Uterine artery Doppler velocimetry and the outcome of pregnancies resulting from ICSI

A. Geipel1,3, M. Ludwig1, U. Germer1, A. Katalinic2, K. Diedrich1 and U. Gembruch1

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
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: An increased incidence of pregnancy complications following assisted reproduction has been reported. The use of uterine artery Doppler ultrasound may aid the prediction of such complications. METHODS: Doppler was performed at 18–24 weeks gestation in 114 singleton and 32 twin pregnancies after intracytoplasmic sperm injection (ICSI) and compared with a control group matched for age, parity and plurality. Outcome variables included gestational age at delivery, prematurity, preterm premature rupture of membrane (PPROM), birth weight, birth weight discordance of >20% in twins, small for gestational age (SGA), mode of delivery, development of pre-eclampsia and placental abruption. RESULTS: Compared with the controls, there were no significant differences concerning uterine Doppler parameters, pregnancy complications and the neonatal outcome, either in singleton or in twin pregnancies. According to Doppler results and/or risk factors by medical history, 42% of singleton ICSI and 39% of spontaneous singleton pregnancies were considered as high risk. In singletons, abnormal Doppler findings were associated with pre-eclampsia in 22% and SGA in 26% of ICSI patients, compared with 33 and 21% in controls; in contrast, 0 and 10% in ICSI and 3 and 6% in controls showed these complications but no risk factors respectively. No correlation was found between PPROM, prematurity, the rate of Caesarean section and pathological Doppler results. CONCLUSIONS: Uterine Doppler examination holds the potential to identify patients with an increased risk for developing pregnancy complications. According to our results, this risk is not elevated after ICSI treatment, therefore the decision of offering an intensified antenatal care should be based on the results of Doppler examination or risks by medical history rather than the mode of conception.

Key words: Doppler ultrasonography/high risk pregnancy/ICSI/pregnancy outcome/uterine and uteroplacental blood flow


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Previous studies on the obstetric outcome after assisted reproduction reported a higher incidence of pregnancy complications such as bleeding, hypertensive disorders, preterm delivery and small for gestational age (SGA) (Doyle et al., 1992Go; Tanbo et al., 1995Go). Although an increased incidence of most of these complications is associated with multiple gestation, this relationship has also been observed in singleton pregnancies established after IVF (Saunders et al., 1988Go; Dhont et al., 1999Go). Others, however, did not find an increased risk of pregnancy-induced hypertension in singleton IVF or intracytoplasmic sperm injection (ICSI) pregnancies (Verlaenen et al., 1995Go; Wisanto et al., 1996Go). Risk factors such as nulliparity and advanced maternal age, which are frequent in this population, are presumed to contribute to maternal and fetal complications.

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., 1991Go; Valensise et al., 1993Go; Harrington et al., 1996Go; Benedetto et al., 1998Go). 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., 1993Go; North et al., 1994Go; Kurdi et al., 1998Go). The clinical benefit is particularly evident in a selected high risk population (Zimmermann et al., 1997Go). 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., 1993Go).

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
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study was done retrospectively from January 1995 to July 1999. A total of 114 singleton and 32 twin pregnancies, following ICSI treatment, including five singletons after epididymal and testicular sperm injection and three after frozen pronucleus transfer, were analysed. This cohort represented all ICSI patients with colour Doppler studies of the uterine arteries between 18 and 24 weeks gestation performed in the division of prenatal medicine as part of the targeted second trimester sonogram described previously (Geipel et al., 1999Go). Doppler studies were routinely performed in all patients attending for fetal anomaly screening. All fetuses with malformations or other indications (suspected abnormality, growth retardation) than screening were excluded from the study. All twin pregnancies in the ICSI as well as in the control group were diamniotic and dichorionic, confirmed by ultrasound examination between 5 and 8 weeks gestation.

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., 1992Go). Because of the normally lower resistance indices in twin pregnancies (Rizzo et al., 1993Go), 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 {chi}2- and Fisher's exact test. Relative risks with 95% confidence intervals (CI) were also calculated. P < 0.05 was considered significant.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 114 singleton and 32 twin pregnancies after ICSI were matched to 114 singletons and 32 pairs of twins after spontaneous conception as a control.

Singletons
Patients characteristics are summarized in Tables I and IIGoGo. 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 IIGo). Pathological Doppler results were obtained in 24% of ICSI patients and 21% of controls (Table III).


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Table I. Patients characteristics
 

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Table II. Maternal age, parity, Doppler ultrasound values and birth data of singletons and twins born after ICSI or spontaneous conception. Data are shown as percentages or mean ± SD
 
Obstetric data are summarized in Tables II and GoIII. None of the observed differences in Table III a between ICSI and controls as well as subgroups reached statistical significance. The mean birth weight was 3195 ± 697 g for the study group and 3372 ± 572 g for the controls, with a mean gestational age at delivery of 39.1 ± 2.8 versus 39.7 ± 2.3 weeks. The slight difference in birth weight corresponds well with the difference in gestational age. There was a high overall Caesarean section rate of 35 and 32%, influenced by factors such as maternal age, primiparity, and patients anxiety. The highest rate was found in patients with a positive medical history rather than in those with pathological Doppler results. There was a tendency towards slightly higher numbers of SGA fetuses (14 versus 9%) in ICSI pregnancies. No significant differences in the frequencies of PPROM, pre-eclampsia, placental abruption and preterm delivery were observed between both groups (Table IIIaGo).


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Table IIIa. Correlation between pregnancy risk, Doppler ultrasound abnormalities and occurrence of pregnancy complications: singletons
 
In both study and control patients, the frequency of SGA and pre-eclampsia were strongly influenced by pathological Doppler results rather than medical risk factors. Despite a comparable gestational age at delivery, there was a trend towards lower birth weights between low and high risk pregnancies. Partial or total placental abruption occurred only in high risk patients. In the ICSI group of women with abnormal Doppler findings, 22% developed pre-eclampsia and 26% delivered an SGA child, in contrast to 0 and 10% in low risk patients (P < 0.001, P = 0.04). Similar findings were obtained in the control group: 33% pre-eclampsia and 21% SGA in patients with pathological Doppler results, but only 3 and 6% in low risk patients (P < 0.01, P < 0.001).

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 IIIaGo).

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 IGo). 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 IIGo).

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 (1.5–12.6, 95% CI; P < 0.03) in ICSI patients and 2.1 (0.7–6.8, 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 IIIbGo).


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Table IIIb. Correlation between pregnancy risk, Doppler ultrasound abnormalities and occurrence of pregnancy complications: twins
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The numbers of publications regarding pregnancy complications after ICSI are limited. We did not observe any major differences for all outcome measures between ICSI and control patients, either in singletons or in twins. However, the numbers of patients included were small. Therefore, the calculation can only give a trend of observations. Wisanto et al. reported on 904 consecutive pregnancies after ICSI and found complications mainly dependent on the multiplicity of pregnancy (Wisanto et al., 1996Go). They described a 0.86 and 1.06% stillbirth rate in singletons and twins respectively (Wisanto et al., 1996Go). This rate was confirmed in the range of 0.4–3.1% in a larger cohort of patients by the same group (Aytoz et al., 1998aGo). Presumably, because patients with indications other than just screening were excluded from the study, and because of the small sample size, no cases of intrauterine fetal death occurred in our series. In the same year, however, higher rates of preterm delivery, low birth weight and early perinatal mortality after ICSI than after natural conception were reported (Aytoz et al., 1998bGo). They analysed their data from 1599 pregnancies also with respect to the source of the spermatozoa used for microinjection. Interestingly, the rate of children with perinatal death (P < 0.001) as well as the rate of infants with low birth weight (<2.500 g) (P = 0.001) were significantly higher in the group of pregnancies established following ICSI with epididymal spermatozoa (n = 79) compared with those with ejaculated sperms (n = 1427). Furthermore, the rate of intrauterine fetal death was significantly higher in those pregnancies established with spermatozoa with two or more pathologies (<5x106/ml, <20% progressive motility, <4% normal morphology) compared with those with only one or no pathologies (P = 0.02 and P < 0.02) (Aytoz et al., 1998aGo). We were unable to conduct a similar analysis due to the small numbers (n = 5) of pregnancies following microinjection with epididymal or testicular spermatozoa in our cohort.

Pre-eclampsia is known to be more frequent in multiple pregnancies and nulliparous women with relative risks of 2.6–3.5 and 4.0 respectively (Douglas and Redman 1994Go; Coonrod et al., 1995Go; Sibai et al., 2000Go). It has also been claimed that the incidence of hypertension requiring hospitalization significantly increases in IVF pregnancies compared with controls (Tan et al., 1992Go). 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., 1999Go). 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., 1996Go). 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 8.9–9.2% 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., 1998bGo). 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 4.5–9% in singletons and 7.5–14% in twins (Wennerholm et al., 1996Go; Wisanto et al., 1996Go). 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., 1997Go). 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 20–24 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 19–21 weeks gestation in a cohort of 1022 unselected women (Kurdi et al., 1998Go). 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., 1996Go). 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., 1997Go). 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., 1996Go; Benedetto et al., 1998Go; Kurdi et al., 1998Go). 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., 1997Go), which reported an additional 3–7-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., 1995Go; van den Elzen et al., 1995Go; Aytoz et al., 1998aGo).

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., 1993Go). 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., 2000Go). As discordant birth weight is higher for infants of opposite sex (Bernasko et al., 1997Go), this could explain the higher rates in IVF and ICSI pregnancies.

In conclusion, Doppler examination of the uterine circulation at 18–24 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
 
3 To whom correspondence should be addressed at: Division of Prenatal Medicine, Medical University of Lübeck,Ratzeburger Allee 233, D-23538 Lübeck, Germany. E-mail: annegeipel{at}hotmail.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on November 1, 2000; accepted on March 9, 2001.