1 Department of Obstetrics and Gynecology, University Medical School, and 2 Institute of Cancer Epidemiology and Institute of Social Medicine, Medical University of Lübeck, Lübeck, Germany
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: Doppler ultrasonography/high risk pregnancy/ICSI/pregnancy outcome/uterine and uteroplacental blood flow
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The use of Doppler studies of the uterine arteries in the prediction of adverse pregnancy outcome in singleton pregnancies as a result of disturbed uteroplacental development has been evaluated by several investigators (Bewley et al., 1991; Valensise et al., 1993
; Harrington et al., 1996
; Benedetto et al., 1998
). With the introduction of colour Doppler imaging and the definition of an early diastolic notch as an abnormal waveform, the predictive value of uterine Doppler examination has been further improved (Bower et al., 1993
; North et al., 1994
; Kurdi et al., 1998
). The clinical benefit is particularly evident in a selected high risk population (Zimmermann et al., 1997
). Because resistance indices from both uterine arteries in twin pregnancies are lower compared with singletons, only a limited use of this measurement has been reported in the prediction of hypertensive disorders in twin pregnancies (Rizzo et al., 1993
).
As pregnancies resulting from assisted reproduction are considered to present obstetrical risk cases, the aim of our study was to assess the efficacy of uterine artery Doppler ultrasound in the prediction of maternal and fetal complications in singleton and twin ICSI pregnancies compared with a matched control group. Furthermore, possible differences concerning blood flow parameters between spontaneously conceived pregnancies and those after ICSI should be evaluated. To the best of our knowledge there is no information available in the literature on uterine Doppler measurements in pregnancies conceived following ICSI treatment.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The control group data were collected from our computerized perinatal database. Patients were matched for maternal age, parity and plurality. Only patients with singletons and twins attending for routine examination were included. The first suitable patient was selected by the first letter of surname. Matched twin pregnancies were according to ultrasonography diamniotic-dichorionic.
Accurate Doppler measurements were obtained in all patients, using an Acuson 128 XP/10oB with a 4.0 and 5.0 MHz phased array sector scanner. Flow velocity waveforms of the right and left uterine artery were recorded at the crossing with the external iliac artery. The resistance index (RI) was calculated as a mean from both sides and the presence and absence of notching was noted. Threshold levels for abnormal flow parameters were used according to Bower et al.: (i) bilateral notch with mean RI >0.55; (ii) unilateral notch with mean RI >0.65; (iii) absence of notch with mean RI >0.70 (Bower et al., 1992). Because of the normally lower resistance indices in twin pregnancies (Rizzo et al., 1993
), only the presence or absence of notching was recorded in this subgroup. None of the patients received any prophylactic treatments such as low dose aspirin, based on the Doppler results.
Patients were considered as high risk by medical history if they had chronic hypertension, diabetes or adiposity (body mass index >27 kg/m2), if they were nullipara 35 years, or if they were multipara with a history of intrauterine growth retardation, pre-eclampsia, placental abruption or intrauterine fetal death.
Maternal and fetal outcomes were obtained from our perinatal database, birth protocols, neonatal records or by telephone interview with the obstetrician. Outcome variables included gestational age at delivery, prematurity, preterm premature rupture of membrane (PPROM), birth weight, birth weight discordance of >20% in twins, SGA, mode of delivery, development of pre-eclampsia or placental abruption. The following definitions have been used. Premature delivery: delivery before 37 weeks gestation, preterm premature rupture of membranes: rupture of membranes before 37 weeks gestation without labour, SGA: birth weight below the 10th centile for the German population, placental abruption: antepartum haemorrhage >28 weeks gestation with retroplacental clot (confirmed at delivery); pre-eclampsia: repeated blood pressure of 140/90 mmHg in combination with proteinuria
500 mg/day.
Outcome parameters of ICSI patients were analysed in comparison with the matched controls separately in singleton and twin pregnancies. Patients identified as high risk were compared with low risk patients of the same group. Statistics were done using a two-sided, heteroscedastic Student's t-test for quantitative variables. For qualitative variables we used contingency tables and 2- and Fisher's exact test. Relative risks with 95% confidence intervals (CI) were also calculated. P < 0.05 was considered significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Singletons
Patients characteristics are summarized in Tables I and II. The mean maternal age was 32.6 years in study group and 32.5 years in the controls. Of the ICSI patients, 84% were nullipara including 21% nullipara
35 years, compared with 83 and 20% in the control group respectively. According to medical risk factors and/or pathological Doppler results, 42% of women in the study group and 39% of the controls were considered as high risk. Karyotyping was performed in 26% in both groups. Although there was a tendency towards slightly higher Doppler indices in ICSI patients, these results were not statistically significant (Table II
). Pathological Doppler results were obtained in 24% of ICSI patients and 21% of controls (Table III).
|
|
|
ICSI patients with pathological Doppler findings had a relative risk of 2.5 (1.06.2) for delivering SGA and of not defined for developing pre-eclampsia. The corresponding numbers for controls were a relative risk of 3.8 (1.211.9) for SGA and 10.0 (2.934.8) for pre-eclampsia with pathological Doppler. On the other hand, risk was reduced towards the level of low risk pregnancies in ICSI and control patients with a positive medical history, if the Doppler measurements were normal. There were no correlations between pathological Doppler results and PPROM, premature delivery and the rate of Caesarean section (Table IIIa).
Twins
The study group consisted of 32 women with a mean age of 31.3 years and 69% of patients without further pre-existent medical risks or pathological Doppler results, compared with 31.4 years and 59% in the matched controls respectively (Table I). The rate of karyotyping was 31% in both groups. As expected, uterine artery RI were lower than in singleton pregnancies, in ICSI and control patients. No differences in Doppler parameters were found between ICSI and control group (Table II
).
Gestational age at delivery and birth weight were comparable in ICSI and control pregnancies, in low and high risk patients. The mean birth weight discordance was 12% in ICSI and 10% in controls, but there appeared to be a higher (22%) intra-pair birth weight difference (of >20%) in ICSI than in control twins (6%), although this failed to achieve significance. In ICSI twins, 17 pairs were same sex (53%) and 15 (47%) were opposite sex. Birth weight discordance >20% occurred in four twin pairs of same sex and three twin pairs of opposite sex. For the control group, 24 pairs were of same sex (75%) and 8 (25%) of opposite sex. Birth weight discordance >20% was observed in one case of same and 1 case of opposite sex. The difference of sex ratios in the two groups was not statistically significant. Pregnancy complications related to multiple gestation were PPROM in 19% and premature delivery in 59%, similar to the controls (13 and 50.0%). The prematurity is also reflected by the high Caesarean section rate of 78 and 66% (Table IIb).
Abnormal Doppler results were associated with 50% SGA in ICSI and 38% in control patients, compared with 8 and 17% in patients without additional risks. The relative risk of delivering an SGA baby was 4.3 (1.512.6, 95% CI; P < 0.03) in ICSI patients and 2.1 (0.76.8, 95% CI; ns) in control patients with pathological Doppler, but was reduced in patients with a positive medical history if Doppler findings were normal. Aside from one pair of ICSI twins who were both SGA, in the remaining cases only one fetus was affected. No correlation was found to PPROM, prematurity and the Caesarean section rate (Table IIIb).
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Pre-eclampsia is known to be more frequent in multiple pregnancies and nulliparous women with relative risks of 2.63.5 and 4.0 respectively (Douglas and Redman 1994; Coonrod et al., 1995
; Sibai et al., 2000
). It has also been claimed that the incidence of hypertension requiring hospitalization significantly increases in IVF pregnancies compared with controls (Tan et al., 1992
). However, in our series there were no differences between pregnancies following ICSI when compared with the control population, either in singletons or in twins. The even lower incidence of pre-eclampsia in our twin groups could be related to a younger maternal age, a higher previous parity, a higher proportion of low risk patients and the small numbers of twin pregnancies. In one of our previous publications in a similar, but not identical, cohort of pregnant patients following ICSI, the rate was 6.0% in singletons (10/168) and 14.3% (5/35) in twins (Ludwig et al., 1999
). In a study by Wennerholm et al., the reported incidence of pre-eclampsia in ICSI patients was 6.8% compared with 2.7% in the general Swedish population, related to higher numbers of maternal risk factors in women conceived after ICSI. In this study, better obstetric results with ICSI compared with standard IVF were achieved. The authors suggested that couples requiring ICSI treatment have mainly a male factor pathology, whilst the women are without major health problems (Wennerholm et al., 1996
). However, 42% of our ICSI patients with singletons and 31% of those with twins were considered as high risk.
The group of Aytoz reported a rate of 8.99.2% in singletons and 53.2-58.0% in twins for preterm delivery after an ICSI treatment. There was no significant difference when those pregnancies with and without invasive prenatal diagnosis were compared (Aytoz et al., 1998b). This is consistent with our own data with 11 and 59% prematurity in singletons and twins respectively.
Previous reports described the frequency of SGA after ICSI with 4.59% in singletons and 7.514% in twins (Wennerholm et al., 1996; Wisanto et al., 1996
). In our series the corresponding numbers were 14% in singletons and 19% in twins.
Until now only one publication dealt with the use of Doppler sonography in conjunction with an ICSI treatment. Here, however, the Doppler was used to assess uterine receptivity in ICSI cycles before embryo transfer (Aytoz et al., 1997). To our knowledge, data regarding Doppler measurements in predicting the pregnancy outcome following ICSI have not yet been reported. The uterine Doppler parameters (mean RI, maximum PI) of ICSI patients were similar to those of controls. Persistent unilateral/bilateral notching in the main uterine artery at 2024 weeks gestation or mean RI >0.70 were the criteria for the definition of abnormal Doppler waveforms in singleton pregnancies in our study. According to these criteria, 24% of the ICSI and 21% of the control patients had pathological Doppler results. This compares well with another study reporting 23% abnormal Doppler findings at 1921 weeks gestation in a cohort of 1022 unselected women (Kurdi et al., 1998
). The percentage of women with an early diastolic notching in the flow velocity waveforms of the uterine arteries is greater in primiparas (11.9%) than in multiparas (6.3%) (Harrington et al., 1996
). A higher incidence (17.6%) of bilateral notching has been reported in patients with a positive medical history, when compared with low risk patients (8%) (Zimmermann et al., 1997
). In our study, however, the rate of pathological Doppler findings in patients with and without risks by medical history was similar.
The most recent colour Doppler studies support the proposal that women with normal uterine artery waveforms have a reduced risk of developing antenatal complications (Harrington et al., 1996; Benedetto et al., 1998
; Kurdi et al., 1998
). In our study, especially in those patients with a positive medical history, a normal Doppler examination lowered the risk of adverse pregnancy outcome considerably. On the other hand, patients with abnormal Doppler results in combination with medical risk factors had the highest incidence of pre-eclampsia (43%), SGA (29%), or placental abruption (14%). These results are confirmed by another study (Zimmermann et al., 1997
), which reported an additional 37-fold increased risk in those women with a positive medical history, if they had pathologic Doppler results.
It has been suggested that advanced maternal age and a lower previous parity might contribute to an increased incidence of maternal and fetal complications. However, recent studies on the pregnancy outcome failed to demonstrate this association in pregnancies after spontaneous conception as well as in pregnancies resulting from assisted reproduction (Tanbo et al., 1995; van den Elzen et al., 1995
; Aytoz et al., 1998a
).
As resistance index values of the uterine arteries in twin pregnancies are normally lower than in singletons, only a limited role for Doppler in the prediction of hypertensive disorders has been suggested for twin gestation (Rizzo et al., 1993). As a result of the small number of patients in our twin groups, Doppler results for pre-eclampsia and placental abruption showed no significance. However, the risk of delivering an SGA baby was clearly reduced, if patients had no medical risk factors and normal Doppler results.
One potentially interesting finding from our study was the higher incidence of birth weight difference of 20%, found in twin pregnancies following ICSI (22%) compared with the control group (6%). However, perhaps resulting from the small numbers of twins, these results failed to reach statistical significance (P = 0.15). In addition, intertwin-discordance rate >25% has been previously reported in IVF twin pregnancies (22.9%) in comparison with spontaneously conceived twins (11.5%) (Koudstaal et al., 2000
). As discordant birth weight is higher for infants of opposite sex (Bernasko et al., 1997
), this could explain the higher rates in IVF and ICSI pregnancies.
In conclusion, Doppler examination of the uterine circulation at 1824 weeks of pregnancy and the evaluation of medical risk factors can identify a large proportion of the high risk population with subsequent development of maternal and fetal complications later in pregnancy. This risk is independent of the mode of conception, and the total rates of abnormal Doppler results were similar in ICSI and control patients. Therefore, all patients in this high risk category (42% of ICSI and 39% of control pregnancies) might benefit from intensified antenatal care.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aytoz, A., Camus, M., Tournaye, H. et al. (1998a) Outcome of pregnancies after intracytoplasmic sperm injection and the effect of sperm origin and quality on this outcome. Fertil. Steril., 70, 500505.[ISI][Medline]
Aytoz, A., De Catte, L., Camus, M. et al. (1998b) Obstetric outcome after prenatal diagnosis in pregnancies obtained after intracytoplasmic sperm injection. Hum. Reprod., 13, 29582961.
Benedetto, C., Valensise, H. and Marozio, L. (1998) A two-stage screening test for pregnancy-induced hypertension and preeclampsia. Obstet. Gynecol., 92, 10051111.
Bernasko, J., Lynch, L., Lapinski, R. et al. (1997) Twin pregnancies conceived by assisted reproduction techniques: maternal and neonatal outcomes. Obstet. Gynecol., 89, 368372,
Bewley, S., Cooper, D. and Campbell, S. (1991) Doppler investigation of uteroplacental blood flow resistance in the second trimester: A screening study for pre-eclampsia and intrauterine growth retardation. Br. J. Obstet. Gynaecol., 98, 871879.[ISI][Medline]
Bower, S., Vyas, S, Campbell, S. et al. (1992) Colour flow imaging of the uterine artery in pregnancy: normal ranges of impedance blood flow, mean velocity and volume flow. Ultrasound Obstet. Gynecol., 2, 2125.
Bower, S., Bewley, S. and Campbell, S. (1993) Improved prediction of preeclampsia by two stage screening of uterine arteries using the early diastolic notch and colour Doppler imaging. Obstet. Gynecol., 82, 7883.[Abstract]
Coonrod, D.V., Hickok, D.E., Zhu, K. et al. (1995) Risk factors for preeclampsia in twin pregnancies: a population based cohort study. Obstet. Gynecol., 85, 645650.
Dhont, M., De Sutter, P., Ruyssinck, G. et al. (1999) Perinatal outcome after assisted reproduction: a case-control study. Am. J. Obstet. Gynecol., 181, 688695.[ISI][Medline]
Douglas, K.A. and Redman, C.W. (1994) Eclampsia in the United Kingdom. Br. Med. J., 309, 13951400.
Doyle, P., Beral, V. and Maconochie, N. (1992) Preterm delivery, low birthweight and small-for-gestational-age in liveborn singleton babies resulting from in-vitro fertilisation. Hum. Reprod., 7, 425428.[Abstract]
Geipel, A., Gembruch, U., Ludwig, M. et al. (1999) `Genetic sonography' as the preferred option of prenatal diagnosis in patients with pregnancies following intracytoplasmic sperm injection. Hum Reprod., 14, 26292634.
Harrington, K., Cooper, D., Lees, C. et al. (1996) Doppler ultrasound of the uterine arteries: the importance of bilateral notching in the prediction of pre-eclampsia, placental abruption or delivery of a small-for-gestational-age baby. Ultrasound Obstet. Gynecol., 7, 182188.[ISI][Medline]
Koudstaal, J., Bruinse, H.W., Helmerhorst, F.M. et al. (2000) Obstetric outcome of twin pregnancies after in-vitro fertilisation: a matched control study in four Dutch University hospitals. Hum. Reprod., 15, 935940.
Kurdi, S., Campbell, S., Aquilina, J. et al. (1998) The role of colour Doppler imaging of the uterine arteries at 20 weeks' gestation in stratifying antenatal care. Ultrasound Obstet. Gynecol., 12, 339345.[ISI][Medline]
Ludwig, M., Geipel, A., Mennicke, K. et al. (1999) Intrazytoplasmatische Spermieninjektion ICSI (I): Verlauf von 310 Schwangerschaften, Ergebnisse der Pränataldiagnostik und Diskussion eines non-invasiven Konzepts zur Pränataldiagnostik. Geburtsh. Frauenheilk., 59, 387394.[ISI]
North, R.A., Ferrier, C., Long, D. et al. (1994) Uterine artery Doppler flow velocity waveform in the second trimester for the prediction of pre-eclampsia and fetal growth retardation. Obstet. Gynecol., 83, 378386.[Abstract]
Rizzo, G., Arduini, D. and Romanini, C. (1993) Uterine artery Doppler velocity waveforms in twin pregnancies. Obstet. Gynecol., 82, 978983.[Abstract]
Saunders, D.M., Mathews, M. and Lancaster, P.A. (1988) The Australian Register: current research and future role. A preliminary report. Ann. NY Acad. Sci., 451, 721.
Sibai, B.M., Hauth, J., Caritis, S. et al. (2000) Hypertensive disorders in twin versus singleton gestations. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am. J. Obstet. Gynecol., 182, 938942.[ISI][Medline]
Tan, S.L., Doyle, P., Campbell, S. et al. (1992) Obstetric outcome of in vitro fertilization pregnancies compared with normally conceived pregnancies. Am. J. Obstet. Gynecol., 167, 778784.[ISI][Medline]
Tanbo, T., Dale, P.O., Lunde, O. et al. (1995) Obstetric outcome in singleton pregnancies after assisted reproduction. Obstet. Gynecol., 86, 188192.
Van den Elzen, H.J., Cohen-Overbeck, T.E., Grobbee, D.E. et al. (1995) Early uterine artery Doppler velocimetry and the outcome of pregnancy in women aged 35 years and older. Ultrasound Obstet. Gynecol., 5, 328333.[ISI][Medline]
Valensise, H., Bezzeccheri, V., Rizzo, G. et al. (1993) Doppler velocimetry of the uterine artery as a screening test for gestational hypertension. Ultrasound Obstet. Gynecol., 3, 1822.[ISI][Medline]
Verlaenen, H., Cammu, H., Derde, M.P. et al. (1995) Singleton pregnancy after in vitro fertilisation: expectations and outcome. Obstet. Gynecol., 86, 906910.
Wennerholm, U.B., Bergh, C., Hamberger, L. et al. (1996) Obstetric and perinatal outcome of pregnancies following intracytoplasmic sperm injection. Hum. Reprod., 11, 11131119.[Abstract]
Wisanto, A., Bonduelle, M., Camus, M. et al. (1996) Obstetric outcome of 904 pregnancies after intracytoplasmic sperm injection. Hum. Reprod., 11 (Suppl. 4), 121129.[Abstract]
Zimmermann, P., Eiriö, V., Koskinen, J. et al. (1997) Doppler assessment of the uterine and uteroplacental circulation in the second trimester in pregnancies at high risk for pre-eclampsia and/or intrauterine growth retardation: comparison and correlation between different Doppler parameters. Ultrasound Obstet. Gynecol., 9, 330338.[ISI][Medline]
Submitted on November 1, 2000; accepted on March 9, 2001.