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Is gestational hypertension beneficial in twin pregnancies?
Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health journal homepage: www.elsevier.com/locate/preghy
Original Article
Is gestational hypertension beneficial in twin pregnancies? Sergio Ferrazzani a, Sascia Moresi a,⇑, Emma De Feo b, Valentina Anna Degennaro a, Silvia Salvi a, Stefania Boccia b, Antonio Lanzone a, Sara De Carolis a a b
Department of Obstetrics and Gynaecology, Catholic University of Sacred Heart, Rome, Italy Institute of Hygiene, Catholic University of Sacred Heart, Rome, Italy
a r t i c l e
i n f o
Article history: Received 15 November 2014 Accepted 27 January 2015 Available online xxxx Keywords: Gestational hypertension Twin pregnancies Birth weight Small for gestational age Inter-twin weight discordance
a b s t r a c t Objectives: Hypertensive disorders of pregnancy are commonly associated with impaired foetal growth. However, some studies observed that gestational hypertension in twin pregnancy could be beneficial for foetal growth. The aim of this study is to investigate the influence of gestational hypertension on neonatal birth weight among twin pregnancies. Study design: This is a retrospective study about the comparison of 196 hypertensive twin pregnancies to 912 normotensive ones, who gave birth in the teaching hospital ‘‘A. Gemelli’’ in Rome from 1980 to 2006. Main outcome measures: Birth weight, inter-twin weight discordance and rate of small for gestational age neonates in the first and second twin. Results: Birth weight, inter-twin weight discordance and rate of small for gestational age neonates were similar between the two groups. In the normotensive group, the discordance >25% was associated with lower gestational age at the delivery (p < 0.00001), data not observed in the hypertensive group. The rate of pregnancies with second twin small for gestational age rose while paralleling the degree of the discordance in both groups. Conclusion: Gestational hypertension in twin pregnancies, if compared to normotensive ones, is not detrimental for foetal growth. Ó 2015 International Society for the Study of Hypertension in Pregnancy Published by Elsevier B.V. All rights reserved.
Introduction Hypertensive disorders are considered among the most common disease in pregnancy, being the main cause of maternal, foetal and neonatal morbidity and mortality in developed countries. The incidence of hypertensive disorders in singleton pregnancies is around 3–5% in Italy, including 1% of preeclampsia [1]. However, the incidence of hypertensive disorders in twin pregnancies is much greater [2–6]. Recent data report that the incidence of gestational hypertension and preeclampsia is double (12.9%
⇑ Corresponding author at: Largo A. Gemelli 8, 00168 Rome, Italy. Tel.: +39 06 30156774; fax: +39 06 3051160. E-mail address: [email protected] (S. Moresi).
vs. 6.3%) and three times greater (12.7% vs. 4.9%) respectively, in twin pregnancies compared to singleton ones [7]. Furthermore, singleton and twin pregnancies complicated by preeclampsia are more frequently characterized by low birth weight and small for gestational age (SGA) neonates compared to normotensive pregnancies [2,8,9]. So far, few studies analyzed the effect of gestational hypertension not complicated by preeclampsia on neonatal outcomes among twin pregnancies. Already in 2000, Sibai et al. [2] demonstrated that twin pregnancies complicated by hypertension had a better outcome as compared with both preeclamptic and normotensive twin pregnancies. A more recent Canadian study [7] on 102,988 twin pregnancies compared to 5,523,797 singletons showed that gestational hypertension in twin pregnancies had
http://dx.doi.org/10.1016/j.preghy.2015.01.003 2210-7789/Ó 2015 International Society for the Study of Hypertension in Pregnancy Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
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S. Ferrazzani et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2015) xxx–xxx
overall better neonatal outcomes in terms of rate of preterm delivery, intra-uterine growth restriction, neonatal death and APGAR score, compared to those of singleton pregnancies. The elevated blood pressure in twin pregnancies, in fact, may be a mere effect of a physiologic response to the need for additional nutrients provided with blood [7]. Since the role of gestational hypertension on birth weight in twin pregnancy has not been previously investigated in Italian women, our study aims to analyze the effect of gestational hypertension on neonatal birth weight among twin pregnancies. Methods Study participants A 27-year (from January 1, 1980 to December 31, 2006) retrospective cohort study involving 1273 consecutive twin pregnancies was conducted at the Department of Obstetrics and Gynaecology at the teaching hospital ‘‘A. Gemelli’’ in Rome. Cases consisted of twin pregnancies with gestational hypertension, defined as a diastolic blood pressure P90 mmHg on two or more consecutive occasions, at 6 h apart, developing after 20 weeks of gestation in a previously normotensive woman. Non-cases were twin normotensive pregnancies. Blood pressure was taken with a standard mercury sphygmomanometer, using phases one and five of the Korotkoff sounds before delivery for systolic and diastolic blood pressure, respectively, and recording with the patient in a semi-recumbent position. Women with preeclampsia, HELLP (haemolytic anemia, elevated liver enzymes, and low platelet count) syndrome, preeclampsia on chronic hypertension, chronic hypertension, major foetal malformations, aneuploidies, type 1 diabetes, foetal hydrops, gestational diabetes, maternal chronic disease and twin-twin transfusion syndrome were excluded from the study. The indications for planning delivery among hypertensive twin pregnancies were: presence of foetal distress as indicated by foetal heart rate recording, oligo-anhydramnios, abnormal Doppler velocimetry, premature rupture of membranes, or any other obstetric indication. The finding of intrauterine foetal discordance was not an indication for planned delivery if not associated with other signs of foetal distress. Corticosteroids were used to accelerate foetal lung maturation in both hypertensive and normotensive twin pregnancies, when appropriate. Data collection Retrospective data collection revealed that among 1273 twin pregnancies with alive twin births: 196 met the case definition, 912 were normotensive twin pregnancies, and 165 twin pregnancies were excluded because of the above mentioned conditions. Information were collected from study subjects by extracting data from medical chart records and entered into a structured database. The following data were collected: prenatal care, duration of gestation (weeks), previous medical history, intrapartum care, delivery and neonatal outcome. Data on maternal age, height, weight before pregnancy, rate of nulliparas, week
of delivery, rate of preterm delivery and of Caesarean section, twins’ birth weight, birth weight discordance, birth order and sex combination were also collected. Small Gestational Age (SGA) was defined as a birth weight lower than 10th percentile according to a national standard curve for singleton births [10]. Twin A was defined as the first born, and twin B as the second one. Inter-twin birth weight discordance was reported as measure of weight discordance. Signed percentage weight discordance (SPWD) was defined as (twin A weight twin B weight) 100/the heavier twin and expressed as a signed percentage. SPWD indicated which twin was heavier according to delivery order. Total birth weight was the sum of twin A plus twin B. The twin B/twin A SGA rate ratio was calculated to allow a direct comparison of SGA frequencies between the two groups of twin pregnancies. Statistical analysis The v2 test or Fisher’s exact test were used to compare frequencies between categorical variables, where appropriate. The comparison of averages for continuous variables was carried out by means of Student’s t-test or Mann–Whitney according to data distribution and values are presented as mean ± standard deviation (SD). To evaluate the distribution of SPWD among hypertensive and normotensive twin pregnancies, it was arbitrarily categorized into four degrees of discordance (>25%, 25– 16%, 15–11% and 610%) and the v2 test was then used. In order to evaluate if week of delivery might influence SPWD considered as a dependent variable, a linear regression analysis was performed using Spearman’s coefficient (r). The goodness of fit was assessed by means of R2 coefficient. To visually look at the strength of the relationship between the two variables, a scatter plot was obtained. The effect of duration of gestation on SPWD degrees and SGA was assessed by using the Kaplan–Meier non parametric method and the differences were tested by log-rank test. Statistical analyses were carried out using STATA software version 10.1 (Stata Corporation, College Station, TX) and were two-sided. Statistical significance was set at a p value of 60.05. Results Table 1 shows main maternal clinical characteristics and pregnancy outcome among 196 hypertensive and 912 normotensive twin pregnancies, while Table 2 details the birth weight features in the compared groups. No significant differences were observed between the groups, both for mothers’ clinical features and twin outcomes. The distribution of the four degrees of SPWD was not significantly different (but borderline) between the two groups of twin births (p = 0.07, Table 2). The rate of SGA was increased in the second twins in both groups, in comparison to that of the first twins. Fig. 1 shows a significant correlation between SPWD and the week of delivery in hypertensive (r = 0.17; p = 0.021), and normotensive pregnancies. (r = 0.07; p = 0.036).
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
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S. Ferrazzani et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2015) xxx–xxx Table 1 Main maternal clinical features and pregnancy outcome among hypertensive and normotensive twin pregnancies.
Age (years) (median ± SD) Height (cm) (mean ± SD) Weight before pregnancy (kg) (mean ± SD) BMI (kg/m2) ± SD Nulliparas, N (%) Median week of delivery (range) Delivery 6 37 weeks, N (%) Caesarean section, N (%)
Hypertensive pregnancies (N = 196)
Normotensive pregnancies (N = 912)
p-Value
31 ± 5.1 165 ± 7.1 60 ± 12.0 22.4 ± 4.2 113 (60.1) 37 (28–41) 114 (58.2) 129 (65.8)
31 ± 4.6 164 ± 6.3 58 ± 10.3 21.9 ± 3.6 399 (57.3) 37 (26–41) 516 (56.6) 614 (67.7)
0.236 0.236 0.138 0.218 0.497 0.637 0.685 0.481
Table 2 Birth twin weight features and signed percentage weight discordance in hypertensive and normotensive twin pregnancies. SGA was defined as a birth weight lower than 10th percentile according to a national standard curve.
Twin A (g) (mean ± SD) SGA Twin A N (%) Twin B (g) (mean ± SD) SGA Twin B N (%) Total birth weight (g) (mean ± SD) (N = 196 2) Inter-twin absolute weight difference (g) (mean ± SD) Inter-twin % weight difference (mean ± SD) Inter-twin signed % weight difference (mean ± SD) Signed percentage weight discordance (SPWD) >25%, N (%) 16%–25%, N (%) 10%–15%, N (%) <10% (%)
Hypertensive pregnancies (N = 916)
Normotensive pregnancies (N = 912)
p-Value
2470 ± 509 30 (15.3) 2450 ± 578 41 (20.9) 4920 ± 989 240 ± 280 9.91 ± 11.4 1.08 ± 17.4
2435 ± 596 127 (14.0) 2385 ± 620 188 (20.7) 4840 ± 1145 230 ± 266 9.94 ± 11.1 1.79 ± 15.7
0.202 0.644 0.101 0.958 0.164 0.141 0.395 0.592
24 (12.2) 16 (8.2) 12 (6.1) 144 (73.5)
76 (8.3) 101 (11.1) 93 (10.2) 642 (70.4)
0.07
Fig. 2 reports the cumulative survival plots of gestational duration according to the four degrees of SPWD. The >25% degree was associated with lower gestational age at delivery in both groups, especially in the normotensive twin pregnancies (p < 0.00001). Fig. 3 shows the percent distribution of pregnancies with various combinations of SGA neonates according to SPWD degrees between hypertensive and normotensive groups. In both groups, the rate of pregnancies with SGA twin B rose as the degree of discordance increased (p-value < 0.001), while the rate of pregnancies with both twins adequate for gestational age (AGA) declined as the degree of discordance increased (p-value < 0.001). On the other hand, the degree of discordance did not seem to influence the rate of pregnancies with SGA twin A (p-value = 0.494). Fig. 4 describes the twin B/twin A SGA rate ratio as a relative measure of the involvement of twin B over twin A. A clear involvement of twin B over twin A was observed with a major degree of discordance in both groups (p-value < 0.0001). In both groups, twin B was constantly more frequently involved than twin A, especially in normotensive pregnancies. Fig. 5 shows the cumulative survival plot for gestational duration in pregnancies according to various combinations of SGA neonates among the twin pairs. No significant difference was observed among hypertensive twin pregnancies, while in the normotensive pregnancies the SGA presence in both twins made delivery significantly closer to term if compared with that with AGA in both twins (p < 0.001).
Discussion In the present study, twin pregnancies complicated by gestational hypertension gave births at similar weeks as compared to normotensive twin pregnancies; moreover, hypertensive and normotensive twin pregnancies had a similar rate of low birth weight neonates. So gestational hypertension in twin pregnancy is associated with a similar neonatal outcome, showing almost a trend towards a higher neonatal weight, as compared with that of twins born to normotensive mothers. In our previous report [8], a comparison of twin pregnancies complicated by preeclampsia versus normotensive ones, showed that preeclampsia was observed associated with a higher rate of SGA neonates than that observed in the normotensive pregnancies. On the contrary, in the present report the infants from twin pregnancies complicated by gestational hypertension seemed to have a higher birthweight trend than that observed in infants born to normotensive women. These results, even if paradoxical, were also reported in the literature. Sibai et al. [2] had already shown that infants born to twin pregnancies complicated by gestational hypertension had a higher birth weight, if compared with infants born to preeclamptic and normotensive twin pregnancies. Furthermore, Luo et al. [7] showed that gestational hypertension had a much more benign effect on twin neonatal outcomes, if compared with singleton hypertensive pregnancies. Their results indicated that, rates of delivery less than both 37 and 32 weeks, Intra Uterine Growth Restriction (IUGR), 5-min Apgar score less than 4, and neonatal death were lower in twin if compared
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
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Fig. 1. Regression lines of signed percent birth weight discordance (SPWD) drawn against duration of gestation. (A) Hypertensive twin pregnancies; (B) normotensive twin pregnancies.
Fig. 2. Survival analysis. Cumulative plot of duration of gestation (weeks) to four arbitrary degrees of percent weight discordance. (A) Hypertensive twin pregnancies: p-value for log-rank test = 0.0617; (B) normotensive twin pregnancies: p-value for log-rank test < 0.00001.
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
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Fig. 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. Twin A is defined as the first born and twin B as the second one. (A) Hypertensive twin pregnancies; (B) normotensive twin pregnancies.
Fig. 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. Twin A is defined as the first born and twin B as the second one. Only significant results are reported.
to those of singleton born to gestational hypertensive mothers. A study conducted in our center [11], concerning the use of the glucose clamp for the measurement of the insulin resistance, designed to assess whether the metabolic characteristics of insulin resistance syndrome were present in singleton preeclamptic, gestational and chronic hypertensive pregnancies, showed that only women with gestational hypertension exhibited metabolic features similar to the patients with insulin resistance syndrome, suggesting that similar abnormalities could be involved in the pathogenesis of these disorders. Assuming that singleton and twin gestational hypertension have the same metabolic characteristics, the trend towards a higher birth weight in twin gestational hypertension could be explained by the increased insulin resistance of these patients during the last trimester of pregnancy if compared to controls. This insulin resistance could lead to an increased transfer of glucose to the foetus.
Similar to the our previous study about preeclamptic twin pregnancies [8], the present study demonstrates that there was a relationship between gestational age at delivery and percentage weight discordance both in the gestational hypertensive and in the normotensive group. Considering the inter-twin birth weight discordance, in the normotensive group the discordance >25% was significantly associated with shorter gestational duration, while in the hypertensive group it did not reach a statistically significant association, probably for the smaller size of the sample. On this topic, our previous work [8] suggested that the discordance >25% was associated with shorter gestational duration both in preeclamptic and in normotensive women. Probably, inter-twin discordance was clinically determinant in the decision of timing of delivery because of the associated conditions: oligo-anhydramnios, foetal distress and abnormal Doppler velocimetry. In addition, the present study shows that the inter-twin discordance was the consequence of the trend to growth restriction of the second twin (twin B) in both hypertensive and normotensive pregnancies, confirming the data observed in our previous work [8]. Both in hypertensive and normotensive twin pregnancies, the rate of pregnancies with SGA twin B rose as the degree of discordance increased, while the rate of pregnancies with both adequate-for-gestational age (AGA) twins declined as the degree of discordance increased. On the other hand, the degree of discordance appeared to have no association between the rate of pregnancies with SGA twin A or with both SGA twins. It is well known that in twin pregnancies, the second twin outcome is more jeopardized than that of the first [12,13]. The findings of this study confirm the assertion by indicating that the rate of SGA increased in the second twins in both groups. In fact, twin B was more compromised in terms of rate of SGA and stillbirth in preeclamptic and normotensive twin pregnancies [8]. In our opinion it can be due to the anatomic unfavourable situation of the second twin regarding the insertion of uterine arteries.
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
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Fig. 5. Survival analysis. Cumulative plots for duration of gestation (weeks) in presence of various combinations of small for gestational age (SGA) twin pairs. (A) Hypertensive twin pregnancies: p-value for log-rank test = 0.2084; (B) normotensive twin pregnancies: p-value for logrank test < 0.00001.
Finally, the paradoxical phenomenon that pregnancies with SGA in both twins delivered closer to term when compared to pregnancies with AGA in both twins could be explained because it is well known that the birth weight of an uneventful twin pregnancy progressively diverges from singleton median birth weight as it approaches the term. 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 labor, the most frequent complication in twin pregnancies. In conclusion, these results may reflect an unknown beneficial role of uncomplicated hypertension in twin pregnancies. Gestational hypertension can be a paraphysiological phenomenon that ensures a better placental perfusion, given the increased demand associated with the twins’ condition. Funding The authors have no support or funding to report. Competing interests The authors have declared that no competing interests exist. References
[2] Sibai BM, Hauth J, Caritis S, Lindheimer MD, MacPherson C, Klebanoff M, et al. Hypertensive disorders in twin versus singleton gestations. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicina Units. Am J Obstet Gynecol 2000;182: 938–42. [3] Ferrazzani S, Caruso A, De Carolis S, Martino IV, Mancuso S. Proteinuria and outcome of 444 pregnancies complicated by hypertension. Am J Obstet Gynecol 1990 Feb;162(2):366–71. [4] Krotz S, Fajardo J, Ghandi S, Patel A, Keith LG. Hypertensive disease in twin pregnancies: a review. Twin Res 2002;5:8–14. [5] Day MC, Barton JR, O’Brien JM, Istwan NB, Sibai BM. The effect of fetal number on the development of hypertensive conditions of pregnancy. Obstet Gynecol 2005;106(5):927–31. [6] Buhling KJ, Henricyh W, Starr E, Lubke M, Bertram S, Siebert G, et al. Risk for gestational diabetes and hypertension for women with twin pregnancy compared to singleton pregnancy. Arch Gynecol Obstet 2003;269:33–6. [7] Luo ZC, Simonet F, An N, Bao FY, Audibert F, Fraser WD. Effect on neonatal outcomes in gestational hypertension in twin compared with singleton pregnancies. Obstet. Gynecol. 2006;108:1138–44. [8] Ferrazzani S, Merola A, De Carolis S, Carducci B, Paradisi G, Caruso A. Birth weight in preeclamptic and normotensive twin pregnancies: an analysis of discordance and growth restriction. Hum Reprod 2000; 15:210–7. [9] Villar J, Carroli G, Wojdyla D, Abalos E, Giordano D, Ba’ageel H, et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet Gynecol 2006;194(4):921–31. [10] Gagliardi L, Preve CU, Cordero di Montezemolo C, et al. Accrescimento uterino ed età gestazionale in un campione di 9774 casi. Ann Ost Gin Med Perin Anno XCVI N 1975;3:147–57. [11] Caruso A, Ferrazzani S, De Carolis S, Lucchese A, Lanzone A, De Santis L, et al. Gestational hypertension but not pre-eclampsia is associated with insulin resistance syndrome characteristics. Hum Reprod 1999 Jan;14(1):219–23. [12] Friedman EA, Sachtleben MR, Friedman LM. Relative birth weights of twins. Obstet Gynecol 1977;49:717–20. [13] Essel JK, Opai-Tetteh ET. Twin birth-weight discordancy in Transkei. S Afr Med J 1994;84:69–71.
[1] ACOG and preeclampsia. Obstet Gynecol 2002. Jan (33).
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
Contents lists available at ScienceDirect
Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health journal homepage: www.elsevier.com/locate/preghy
Original Article
Is gestational hypertension beneficial in twin pregnancies? Sergio Ferrazzani a, Sascia Moresi a,⇑, Emma De Feo b, Valentina Anna Degennaro a, Silvia Salvi a, Stefania Boccia b, Antonio Lanzone a, Sara De Carolis a a b
Department of Obstetrics and Gynaecology, Catholic University of Sacred Heart, Rome, Italy Institute of Hygiene, Catholic University of Sacred Heart, Rome, Italy
a r t i c l e
i n f o
Article history: Received 15 November 2014 Accepted 27 January 2015 Available online xxxx Keywords: Gestational hypertension Twin pregnancies Birth weight Small for gestational age Inter-twin weight discordance
a b s t r a c t Objectives: Hypertensive disorders of pregnancy are commonly associated with impaired foetal growth. However, some studies observed that gestational hypertension in twin pregnancy could be beneficial for foetal growth. The aim of this study is to investigate the influence of gestational hypertension on neonatal birth weight among twin pregnancies. Study design: This is a retrospective study about the comparison of 196 hypertensive twin pregnancies to 912 normotensive ones, who gave birth in the teaching hospital ‘‘A. Gemelli’’ in Rome from 1980 to 2006. Main outcome measures: Birth weight, inter-twin weight discordance and rate of small for gestational age neonates in the first and second twin. Results: Birth weight, inter-twin weight discordance and rate of small for gestational age neonates were similar between the two groups. In the normotensive group, the discordance >25% was associated with lower gestational age at the delivery (p < 0.00001), data not observed in the hypertensive group. The rate of pregnancies with second twin small for gestational age rose while paralleling the degree of the discordance in both groups. Conclusion: Gestational hypertension in twin pregnancies, if compared to normotensive ones, is not detrimental for foetal growth. Ó 2015 International Society for the Study of Hypertension in Pregnancy Published by Elsevier B.V. All rights reserved.
Introduction Hypertensive disorders are considered among the most common disease in pregnancy, being the main cause of maternal, foetal and neonatal morbidity and mortality in developed countries. The incidence of hypertensive disorders in singleton pregnancies is around 3–5% in Italy, including 1% of preeclampsia [1]. However, the incidence of hypertensive disorders in twin pregnancies is much greater [2–6]. Recent data report that the incidence of gestational hypertension and preeclampsia is double (12.9%
⇑ Corresponding author at: Largo A. Gemelli 8, 00168 Rome, Italy. Tel.: +39 06 30156774; fax: +39 06 3051160. E-mail address: [email protected] (S. Moresi).
vs. 6.3%) and three times greater (12.7% vs. 4.9%) respectively, in twin pregnancies compared to singleton ones [7]. Furthermore, singleton and twin pregnancies complicated by preeclampsia are more frequently characterized by low birth weight and small for gestational age (SGA) neonates compared to normotensive pregnancies [2,8,9]. So far, few studies analyzed the effect of gestational hypertension not complicated by preeclampsia on neonatal outcomes among twin pregnancies. Already in 2000, Sibai et al. [2] demonstrated that twin pregnancies complicated by hypertension had a better outcome as compared with both preeclamptic and normotensive twin pregnancies. A more recent Canadian study [7] on 102,988 twin pregnancies compared to 5,523,797 singletons showed that gestational hypertension in twin pregnancies had
http://dx.doi.org/10.1016/j.preghy.2015.01.003 2210-7789/Ó 2015 International Society for the Study of Hypertension in Pregnancy Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
2
S. Ferrazzani et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2015) xxx–xxx
overall better neonatal outcomes in terms of rate of preterm delivery, intra-uterine growth restriction, neonatal death and APGAR score, compared to those of singleton pregnancies. The elevated blood pressure in twin pregnancies, in fact, may be a mere effect of a physiologic response to the need for additional nutrients provided with blood [7]. Since the role of gestational hypertension on birth weight in twin pregnancy has not been previously investigated in Italian women, our study aims to analyze the effect of gestational hypertension on neonatal birth weight among twin pregnancies. Methods Study participants A 27-year (from January 1, 1980 to December 31, 2006) retrospective cohort study involving 1273 consecutive twin pregnancies was conducted at the Department of Obstetrics and Gynaecology at the teaching hospital ‘‘A. Gemelli’’ in Rome. Cases consisted of twin pregnancies with gestational hypertension, defined as a diastolic blood pressure P90 mmHg on two or more consecutive occasions, at 6 h apart, developing after 20 weeks of gestation in a previously normotensive woman. Non-cases were twin normotensive pregnancies. Blood pressure was taken with a standard mercury sphygmomanometer, using phases one and five of the Korotkoff sounds before delivery for systolic and diastolic blood pressure, respectively, and recording with the patient in a semi-recumbent position. Women with preeclampsia, HELLP (haemolytic anemia, elevated liver enzymes, and low platelet count) syndrome, preeclampsia on chronic hypertension, chronic hypertension, major foetal malformations, aneuploidies, type 1 diabetes, foetal hydrops, gestational diabetes, maternal chronic disease and twin-twin transfusion syndrome were excluded from the study. The indications for planning delivery among hypertensive twin pregnancies were: presence of foetal distress as indicated by foetal heart rate recording, oligo-anhydramnios, abnormal Doppler velocimetry, premature rupture of membranes, or any other obstetric indication. The finding of intrauterine foetal discordance was not an indication for planned delivery if not associated with other signs of foetal distress. Corticosteroids were used to accelerate foetal lung maturation in both hypertensive and normotensive twin pregnancies, when appropriate. Data collection Retrospective data collection revealed that among 1273 twin pregnancies with alive twin births: 196 met the case definition, 912 were normotensive twin pregnancies, and 165 twin pregnancies were excluded because of the above mentioned conditions. Information were collected from study subjects by extracting data from medical chart records and entered into a structured database. The following data were collected: prenatal care, duration of gestation (weeks), previous medical history, intrapartum care, delivery and neonatal outcome. Data on maternal age, height, weight before pregnancy, rate of nulliparas, week
of delivery, rate of preterm delivery and of Caesarean section, twins’ birth weight, birth weight discordance, birth order and sex combination were also collected. Small Gestational Age (SGA) was defined as a birth weight lower than 10th percentile according to a national standard curve for singleton births [10]. Twin A was defined as the first born, and twin B as the second one. Inter-twin birth weight discordance was reported as measure of weight discordance. Signed percentage weight discordance (SPWD) was defined as (twin A weight twin B weight) 100/the heavier twin and expressed as a signed percentage. SPWD indicated which twin was heavier according to delivery order. Total birth weight was the sum of twin A plus twin B. The twin B/twin A SGA rate ratio was calculated to allow a direct comparison of SGA frequencies between the two groups of twin pregnancies. Statistical analysis The v2 test or Fisher’s exact test were used to compare frequencies between categorical variables, where appropriate. The comparison of averages for continuous variables was carried out by means of Student’s t-test or Mann–Whitney according to data distribution and values are presented as mean ± standard deviation (SD). To evaluate the distribution of SPWD among hypertensive and normotensive twin pregnancies, it was arbitrarily categorized into four degrees of discordance (>25%, 25– 16%, 15–11% and 610%) and the v2 test was then used. In order to evaluate if week of delivery might influence SPWD considered as a dependent variable, a linear regression analysis was performed using Spearman’s coefficient (r). The goodness of fit was assessed by means of R2 coefficient. To visually look at the strength of the relationship between the two variables, a scatter plot was obtained. The effect of duration of gestation on SPWD degrees and SGA was assessed by using the Kaplan–Meier non parametric method and the differences were tested by log-rank test. Statistical analyses were carried out using STATA software version 10.1 (Stata Corporation, College Station, TX) and were two-sided. Statistical significance was set at a p value of 60.05. Results Table 1 shows main maternal clinical characteristics and pregnancy outcome among 196 hypertensive and 912 normotensive twin pregnancies, while Table 2 details the birth weight features in the compared groups. No significant differences were observed between the groups, both for mothers’ clinical features and twin outcomes. The distribution of the four degrees of SPWD was not significantly different (but borderline) between the two groups of twin births (p = 0.07, Table 2). The rate of SGA was increased in the second twins in both groups, in comparison to that of the first twins. Fig. 1 shows a significant correlation between SPWD and the week of delivery in hypertensive (r = 0.17; p = 0.021), and normotensive pregnancies. (r = 0.07; p = 0.036).
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
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S. Ferrazzani et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2015) xxx–xxx Table 1 Main maternal clinical features and pregnancy outcome among hypertensive and normotensive twin pregnancies.
Age (years) (median ± SD) Height (cm) (mean ± SD) Weight before pregnancy (kg) (mean ± SD) BMI (kg/m2) ± SD Nulliparas, N (%) Median week of delivery (range) Delivery 6 37 weeks, N (%) Caesarean section, N (%)
Hypertensive pregnancies (N = 196)
Normotensive pregnancies (N = 912)
p-Value
31 ± 5.1 165 ± 7.1 60 ± 12.0 22.4 ± 4.2 113 (60.1) 37 (28–41) 114 (58.2) 129 (65.8)
31 ± 4.6 164 ± 6.3 58 ± 10.3 21.9 ± 3.6 399 (57.3) 37 (26–41) 516 (56.6) 614 (67.7)
0.236 0.236 0.138 0.218 0.497 0.637 0.685 0.481
Table 2 Birth twin weight features and signed percentage weight discordance in hypertensive and normotensive twin pregnancies. SGA was defined as a birth weight lower than 10th percentile according to a national standard curve.
Twin A (g) (mean ± SD) SGA Twin A N (%) Twin B (g) (mean ± SD) SGA Twin B N (%) Total birth weight (g) (mean ± SD) (N = 196 2) Inter-twin absolute weight difference (g) (mean ± SD) Inter-twin % weight difference (mean ± SD) Inter-twin signed % weight difference (mean ± SD) Signed percentage weight discordance (SPWD) >25%, N (%) 16%–25%, N (%) 10%–15%, N (%) <10% (%)
Hypertensive pregnancies (N = 916)
Normotensive pregnancies (N = 912)
p-Value
2470 ± 509 30 (15.3) 2450 ± 578 41 (20.9) 4920 ± 989 240 ± 280 9.91 ± 11.4 1.08 ± 17.4
2435 ± 596 127 (14.0) 2385 ± 620 188 (20.7) 4840 ± 1145 230 ± 266 9.94 ± 11.1 1.79 ± 15.7
0.202 0.644 0.101 0.958 0.164 0.141 0.395 0.592
24 (12.2) 16 (8.2) 12 (6.1) 144 (73.5)
76 (8.3) 101 (11.1) 93 (10.2) 642 (70.4)
0.07
Fig. 2 reports the cumulative survival plots of gestational duration according to the four degrees of SPWD. The >25% degree was associated with lower gestational age at delivery in both groups, especially in the normotensive twin pregnancies (p < 0.00001). Fig. 3 shows the percent distribution of pregnancies with various combinations of SGA neonates according to SPWD degrees between hypertensive and normotensive groups. In both groups, the rate of pregnancies with SGA twin B rose as the degree of discordance increased (p-value < 0.001), while the rate of pregnancies with both twins adequate for gestational age (AGA) declined as the degree of discordance increased (p-value < 0.001). On the other hand, the degree of discordance did not seem to influence the rate of pregnancies with SGA twin A (p-value = 0.494). Fig. 4 describes the twin B/twin A SGA rate ratio as a relative measure of the involvement of twin B over twin A. A clear involvement of twin B over twin A was observed with a major degree of discordance in both groups (p-value < 0.0001). In both groups, twin B was constantly more frequently involved than twin A, especially in normotensive pregnancies. Fig. 5 shows the cumulative survival plot for gestational duration in pregnancies according to various combinations of SGA neonates among the twin pairs. No significant difference was observed among hypertensive twin pregnancies, while in the normotensive pregnancies the SGA presence in both twins made delivery significantly closer to term if compared with that with AGA in both twins (p < 0.001).
Discussion In the present study, twin pregnancies complicated by gestational hypertension gave births at similar weeks as compared to normotensive twin pregnancies; moreover, hypertensive and normotensive twin pregnancies had a similar rate of low birth weight neonates. So gestational hypertension in twin pregnancy is associated with a similar neonatal outcome, showing almost a trend towards a higher neonatal weight, as compared with that of twins born to normotensive mothers. In our previous report [8], a comparison of twin pregnancies complicated by preeclampsia versus normotensive ones, showed that preeclampsia was observed associated with a higher rate of SGA neonates than that observed in the normotensive pregnancies. On the contrary, in the present report the infants from twin pregnancies complicated by gestational hypertension seemed to have a higher birthweight trend than that observed in infants born to normotensive women. These results, even if paradoxical, were also reported in the literature. Sibai et al. [2] had already shown that infants born to twin pregnancies complicated by gestational hypertension had a higher birth weight, if compared with infants born to preeclamptic and normotensive twin pregnancies. Furthermore, Luo et al. [7] showed that gestational hypertension had a much more benign effect on twin neonatal outcomes, if compared with singleton hypertensive pregnancies. Their results indicated that, rates of delivery less than both 37 and 32 weeks, Intra Uterine Growth Restriction (IUGR), 5-min Apgar score less than 4, and neonatal death were lower in twin if compared
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
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Fig. 1. Regression lines of signed percent birth weight discordance (SPWD) drawn against duration of gestation. (A) Hypertensive twin pregnancies; (B) normotensive twin pregnancies.
Fig. 2. Survival analysis. Cumulative plot of duration of gestation (weeks) to four arbitrary degrees of percent weight discordance. (A) Hypertensive twin pregnancies: p-value for log-rank test = 0.0617; (B) normotensive twin pregnancies: p-value for log-rank test < 0.00001.
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
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Fig. 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. Twin A is defined as the first born and twin B as the second one. (A) Hypertensive twin pregnancies; (B) normotensive twin pregnancies.
Fig. 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. Twin A is defined as the first born and twin B as the second one. Only significant results are reported.
to those of singleton born to gestational hypertensive mothers. A study conducted in our center [11], concerning the use of the glucose clamp for the measurement of the insulin resistance, designed to assess whether the metabolic characteristics of insulin resistance syndrome were present in singleton preeclamptic, gestational and chronic hypertensive pregnancies, showed that only women with gestational hypertension exhibited metabolic features similar to the patients with insulin resistance syndrome, suggesting that similar abnormalities could be involved in the pathogenesis of these disorders. Assuming that singleton and twin gestational hypertension have the same metabolic characteristics, the trend towards a higher birth weight in twin gestational hypertension could be explained by the increased insulin resistance of these patients during the last trimester of pregnancy if compared to controls. This insulin resistance could lead to an increased transfer of glucose to the foetus.
Similar to the our previous study about preeclamptic twin pregnancies [8], the present study demonstrates that there was a relationship between gestational age at delivery and percentage weight discordance both in the gestational hypertensive and in the normotensive group. Considering the inter-twin birth weight discordance, in the normotensive group the discordance >25% was significantly associated with shorter gestational duration, while in the hypertensive group it did not reach a statistically significant association, probably for the smaller size of the sample. On this topic, our previous work [8] suggested that the discordance >25% was associated with shorter gestational duration both in preeclamptic and in normotensive women. Probably, inter-twin discordance was clinically determinant in the decision of timing of delivery because of the associated conditions: oligo-anhydramnios, foetal distress and abnormal Doppler velocimetry. In addition, the present study shows that the inter-twin discordance was the consequence of the trend to growth restriction of the second twin (twin B) in both hypertensive and normotensive pregnancies, confirming the data observed in our previous work [8]. Both in hypertensive and normotensive twin pregnancies, the rate of pregnancies with SGA twin B rose as the degree of discordance increased, while the rate of pregnancies with both adequate-for-gestational age (AGA) twins declined as the degree of discordance increased. On the other hand, the degree of discordance appeared to have no association between the rate of pregnancies with SGA twin A or with both SGA twins. It is well known that in twin pregnancies, the second twin outcome is more jeopardized than that of the first [12,13]. The findings of this study confirm the assertion by indicating that the rate of SGA increased in the second twins in both groups. In fact, twin B was more compromised in terms of rate of SGA and stillbirth in preeclamptic and normotensive twin pregnancies [8]. In our opinion it can be due to the anatomic unfavourable situation of the second twin regarding the insertion of uterine arteries.
Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003
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S. Ferrazzani et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health xxx (2015) xxx–xxx
Fig. 5. Survival analysis. Cumulative plots for duration of gestation (weeks) in presence of various combinations of small for gestational age (SGA) twin pairs. (A) Hypertensive twin pregnancies: p-value for log-rank test = 0.2084; (B) normotensive twin pregnancies: p-value for logrank test < 0.00001.
Finally, the paradoxical phenomenon that pregnancies with SGA in both twins delivered closer to term when compared to pregnancies with AGA in both twins could be explained because it is well known that the birth weight of an uneventful twin pregnancy progressively diverges from singleton median birth weight as it approaches the term. 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 labor, the most frequent complication in twin pregnancies. In conclusion, these results may reflect an unknown beneficial role of uncomplicated hypertension in twin pregnancies. Gestational hypertension can be a paraphysiological phenomenon that ensures a better placental perfusion, given the increased demand associated with the twins’ condition. Funding The authors have no support or funding to report. Competing interests The authors have declared that no competing interests exist. References
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Please cite this article in press as: Ferrazzani S et al. Is gestational hypertension beneficial in twin pregnancies?. Preg Hyper: An Int J Women’s Card Health (2015), http://dx.doi.org/10.1016/j.preghy.2015.01.003