Birth weight in pre-eclamptic and normotensive twin pregnancies: an analysis of discordance and growth restriction

Sergio Ferrazzani1, Annamaria Merola, Sara De Carolis, Brigida Carducci, Giancarlo Paradisi and Alessandro Caruso

Department of Obstetrics and Gynaecology, Catholic University, School of Medicine, 00168 Rome, Italy


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The aim of this study was to verify whether twin pregnancies complicated by pre-eclampsia were associated with a higher rate of inter-twin weight discordance or an increased prevalence of small for gestational age (SGA) neonates than in normotensive twin pregnancies. A 17 year retrospective study was undertaken by examining 76 twin pregnancies complicated by pre-eclampsia and comparing them with 400 normotensive twin pregnancies. The case notes were reviewed in reference to birth weight differences, birth order, pregnancy outcome and inter-twin birth weight discordance. Statistical analyses were performed with t-test, contingency tables, regression curves, rank sum test and non-parametric survival plots. Power analysis was also carried out. Pre-eclamptic twin pregnancies were delivered at similar weeks of gestation to normotensive. They resulted in a smaller size for the second twin the earlier the delivery week, while in normotensive twin pregnancies no significant difference occurred at any week. Twin pregnancies complicated by pre-eclampsia showed higher rates of SGA neonates among second twins than those with normal pressure. The >25% discordance was associated with lower gestational age at delivery in each group [mean (range) 33 weeks (27–38) versus 37 (29–41), P < 0.005 pre-eclampsia and 35 weeks (25–41) versus 38 (25–42), P < 0.001 normotensive]. In pre-eclampsia the concomitant occurrence of SGA second twin and the discordance >25% was associated with shorter gestation while the presence of SGA second twin alone was not.

Key words: birth weight discordance/growth restriction/pre-eclampsia/twin pregnancy


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
It is well known that singleton pregnancies complicated by pre-eclampsia are characterized more frequently by low birth weight and small for gestational age (SGA) neonates than normotensive pregnancies (Ananth et al., 1995Go). This increased prevalence of low birth weight has also been reported in twin pregnancies complicated by pre-eclampsia (McMullan et al., 1984Go; Long and Oats, 1987Go), although some authors did not find any difference in the rate of low birth weight compared with normotensive twin pregnancies (Campbell, 1995Go). Recent studies have shown that birth weight patterns in twin pregnancies should be analysed as inter-twin weight discordance (Blickstein and Lancet, 1988Go), rather than as absolute weight. In fact, in a twin pregnancy, the increase of weight discordance between the two twins is associated with a worsening of perinatal outcome (Blickstein and Lancet, 1988Go). This is probably a result of the higher rate of SGA neonates (O'Brien et al., 1986Go). Therefore, it could be argued that the co-existence of two conditions, such as pre-eclampsia and twin pregnancy, characterized by high rate of low birth weight, could determine an increased perinatal risk.

The present study was carried out to verify whether twin pregnancies complicated by pre-eclampsia are associated with: (i) negative fetal outcome in terms of low birth weight and preterm delivery; (ii) higher rate of inter-twin weight discordance; and (iii) higher prevalence of SGA compared with normotensive twin pregnancies.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A 17 year retrospective study of twin pregnancies complicated by pre-eclampsia in comparison with normotensive twin pregnancies was carried out at the Department of Obstetrics and Gynaecology at the Catholic University of Rome, covering the period January 1, 1980 to December 31, 1996. A total of 661 consecutive twin births were taken into consideration in a total of 47 664 deliveries. Among the twin pregnancies, 76 complicated by pre-eclampsia were studied and 400 normotensive pregnancies were considered as controls. The remaining 185 twin pregnancies were excluded due to the following: gestational hypertension (n = 135), major fetal malformations or aneuploidies (n = 16), delivery before 25 weeks gestation (n = 4), uncomplicated chronic hypertension (n = 6), renal disease (n = 2), proteinuria without hypertension (n = 7), incomplete information or uncertain gestational age (n = 4), HELLP (haemolytic anaemia, elevated liver enzymes, low platelet counts) syndrome without hypertension (n = 1) and twin–twin transfusion syndrome (n = 10). Gestational hypertension was defined as a diastolic blood pressure >=90 mmHg on two or more consecutive occasions, at 6 h apart, developing after 20 weeks of gestation in a previously normotensive patient. Pre-eclampsia was considered when gestational hypertension was associated with proteinuria. Chronic hypertension was hypertension documented before pregnancy or before 20 weeks of gestation. Proteinuria was defined as one urine collection with a total protein excretion >=300 mg/24 h or >1 g/l (or ++ with dipstick) in a random sample, without urinary infection. Blood pressure was taken with a standard mercury sphygmomanometer, using phases one and four of the Korotkoff sounds before delivery for systolic and diastolic blood pressure, respectively, and recording with the patient in a semi-recumbent position.

The study population was of ethnic uniformity due to the large predominance of white Italians (97%). During the time period covered by this study, no policy of special antenatal clinical care was enforced for twin gestations other than encouraging bed rest. Across all subjects, the indications for planning delivery were: severe pre-eclampsia according to ACOG (American College of Obstetricians and Gynecologists, 1986), presence of fetal distress as indicated by fetal heart rate recording, oligo-anhydramnios, premature rupture of membranes, cholestasis in presence of a mature lecithin/sphingomyeline ratio, chorionamnionitis or any other general obstetric indication. The finding of intrauterine fetal discordance was not an indication for planned delivery if not associated with other signs of fetal distress. In case of intrauterine demise of one fetus, delivery was immediately planned after 27 weeks gestation, when placentation was monochorial, or as soon as lecithin/sphingomyeline ratio was more than 2 when the placentation was dichorial. Corticosteroids were used to accelerate fetal lung maturation in both pre-eclamptic and normotensive twin pregnancies.

For the purpose of data analysis, information was extracted from the records and entered into a personal computer database. Information included aspects of prenatal care, previous medical history, complications, intrapartum care, delivery, fetal outcome and post-partum course. Data entries were then accumulated and organized in tabular form on a spreadsheet database. Case notes on the twins were reviewed with reference to birth weight differences, birth order and sex combination. In each case, the membrane separating the amniotic sacs had been examined to determine whether it was monochorionic or dichorionic. In the case of same sex twins and fused placentae, the membranes separating the amniotic sacs were microscopically examined by our pathologists to exclude the presence of chorionic tissue. Although examination of the placentae and membranes is not the most accurate way to diagnose specific twin type, the margin of error was considered negligible and other methods were not used. Where clinical and ultrasound evidence of twin–twin transfusion syndrome was available, a difference in haemoglobin concentration of 5 g/dl at birth was considered as corroborative when the placental type was monochorionic.

Eighty-nine per cent of all pregnancies during the study period under consideration were evaluated with routine ultrasound in the early second trimester. No correction was made when significant differences (more than 7 days) were not evident in comparing gestational age between ultrasound and last menstrual period. A case was excluded from analysis in the absence of ultrasound or when this was only performed near delivery with uncertain information on gestational age.

SGA was diagnosed as a birth weight lower than the 10th percentile according to either a national standard curve for singleton births (Gagliardi et al., 1975Go) or a recently elaborated standard curve for twin births from white population (Cohen et al., 1997Go).

Inter-twin birth weight difference was reported as weight discordance. Twin A was defined as first born and twin B as second born. The absolute weight discordance (AWD) between two twins was defined as heavier twin minus lighter twin and expressed in grams. The percentage weight discordance (PWD) was defined as (heavier twin – lighter twin)x100/(the heavier of the two) and expressed as a percentage. Signed percentage weight discordance (SPWD) was defined as (twin A – twin B)x100/(the heavier of the two twins) and expressed as signed percentage. The latter, unlike other measures of weight discordance, indicates which twin is heavier according to delivery order. The twin B/twin A SGA rate ratio was calculated to allow a direct comparison of frequencies between the two groups of twin pregnancies.

Statistical analysis included the Student's t-test for comparison of averages, the Wilcoxon rank sum test for comparison of medians when the distribution of the data was not normal and the {chi}2 or Fisher's exact test when appropriate for comparison of frequencies. P values < 0.05 (two-tailed) were considered significant. A power analysis was performed for statistical inference. The value reported in the tables represents the power of the statistical test used to detect the observed difference between two sample mean values or frequencies. This value is derived from assessing {alpha} = 0.05 and a sample size of 76 when the t-test is used (Glanz, 1987Go) or a 5.3 ratio (400/76) when the {chi}2 is applied (Marascuilo and McSweeney, 1977Go).

Power determination in regression analysis was obtained according to Cohen (Cohen, 1977Go) by using the Fisher z transformation for the critical value of r and for sample r. Survival statistics and plots were obtained by using the Kaplan–Meier non-parametric method and the P value was obtained through the log rank (Mantel–Cox). Multiple comparisons with Bonferroni correction were used to isolate differences between groups. All computations were performed on an Apple Macintosh Performa 6400/200 with appropriate software (Microsoft Excel, Abacus StatView).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Table IGo shows some main clinical characteristics and pregnancy outcomes in the two groups. No significant differences regarding height, weight before pregnancy or maternal age were observed. The rate of nulliparas was 19% higher in pre-eclamptic twin pregnancies as compared to normotensive. Systolic and diastolic blood pressures were higher in pre-eclamptic twin pregnancies, as expected. Delivery week rate of premature delivery (under 37 weeks) and rate of low birth weight neonates were similar in both groups. The Caesarean section rate was higher in pre-eclamptic pregnancies, as expected. Twin pre-eclamptic women had a higher prevalence of SGA neonates. Stillbirth prevalence showed no significant difference between pre-eclamptic and normotensive twin pregnancies. In pre-eclamptic twin pregnancies, stillbirth involved both twins in two cases, twin A in one case and twin B in two cases. In normotensive twin pregnancies stillbirth occurred in both twins in two cases, twin A in five cases and twin B in 11 cases. The involvement rate of twin B was double that of twin A in each group.


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Table I. Main maternal clinical features and pregnancy outcome in twin pregnancies
 
Table IIGo shows some detailed birth weight features in the two groups. No significant differences were observed between the two groups of pregnancies in regard to birth weight according to delivery order. However, a higher proportion of SGA neonates in pre-eclamptic pregnancies involved the second twin. This pattern remained significant even after exclusion of stillbirths (P = 0.03). There was also a significantly higher inter-twin absolute (1.3 times), percentage (1.4 times) and signed percentage weight discordance (3.7 times) in the pre-eclamptic group than in the normotensive. These findings were observed despite similarities in total birth weight and in the monochorionic placental type distribution between the two groups.


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Table II. Some birth weight features of twin pregnancies
 
Figure 1Go shows that in pre-eclamptic twin pregnancies there was a significant negative correlation between inter-twin signed percentage weight discordance and the week of delivery. This correlation was even more significant after exclusion of cases of intrauterine death (r = –0.33, P = 0.005, power = 0.80). On the other hand, the same regression line drawn in normotensive twin pregnancies was not significantly different from the equality line between twin pairs, even after excluding intrauterine deaths (r= -0.0004, P = 0.99, power = 0.97).



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Figure 1. Regression lines of signed percent birthweight discordance (SPWD) drawn against duration of gestation.

 
Figure 2Go reports the cumulative survival plots for the gestational duration related to four degrees of percentage weight discordance (>25%, 25–>15%, 15–>10% and 10%). As shown, in both groups of twin pregnancies, the discordance >25% was associated with shorter gestational duration. This association was particularly evident in pre-eclamptic twin pregnancies where the survival function of the discordance >25% was significantly different from all the other functions. Conversely, in normotensive twin pregnancies the survival function of the discordance >25% was only different from discordance <=10%. The median (range) weeks of gestation at delivery in women with inter-twin weight discordance >25% when compared to those with discordance <=25% was 33 (27–38) versus 37 (29–41), P < 0.005 and 35 (25–41) versus 38 (25–42), P < 0.001, in pre-eclamptic and normotensive pregnancies respectively.



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Figure 2. Survival analysis. Cumulative plot for duration of gestation in relation to four arbitrary degrees of percent weight discordance (PWD). Only significant results are reported.

 
The distribution of the four degrees of discordance was not significantly different between the two groups (Table IIIGo).


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Table III. Distribution of the four degrees of discordance between pre-eclamptic and normotensive women
 
Figure 3Go shows percentage distribution of pregnancies with various combinations of SGA neonates according to the degree of inter-twin percentage weight discordance in both groups. Using both singleton and twin growth curves, the rate of pregnancies with SGA twin B rose as the degree of discordance increased, while the rate of pregnancies with both twins adequate for gestational age (AGA) declined as the degree of discordance increased (according to singleton growth curve: pre-eclamptic, {chi}2 20.1, P < 0.02; normotensive, {chi}2 98.9, P < 0.001; according to twin growth curve: pre-eclamptic, {chi}2 22.5, P < 0.01; normotensive, {chi}2 96.9, P < 0.001). On the other hand, in the two graphs plotted using singleton growth curve the degree of discordance appeared to have no effect on the rate of pregnancies with SGA twin A or with both SGA twins. In contrast, in the two graphs plotted using twin growth curve, the greater the degree of discordance, the higher was the rate of pregnancies with all the combinations of SGA.



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Figure 3. Percent distribution of various combinations of small for gestational age (SGA) neonates according to the degree of inter-twin percentage weight discordance in the two groups, according to singleton and twin growth curves. Twin A is defined as first born and twin B as second born.

 
Figure 4Go describes the twin B/twin A SGA rate ratio as a relative measure of the involvement of twin B over twin A. According to the singleton growth curve, in normotensive twin pregnancy, a clear involvement of twin B over twin A was reached with a degree of weight discordance of 25–>15%. In pre-eclamptic twin pregnancies, this involvement was already evident with a relatively low degree of weight discordance of 15–>10%. According to the twin growth curve, in either pre-eclamptic and normotensive twin pregnancies, a clear involvement of twin B over twin A was reached with a degree of discordance of 25–>15%. In both graphs, twin B was constantly more frequently involved than twin A in pre-eclamptic than in normotensive twin pregnancy.



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Figure 4. The histograms describe twin B/twin A small for gestational age (SGA) rate ratio as a relative measure of the involvement of twin B over twin A. Only significant results are reported.

 
Figure 5Go gives cumulative survival plots for gestational duration in pregnancies with various combinations of SGA neonates among twin pairs. With pre-eclampsia no significant differences were observed among the survival functions. In normotensive pregnancies with SGA in both twins delivery was significantly closer to term, with respect to that of pregnancies with AGA in both twins. This finding was present only when SGA was defined according to the singleton growth curve.



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Figure 5. Survival analysis. Cumulative plots for duration of gestation in presence of various combinations of small for gestational age (SGA) twin pairs according to singleton and twin growth curves. Only significant results are reported.

 
Figure 6Go shows survival plots for the gestational duration in relation to pregnancies with concomitance of both SGA twin B and discordance (according to the various degrees). Pre-eclamptic pregnancies with SGA twin B in the context of discordance >25% were significantly related to shorter gestational duration than pregnancies with AGA twin B. This association was more evident in pre-eclampsia when the definition of SGA was made according to twin growth curve. In normotensive twin pregnancies there was no significant difference among the survival functions.



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Figure 6. Survival analysis. Cumulative plot for duration of gestation related to pregnancies with the concomitance of both small for gestational age (SGA) twin B and discordance (according to the various degrees) according to singleton and twin growth curves. Only significant results are reported.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In the present study, twin pregnancies complicated by pre-eclampsia gave birth at similar weeks, having similar rates of low birth weight neonates and stillbirths as compared to the normotensive twin pregnancies. However, pre-eclamptic twin pregnancies were subject to a higher rate of SGA neonates. The use of individualized growth curves has shown that twins are capable of achieving a normal growth potential (Xu et al., 1985Go; Simon et al., 1989Go). Consistently, accelerated post-natal growth of low birth weight twins suggests that in-utero malnutrition is a result of limited maternal potential to nurture multiple fetuses (McKeown and Record, 1952Go; Naeye, 1964Go; Leveno et al., 1980Go). Given the equivocal consensus on whether to evaluate growth restriction in twins on the basis of singleton or twin standards, it was decided to use both singleton (Bronsteen et al., 1989Go; Nellson, 1989Go) and twin growth curves for the comparison of twin birth weight.

The higher rate of SGA neonates in pre-eclamptic twin pregnancies suggested more detailed analysis of the birth weight characteristics in each twin pregnancy. Despite a total birth weight difference of about 200 g between the two study groups (not significant), some significant differences were found in inter-twin weight discordance however expressed (whether as absolute or percent or signed percent). Like other studies (Taylor et al., 1998Go), in normotensive twin pregnancies no significant differences were observed in the birth weight within pairs at any week. While lack of significance could be ascribed to a type II error, it still indicates that if a mean size difference should exist, it would be negligible. In twin pregnancies with pre-eclampsia this difference became clear. It has previously been reported that early onset pre-eclampsia in singleton pregnancies was associated with higher frequency of SGA neonates (Ferrazzani et al., 1990Go). Similarly, in twin pregnancies it was observed that early onset pre-eclampsia was associated with a higher degree of percentage discordance as a consequence of lower size in second twins. It is important to note that in our sample the median time interval between the first observation of proteinuria and delivery was 3 days (range 0–25). So early onset pre-eclampsia was approximately coincident with early birth.

Observed from a different point of view, the findings argue that growth discordance higher than 25% was associated with lower gestational age at delivery in both pre-eclampsia and normotensive twin pregnancies. No other authors have observed this relationship between growth discordance and gestational age (Blickstein et al., 1987Go; Taylor et al., 1998Go), probably because they studied only normotensive twin pregnancies where this association is much less evident. Since this was a retrospective study, it was not possible to control for timing of delivery and factors that may have contributed to the decision to deliver preterm twins. All twin pregnancies during the study period, regardless of indication for delivery were considered. To a certain extent we were able to minimize some of these concerns by documenting a comparable gestational age distribution in both groups.

Twin pregnancies with more than 25% growth discordance were delivered (or had to be delivered) earlier. The low gestational age at delivery in the presence of severe percent weight discordance could be related to the high rate of SGA among second twins. This association was much more evident in pre-eclampsia than in normotensive twin pregnancies, probably because in women with pre-eclampsia there is an increased likelihood of the second twin being SGA. It is well known that in twin pregnancies, second twin outcome is more jeopardized than the first (Friedman et al., 1977Go; Essel and Opai-Tetteh, 1994Go). The findings of this study confirm this assertion by indicating that the rate of SGA and stillbirth increased in second twins in both groups. However, even if not in a significant manner, the stillbirth rate in pre-eclampsia was almost double that in normotensive twin pregnancies. It seems reasonable to consider this as relevant to the higher rate of SGA among second twins in pre-eclampsia.

The findings of this study highlight that when both twins are SGA without discordance, delivery is closer to term in normotensive pregnancy. On the other hand, when both twins are AGA without discordance, delivery is more distant from term. The paradox is only apparent and only evident when SGA is defined according to the singleton growth curve. In fact, it is well known that the birth weight of an uneventful twin pregnancy progressively diverges from singleton median birth weight as it approaches term. In other words, neonates born from an uncomplicated twin pregnancy at term are SGA when compared to singleton standards. When the week of delivery is earlier, birth weight may still be within normal limits for singleton standards. The reason for a premature delivery when both twins are AGA could simply be ascribed to premature labour, the most frequent complication in twin pregnancies. In pre-eclampsia there was no significant relationship between the occurrence of SGA neonates and duration of gestation, probably because the maternal indication for timing of delivery could have interfered with the natural evolution of pregnancy.

In conclusion, the rate of inter-twin birth weight discordance is similar between pre-eclamptic and normotensive pregnancies. In the presence of similar gestational weeks at delivery, pre-eclampsia shows a higher rate of SGA among second twins than in normotensive pregnancies. In both pre-eclamptic and normotensive twin pregnancies, earlier delivery weeks were related to birth weight discordance >25% or to the concomitant occurrence of SGA second twin and discordance >25%, but not to the presence of SGA second twin alone. These associations were more strongly evident in pre-eclampsia.

The term SGA, deriving from a statistical concept, does not distinguish normal and healthy fetuses that have a weight below the 10th percentile from those who are small because of intrauterine malnutrition. The `healthy SGA' could be defined as the neonate being constitutionally small with no deprivation of in-utero nutrients, and the `at-risk SGA' could be identified as the malnourished fetus that is small because of in-utero deprivation of nutrients and oxygen, as a consequence of placental insufficiency. In pre-eclampsia placental insufficiency is frequently observed and it can be associated with endothelial activation and damage (Myatt et al., 1997Go; Daniel et al., 1998Go). In the light of the findings by other authors (Blickstein and Lancet, 1988Go), indicating that the smallest discordant twin delivered at term has normal outcome, the data presented here suggest that also in twin pregnancies there are two types of SGA neonates: healthy (probably constitutional) and at risk (malnourished). In general, the `healthy SGA' neonate can be identified in twin pregnancies where one (generally the first presenting) or both twins are under the 10th percentile and pregnancy can end close to term. The `at-risk SGA' neonate is to be found prevalently among second twins when growth discordance is evident.

Prospective studies are needed to confirm the findings of this study.


    Notes
 
1 To whom correspondence should be addressed Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on May 17, 1999; accepted on September 27, 1999.





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