measurements was < 10%. All the women had oocyte retrieval and ET by an experienced operator using the same methods as described previously (3). Ovarian hyperstimulation syndrome was graded using standard criteria as described previously (4). For the purpose of analysis, for each woman who was admitted for moderate or severe OHSS and did not conceive (group 1, n = 8 cases), we chose two women with similar number offollicles, age (within 5-year age group), and duration ofinfertility who had their hCG, oocyte retrieval, and ET during the same period and neither had developed OHSS nor conceived to act as controls (group 2; n = 16 controls). Continuous data were expressed as means ± SD and were assessed for normality by using Shapiro and Francia's W' test. Comparison was performed by using either Student's t-test or Mann Whitney test as appropriate. P < 0.05 was considered as an indication of a significant difference. RESULTS
The mean age (32.63 ± 1.77 versus 31.48 ± 3.87 years), duration of infertility (6.00 ± 2.19 versus 5.29 ± 2.73 years), number of follicles (37.37 ± 12.55 versus 32.90 ± 8.09 mm), and maximum follicular diameter (22.00 ± 0.01 versus 22.23 ± 2.00 mm) were similar in the two groups (P > 0.05; not significant [NS]). There was no statistically significant differVol. 65, No.4, April 1996
ence in the mean peak systolic velocity (0.25 ± 0.16 versus 0.26 ± 0.21 m/s), mean of six maximal peak systolic velocities (0.15 ± 0.04 versus 0.21 ± 0.10 m/s), mean minimal pulsatility index (0.76 ± 0.26 versus 0.59 ± 0.23 ), mean of six minimal pulsatility indexes (0.89 ± 0.30 versus 0.79 ± 0.14 m/s), mean minimal resistance index (0.47 ± 0.06 versus 0.41 ± 0.10), and mean of six minimal resistance indexes (0.56 ± 0.05 versus 0.53 ± 0.06) between the two groups (P > 0.05; NS) (Table 1). Thus, the velocity and measures of impedance to blood flow were similar in those who progressed to OHSS and those who did not. DISCUSSION
The occurrence ofincreased capillary permeability is central to the etiopathogenesis of OHSS (4). We therefore hypothesized that because intravascular hemodynamics are known to alter capillary permeability, any method that measures the indexes of hemodynamics could be used to predict OHSS. In view of the small number of cases of moderate-severe OHSS, we were keen to eliminate other possible confounding variables and therefore matched for number of follicles, age, indication and duration of infertility, and absence of pregnancy. We controlled for pregnancy because endogenous hCG production by the successfully implanted embryos occurs in pregnant women and contributes to the worsening of a primary and the development of a secondary OHSS (5) and would have introduced an additional confounding variable. One previous study has shown a dramatic increase in peak systolic velocities of intrafollicular blood flow around the time of the LH surge (6). We therefore expected such dramatic increase in peak systolic velocities to occur before hCG administration in women prone to OHSS. We chose three follicles with maximal flow velocities in each ovary as we felt it was the practical approach and such follicles would be representative of the ovaries to which they belong. It is possible, but we believe it is unlikely, that other follicles not sampled could contribute to OHSS. We were surprised that the Oyesanya et al. Communications-in-brief
875
peak systolic velocity, pulsatility index, and resistance index were similar in the two study groups. It is possible that there are other intraovarian factors that affect capillary permeability in women at risk ofOHSS (1). Further studies are required to identify such factors so that the pathogenesis of OHSS becomes clearer.
4.
REFERENCES
5.
1. Goldsman MP, Pedram A, Dominguez CE, Ciuffardi I, Levin E, Asch RH. Increased capillary permeability induced by human follicular fluid: a hypothesis for an ovarian origin of the hyperstimulation syndrome. Fertil Steril 1995;63:268-72. 2. Fadnes HO, Oian P. Transcapillary fluid balance and plasma
6.
876
Oyesanya et al.
Communications· in-brief
3.
volume regulation: a review. Obstet Gynecol Surv 1989;44: 769-73. Oyesanya OA, Teo SK, Quah E, Abdurazak N, Lee FY, Cheng WC. Pituitary down regulation prior to in-vitro fertilization and embryo transfer: a comparison between a single dose of Zoladex depot and multiple daily doses of Suprefact. Hum Reprod 1995; 10: 5:1042-4. Golan A, Ron-EI R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989;44:430-40. Dahl Lyons CA, Wheeler CA, Frishman GN, Hackett RJ, Seifer D B, Haning RV. Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors. Hum Reprod 1994;9:792-9. Campbell S, Bourne TH, Waterstone J, Reynolds KM, Crayford TJB, Jurkovic D. Transvaginal color blood flow imaging of the periovulatory follicle. Fertil Steril 1993;60:433-8.
Fertility and Sterility