In the present study, the authors focused on the association between inter-twin growth discordance (ITGD) based on estimated fetal weight (EFW) using ultrasound during pregnancy and the later development of preeclampsia (PE) [1]. ITGD is defined as the percentage difference in EFW or actual birth weight between neonates in a twin pregnancy. It is well established that both multiple pregnancies [2] and preceding fetal growth restriction (FGR) [3] are risk factors for the later development of PE. However, it has not been determined whether ITGD (involving both multiple pregnancy and FGR) in women with monochorionic (MC) twins, as well as dichorionic (DC) twins, is an independent risk factors for PE. Recently, the authors demonstrated that ITGD > 20% in actual birth weight in women with DC twin pregnancies (but not fetal growth discordance in women with MC twin pregnancies) was associated with an increased risk of gestational hypertension/preeclampsia (GH/PE), all types of PE, mild PE, severe PE, and early-onset (EO-) PE, based on a cohort of 2,122 women with twin pregnancies [4]. In the present study, the incidences of ITGD ≥ 10% in EFW was 31.4%, and the prevalence of MC twins was 9.3%, based on a cohort of 4,396 women with twin pregnancies [1]. Therefore, the authors were able to collect a sufficiently large sample size with target risk factor in women with MC twins, allowing for a subgroup analysis based on chorionicity (DC and MC twins) with adequate statistical power. The authors found that ITGD, not only in DD twins but also MC twins, was associated with an increased risk of various types of PE compared with non-ITGD: ITGD ≥ 10% in DC twins was associated with GH/PE, all types of PE,EO-PE, late-onset (LO-) PE, mild PE and severe PE [1]. Similarly, ITGD ≥ 10% in MC twins was associated with GH/PE, all types of PE, EO-PE, LO-PE, mild PE, and severe PE [1]. Thus, for the first time to our knowledge, the authors demonstrated that ITGD in both DC and MC twins was associated with an increased risk of PE [5, 6].

Bartsch et al. [1] reviewed 7,309,327 women with multiple pregnancies from eight studies; estimating a pooled unadjusted relative risk (RR) of 2.9 (95% CI: 2.6 to 3.1) (Fig. 1). In the present study, the adjusted odds ratio (AOR) for ITGD ≥ 10% in women with DC twins was 1.285 (95% CI: 1.143 to 1.444), and the AOR with 95% CI of ITGD ≥ 10% in women with MC twins was 2.410 (95% CI: 1.452 to 3.400) [1] (Fig. 1). Therefore, in women with both DD twins and ITGD ≥ 10%, the RR was estimated to be approximately 3.7, and in women with both MC twins and ITGD ≥ 10%, the RR was estimated to be 7.0. Likewise, the AOR for ITGD ≥ 15% in women with DC twins was 1.356 (95% CI: 1.111 to 1.540), and the AOR for ITGD ≥ 15% in women with MC twins was 1.909 (1.064 to 3.426) [1]. Therefore, in women with both DD twins and ITGD ≥ 15%, the RR was estimated to be approximately 3.9, and in women with both MC twins and ITGD ≥ 15%, the RR was estimated to be 5.5. Although ITGD ≥ 20% in women with MC twins was not associated with an increased risk of PE [1], this may be due to the exclusion of twin-to-twin transfusion syndrome (TTTS) and/or twin anemia polycythemia sequence (TAPS) in the present study. Nevertheless, the present study clearly shows significant associations between ITGD ≥ 10% and PE.

Fig. 1
Fig. 1
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A Relative risk (RR) and 95% confidence interval CI for the development of preeclampsia (PE) in women with multiple pregnancies, with women having singleton pregnancies used as controls [2]. B Blue bar: Odds ratio (OR) and 95% CI for the development of PE in women with inter-twin growth discordance (ITGD) ≥ 10% in dichorionic (DC) twins, with women without ITGD in DC twins used as controls; Red bar: OR and 95% CI for the development of PE in women with ITGD ≥ 10% in monochorionic (MC) twins, with women without ITGD in MC twins used as controls

The authors also found that 8% of twins belonged to the changing trajectory (CT) group, while 92% of twins belonged to the stable trajectory (ST) group, based on group-based trajectory modeling (GBTM) using the “traj” package in Stata [1]. Interestingly, a previous study classified discordance patterns in twins into 4 patterns: (1) pattern 1: no significant discordance group (similar to the ST group in the present study); (2) pattern 2: early progressive discordance group, where discordance of ≥10% was first noted before 24 weeks of gestation and progressively increased by ≥0.5% per week (similar to the CT group in the present study); (3) pattern 3: early discordance with plateau group, where discordance of ≥10% was first noted before 24 weeks of gestation, but remained stable thereafter; and (4) pattern 4: late discordance group, where discordance of ≥10% was first noted at or after 24 weeks of gestation [4]. The frequencies of these patterns were 57%, 2%, 25%, and 26%, respectively. Notably, in the present study, there were no cases that matched either pattern 3 or pattern 4 from the earlier study [1]. The difference may be due to the difference of racial/ethnic between the two studies (the previous study focused primarily on European subjects, while the present study was performed in Easten Asian subjects), and possibly due to the cessation of the EFW measurement after the occurrence of PE in the present study. Regardless, both studies found that the CT group was associated with a higher risk of PE compared with the ST group, suggesting that significant discordance of EFW before 24 weeks of gestation is a risk factor for the later development of PE.

As for the mechanisms behind the association between ITGD and PE, the authors did not provide clear explanation [1]. We hypothesize that the association may be related to (1) an increased incidence of small-for-gestational-age (SGA) infants in both DC and MC twins, and (2) an increased ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) (sFlt-1/PlGF ratio) in these twins. Firstly, the incidence of SGA in twin pregnancies was ~4.5 times higher than in singleton pregnancies [7], indicating that there are more SGA infants in twin pregnancies. FGR is known to be a risk factor for PE in singleton pregnancies, with PE occurring in 13.9% of a cohort of 173 FGR cases diagnosed by ultrasound [8]. Thus, twin pregnancies with SGA infants are likely to develop PE more frequently than twin pregnancies without SGA infants. Secondly, the expression of sFlt-1 protein is significantly increased (almost 2.5 times) in the small FGR DC and MC twin placentas compared with the normal cotwin placentas [9]. Because elevated levels of sFlt-1 or sFlt-1/PlGF ratio are strongly associated with the development of PE in twin pregnancies [10], it is plausible that small FGR placentas from discordant twin pregnancies contribute to PE development through the increased production of sFlt-1.

In the present study, the authors excluded complicated twin pregnancies, such as those involving TTTS and TAPS [1], which may have resulted in insufficient power for analyzing the effect of ITGD ≥ 20% on PE. Theoretically, it seems that larger inter-twin weight differences are associated with a higher frequency of PE. However, in present study, no association was found between ITGD ≥ 20% and PE in women with MC twins [1], possibly due to the exclusion of TTTS and TAPS cases. Future studies should include such cases in the analysis. Additionally, chronic hypertension and kidney diseases were also excluded in this study [1], resulting in no results regarding the effects of ITGD on super-imposed PE. Future studies should include pregnant women with chronic hypertension or kidney disease.