Timing of the onset of weight discordance in pathologic monochorionic twin pregnancies.

doi:10.21203/rs.3.rs-1428712/v1

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Research Article

Timing of the onset of weight discordance in pathologic monochorionic twin pregnancies.

https://doi.org/10.21203/rs.3.rs-1428712/v1

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posted 11 Mar, 2022

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PURPOSE: Monochorionic twins (MC) have twofold higher mortality than dichorionic twins (DC) and fourfold higher when compared to singletons. We analyzed the development of weight discordance and the average time of diagnosis/morbidity in MC.

METHODS: Retrospective analysis of the intertwin weight discordance during pregnancy in Twin-Twin Transfusion Syndrome (TTTS) and Selective Intrauterine Growth Retardation (sIUGR), using a linear mixed model and single-factor analysis of variance in a cohort of MC at our institution.

RESULTS: In a cohort of 143 MC the development of the intertwin weight difference varies significantly between uncomplicated and pathologic MC (P<0,001). An intertwin weight difference is detectable starting with the 16th weeks’ of gestation, however, the first diagnosis is routinely made in the 21 weeks’ gestation (20.6 ± 3.9 TTTS, 19.6 ± 3.4 sIUGR). Compared to concordant MC, both TTTS and sIUGR had increased mortality with higher rates of intrauterine fetal demise (18.2% vs. 7.7%; P=0.243) and antenatal corticosteroids (85,7% vs. 65,2%). Delivered 2-3 weeks earlier, pathologic twins had a lower birth weight, lower APGAR and pH values, and a higher demand for neonatal intensive care for longer periods. Artificial reproduction techniques resulted in a 3.6-fold increased risk of developing TTTS (38.4% vs. 21.9%, P = 0.061) and sIUGR (30.8% vs. 21.9%, P=0.061).

CONCLUSIONS: The mortality and morbidity in MC highly correlates with the stage and time of the initial diagnosis. Expediting diagnosis and treatment, starting with the 16th week of gestation could arguably decrease intrauterine fetal demise, neurological morbidity, and prematurity.

Monochorionic

Twins

Development

Discordant

TTTS

sIUGR

Perinatal mortality and morbidity in Monochorionic twin pregnancies (MC) is increased compared to dichorionic twins (2.8% vs. 1.6%) and four times higher when compared to singletons (0.7%) commanding intensified prenatal monitoring [1–3].

Placental anastomoses and the distribution of the individual placenta supply areas determine fetal development and pathology: Twin-Twin Transfusion Syndrome (TTTS) and selective intrauterine growth retardation (sIUGR) [4] with a higher risk of extreme prematurity and neonatal morbidity and mortality [5–6].

Unbalanced transfusions, placenta dysfunction, or progression from sIUGR are the accepted causes of TTTS. Biochemically, the donor shows lower levels of growth factors, e.g., Insulin-like growth factor-II, with insufficient placental development, growth retardation, increasing placental resistance and transfusion rates towards the acceptor [7].

TTTS occurs in 8–15% of all MC twins [6, 8, 9] and is routinely diagnosed between the 18–24 week of gestation [10, 11]. sIUGR affects 10–15% of MC [1, 6] with a lower mortality (9–22%), and morbidity than TTTS (15–55%) [6, 9, 12, 13] and a weight discordance of > 25% requires a referral to a perinatal center. While smaller twins show a higher rate of intrauterine demise, the larger twins show a higher rate of neonatal mortality [14].

Both pathologies show a dynamic course, therefore predicting progress remains difficult [15, 16]. Although early diagnosis is crucial (< 16weeks’) [17, 18, 19], insufficient data hinders understanding the exact course of TTTS/sIUGR in the early phase. Hence, the primary aim of this study was to analyze the earliest time point of measurable weight discordance in MC, the interval between this point in time and the average time of diagnosis and its effect on the outcome. Intertwin discrepancies in the middle cerebral artery peak systolic velocity (MCA-PSV) were also evaluated.

Study sample

A total of 191 MC referred to the Department of Obstetrics and Gynecology of the Heidelberg University Medical Center between 2006 and 2016 were considered. 37 were excluded due to missing data, malformations, macrosomia, abortion, intrauterine fetal demise without a history of TTTS/sIUGR, intrauterine growth retardation of both twins, and twin reversed arterial perfusion syndrome (TRAP). 171 patients were included in the statistical analysis.

For the main question, all MC with TTTS, early-onset sIUGR (EO), or concordant twins (CC) were included. Cases where intrauterine fetal demise occurred, or laser therapy was performed, were excluded following this event. Subsequently, 143 MC were evaluated as part of the main question (Fig 1). For the secondary question, the evaluation of the correlation between the MCA-PSV and discordant birth weight in CC was compared with EO and LO sIUGR.

Definition of patient groups

Groups and subgroups were formed, which were defined as follows:

CC as an estimated fetal weight (EFW) discordance of <25% [9]. TTTS as polyhydramnios in one twin (single deepest pocket > 8cm) and oligohydramnios in the other twin (single deepest pocket < 2cm) [20]. sIUGR as an EFW of one fetus <10% and a weight discordance of >25% [10,17]. sIUGR was subdivided into EO sIUGR (onset <28 weeks of gestation) and LO sIUGR (onset >28 weeks of gestation) [21].

Data collection and processing

We collected ultrasound data from Viewpoint (GE Healthcare, Wessling, Germany). Moreover, general anamnestic data was collected from IS-H med (SAP) to be evaluated in Microsoft Excel 2010.

Statistical analysis

The statistical analysis was performed using IBM SPSS Statistics version 24.0.0.0 (2016; SPSS, Inc., Chicago, Illinois, USA). The decision for each test was based on the type of data assuming a normal or an oblique distribution²². Data was analyzed using Student t-test (applying variance heterogeneity), Mann-Whitney U-test, Chi-square (Pearson), Welch test, and Kruskal-Wallis-test as appropriate.

Due to the explorative design of this study, an adjustment for multiplicity is not possible for all statistical tests performed. The resulting P-values are interpreted purely descriptively (significant results from a P-value of 0.05).

Regarding the main question, Subgroups of TTTS (donor/acceptor), sIUGR (smaller/larger twin), and CC (twin1/twin2) were established, plotting the EFW of each fetus against the corresponding week of gestation, rendering 12 measurement points between 12-34 weeks of gestation.

We assumed that the intertwin weight discordance in TTTS and sIUGR groups increases during pregnancy, whereas, in CC, generally does not. The aim was to fit a model to the difference between the slopes of these three groups. The current study consists of longitudinal data measured at several times in the same individual, showing individual changes over time and variations between individuals. To represent these dependencies and compensate for incomplete data for the analysis of the development of weight discordance we used a linear mixed-effects model combining random effects and fixed effects [23]. As a covariance structure, a first-order autoregressive structure with heterogenous variances was used. We assumed that this model shows an increase in intertwin weight discordance (dependent variable) by increasing gestational age (fixed effect) with a linear slope. Furthermore, patient groups (CC, TTTS, sIUGR) represent another fixed effect influencing the linear model. The patient-ID was introduced as a random factor with random slopes for every twin pair representing the individual weight development. As these individual twin pairs´ slopes tend to differ between the subjects, the random slopes and intercepts model seems to be the fitting model.

Furthermore, evaluating the mean weight development of MC in each group (concordant, TTTS, sIUGR), there is a time point where the growth curve of twins with TTTS and sIUGR is divergent compared to CC.

To determine this time point, a single factor analysis of variance of the mean values of the intertwin weight discordance in the three groups was performed at each measurement point. Due to this multiple testing, the usual significance level α of 0.05 was adjusted after the Bonferroni correction resulting in an adjusted significance level P=∝/n=0.05/12≈0.0042.

Regarding the secondary question, measured values of MCA-PSV were converted into multiples of the median (MoM), based on published reference lists [24]. Receiver-operating-characteristics (ROC) curves were applied to determine the intertwin discrepancy in MCA-PSV as a predictor of EO sIUGR or LO sIUGR.

Logistic regression was performed to map the relationship between individual variables and the sIUGR at birth or difference in the interfetal EFW. The resulting odds ratio was reported with the corresponding 95% confidence interval.

In the examined population (n=171), a total of 49.1% (n = 84) were concordant, 19.3% (n = 33) TTTS and 21.6% (n = 37) sIUGR, of which 70.3% (n = 26) early-onset (EO) sIUGR and 29.7% (n = 11) late-onset (LO) sIUGR. Within the TTTS group, 48.5% (n = 16) received a conservative approach with regular follow-ups, 39.4% (n=13) a fetoscopic laser therapy and 12.1% (n=4) an amnioreduction. In the conservative treatment group, a single intrauterine fetal demise of the donor occurred in 4 cases, while a double demise occurred in 3 cases, resulting in overall mortality of 26.7%. In the group treated with laser therapy, one selective feticide was performed due to hydrops fetalis, resulting in a mortality rate of 7.7%.

The linear mixed model showed a positive coefficient of the gestational age (fixed effect), representing a linear increase in interfetal weight difference depending on the gestational age (P>0.001). The relationship of patient groups and progressive interfetal weight difference over time (gestational age) also showed a significant correlation (P<0,001), (Tab. 1.) Hence, interfetal weight discordance differs over time and in between patient groups, (Fig. 2.) The mixed-effects model seems appropriate to the data as estimates of variance and covariance were all significant (P<0.001). Analysis of normality plots (Q-Q-plot) and Shapiro-Wilk test (P<0,001) of the residuals of the mixed model showed that they are not normally distributed.

For the determination of the onset of weight discordance in twin pairs, the interfetal weight difference of all included twin pairs was compared at the corresponding gestational age. (Fig. 3, Fig. 3a-c).

While CC show a parallel growth course, TTTS and sIUGR show a progressively divergent weight difference starting at the 16^th GW, which is statistically significant throughout the pregnancy (Tab. 2 and Fig. 4).

Although statistically significant, the absolute estimated weight discordance in the 16th week of gestation is <100 g. A weight difference to compensate for interobserver variability (>100g) is measurable starting the 20^th weeks of gestation (TTTS: 99.86 ± 74.81 g; sIUGR: 93.36 ± 52.61 g). On average the initial time of diagnosis of a TTTS was thus in the 21^st week of gestation (20.6 ± 3.9 weeks) and of sIUGR in the 20^th week of gestation (19.6 ± 3.4 weeks, P = 0.969), some 4-5 weeks after a statistically significant intertwin estimated weight discordance (Fig. 5).

Comparing the main patient groups of CC, TTTS, EO sIUGR and LO sIUGR (n=154) there were no significant differences regarding conception, delivery mode, maternal age or parity. However, it showed significant differences in complications such as intrauterine fetal demise and prematurity, as well as postnatal parameters such as birth weight, percentiles, and the scope of neo-intensive care (Tab. 3).

Compared to CC, the EO sIUGR group showed a higher proportion of artificial insemination (4,8% vs. 16%; P = 0.061), an increased rate of cervical insufficiency (8.7% vs. 33.8%; P = 0.019), and a need for antenatal corticosteroids (40,5% vs. 65%; P = 0.038). Patients in the EO sIUGR group delivered 2 weeks earlier (36 ± 2 vs. 34 ± 4 weeks; P = 0.003) with lower birth weight (2342 ± 457 g vs. 1735 ± 705 g; P <0.001), APGAR and pH values and a higher need for neonatal intensive care (43.6% vs. 69,2%; P = 0.005) for longer periods (0 vs. 15 days; P = 0.002). Overall, they had an increased mortality rate both intrauterine (7.7% vs. 0%; P = 0.01) and postpartum (11.5% vs. 1.2%; P = 0.015).

Compared to CC, the TTTS group showed increased proportion of nulliparity (69.6% vs. 50.6%, P = 0.062) and artificial reproductive techniques (4,8% vs. 15.2%; P = 0.061), a rate of intrauterine fetal demise (0% vs. 18.2%; P <0.001). As a combination of fetal and maternal indications, the rate of antenatal corticosteroids was higher in the TTTS group (40,5% vs. 85.7%; P = <0.001). They were delivered 3 weeks earlier (36 ± 2 vs. 33 ± 4 weeks; P <0.001) due to intrauterine deterioration such as pathological flow in doppler or pathological cardiotocograph (8,5% vs. 30.8%; P = 0.006). They also had lower birth weights (2342 ± 457g vs. 1824 ± 694g; P <0.001), APGAR scores and a higher need for neonatal intensive care (85.1% vs. 43.6%; P <0.001), for longer periods (0 vs 23 days; P <0.001).

In the TTTS group compared to sIUGR cervical insufficiency was more frequent due to polyhydramnios (33.3% vs. 8.7%; P = 0.034), while preeclampsia and HELLP syndrome are frequent in sIUGR (0% vs. 17.4%; P = 0.018). The TTTS group showed a high proportion of antenatal corticosteroids (85.7% vs. 65.2%; P = 0.086). However, in the sIUGR group, this was more often administered due to fetal indication (sIUGR 80% vs. TTTS 54; P<0,001). The rate of fetal intrauterine demise was higher in the FFTS group (18.2% vs. 7.7%; P = 0.243). Twins with TTTS were also delivered one week earlier with lower APGAR scores and an increased need for neonatal intensive care (85.1% vs. 69.2%; P = 0.077) for longer periods (23 vs. 15 days; P = 0.035).

Comparing EO sIUGR and LO sIUGR, the latter showed cervical insufficiency more often (8,7% vs. 40%, P = 0.032) and had lower birth percentiles (9 vs. 5, P = 0.022). However, the EO sIUGR group had a significantly higher prematurity rate (34 ± 4 weeks vs. at 37 ± 1 weeks, P<0,001). Twins with EO sIUGR also displayed significant differences in the absolute birth weight (1735 ± 705 g vs. 2095 ± 281 g, P = 0.025), body length (42 ± 6.3 cm vs. 45 ± 2.4 cm, P = 0.39 ) and head circumference (29.4 ± 4.1 cm vs. 31.7 ± 1.3 cm, P = 0.015) with significantly lower APGAR scores, higher morbidity and longer neonatal intensive care (15 vs. 5 days, P = 0.094) and higher postnatal mortality (11.5% vs. 0%, P = 0.24). The postnatal pH values hardly differed.

Due to the increased prematurity, antenatal corticosteroids play a significant role in the care of monochorionic twin pregnancies. In the CC group, it was applied in 40.5%, almost exclusively (96.7%) due to maternal indications (cervical insufficiency, premature labor). However, it was significantly more common in the groups of TTTS (85.7%) and sIUGR (65.2%). While in the sIUGR group, almost 80% of the RDS prophylaxis was based on fetal indication, in TTTS, half of it is based on fetal (54%) and a half on maternal indication (45.7%) (polyhydramnios, cervical insufficiency).

To evaluate the relationship between MCA-PSV and EO sIUGR, we compared all CC (n = 84) with the EO sIUGR group (n = 26). From this patient population (n = 110), 32 CC cases and 7 EO sIUGR cases were excluded due to lack of data on MCA-PSV and birth weight, resulting in a study population of 71 patients (52 CC and 19 sIUGR).

The EO sIUGR group showed an increased intertwin difference in MCA-PSV compared to the CC (P = 0.017). The difference in MCA-PSV shows an AUC of 0.67 (95% CI: 0.53-0.84). The optimal cut-off point is 0.2 MoM, with a sensitivity of 74% and a specificity of 64%. (Fig. 6) Based on the cut-off point, twins with an MCA-PSV difference > 0.2 MoM showed a significantly lower birth weight (2109 ± 681g vs. 2305 ± 397 g; P = 0.041), a lower gestational age at birth (35 ± 3 GW vs. 36 ± 2 GW; P = 0.042) and longer neonatal intensive care stays (9.5 vs. 18.9 days, P = 0.012).

The relationship between the MCA-PSV and LO sIUGR was also examined. Of 61 patients enrolled, 49 had a normal birth weight, and 12 had a birth weight <5th percentile. The AUC of the difference in MCA-PSV to predict LO sIUGR is 0.65 (95% CI: 0.48-0.82). It is not significant (P = 0.101). (Fig. 6)

To compare the Type I and Type III (Gratacos) sIUGR, 22 pairs of twins type I and 4 pairs of Type III were examined. Type III twins were born significantly earlier vs. Type I (28 ± 1 vs. 35 ± 4, P <0.001) with lower birth weight (880 ± 223 vs. 1919 ± 632, P <0.001), length (34.3 ± 3.0 vs. 43.7 ± 5.5, P <0.001) and head circumference (23.7 ± 2.0 vs. 30.6 ± 3.3, P <0.001), but higher birth percentiles (22.5 vs. 8, P = 0.021). Besides, Type III showed significantly lower APGAR scores (P <0.001) with neonatal intensive care needed in 69.2% (P = 0.052) with significantly longer stays (91 vs. 8 days, P <0.001). The intrauterine or neonatal mortality showed no significant differences between the groups.

Comparison between artificial insemination and spontaneous conception

The group of artificial insemination had a higher proportion of TTTS (P = 0.061) and sIUGR (P = 0.061). Pooling these pathological pairs of twins showed a significant difference between pregnancies following artificial insemination vs. spontaneous conception (69.2% vs. 38.3%, P = 0.031). Consequently, artificial insemination results in a 3.6-fold increased risk of developing one of the MC complications.

Monochorionic twin pairs with TTTS / sIUGR from the 16 GW onwards show a significant intertwin weight discordance compared to CC. In the present study, TTTS and sIUGR were diagnosed between the 18–22 GW, consistent with current literature [18, 25, 26]. As such, there is a gap of up to five weeks between the first appearance of a significant weight discordance as a sign of pathology and the actual clinical diagnosis of these pathologies.

In sIUGR, we showed that starting with the 16 GW, a significant weight discordance > 20% seems to be a more sensitive diagnostic parameter than the EFW < 10. percentile. However, at this stage the absolute weight difference of < 100g (93.36 ± 52.61g), an absent end-diastolic flow in the umbilical artery, corresponding to a full-blown sIUGR or a difference in MCA-PSV can be difficult to detect.

The mortality rate of sIUGR fetuses was 19.2% (7.7% intrauterine and 11.5% postpartum), consistent with the current literature (9–22%) [6, 9, 12, 27].

Despite the early diagnosis, the treatment of sIUGR is challenging. In the absence of curative therapy, close monitoring and early delivery can reduce the rate of intrauterine fetal demise (IUFD) at the expense of extreme prematurity.

As in singleton pregnancies [28], an increased MCA-PSV has a predictive value for growth-restricted fetuses and intertwin MCA-PSV discrepancies are an additional screening parameter for the detection of sIUGR and pathological outcome in MC. An MCA-PSV difference above the cut-off of 0.2 MoM showed a significant discrepancy in the postpartum outcome, with an increased rate of prematurity and need for neonatal intensive care.

Pathological doppler values at 20 GW increase the risk for IUFD of the smaller twin with an increased risk of neurological damage for the surviving twin [18, 29].

The intrauterine fetal demise in the TTTS group was 18.2%. Like others [30–34], our results show that laser ablation, as treatment of choice significantly reduces the mortality of TTTS [33, 34], underlining an early diagnosis (16 GW), in line with the findings of this study.

Nevertheless, the natural history of early TTTS and whether stage 1 TTTS truly represents the first in a chronological series of stages of deterioration or rather represents a progression of sIUGR remains unclear [35]. Left untreated, early TTTS leads to IUFD in up to 90% of cases, with morbidity rates in survivors of over 50% [32, 36]. Showing a variable progression rate anywhere between 10–50% [35, 37–39], at least one-quarter of the pregnancies will progress to a higher stage.

Considering pathophysiological, biochemical, and clinical changes is arguable that early-stage TTTS and sIUGR might represent opposite sides of the same coin. Thus, early diagnosis, at 16 GW, can pinpoint the onset of the pathological development of MC. Expediting diagnosis and treatment could arguably prevent IUFD and neurological morbidity, as well as prematurity and related mortality and morbidity.

The retrospective design allowed us to examine cases seen over a period of 10 years, however, it presents difficulties, which influenced the results of this study: with cases referred to the tertiary center at varying stages, a continuous follow up throughout the pregnancy was not possible in all cases rendering variable number of cases at certain examination times. Also, fetoscopic laser therapy was not offered at this center, thus some TTTS cases seen were referred to other centers, diminishing the study group at follow-up time points. To compensate the failing continuity in some cases a linear mixed model was used to fit this data set. Limitations to the linear mixed model, like the difficulty to analyze the earliest time point of weight difference, remain. Therefore, graphed the onset of discordant growth and performed a single factor analysis of variance at every time point. P-values should be interpreted descriptively. Overall, the use of the EFW in connection with the diagnosis of a TTTS must also be viewed critically. While weight discordance is not part of the diagnostic or staging criteria of TTTS [40], if weight discrepancy is considered, it could be selecting for cases with TTTS [41], and weekly monitoring is recommended.

MC, DC, TTTS, sIUGR, EO sIUGR, LO sIUGR, CC, EFW, MCA-PSV, IUFD

The author(s) declare(s) that there is no conflict of interest regarding the publication of this article.

Author contributions:

T. Reinbach: Study conception and design, Protocol/project development, Data collection or management, Data analysis, Manuscript writing/editing

G. Rauch: Study conception and design, Data analysis

I. Kyvernitakis: Manuscript writing/editing

D. Lapa: Protocol/project development, Manuscript writing/editing

S. Wallwiener: Study conception and design, Protocol/project development, Data analysis, Manuscript writing/editing

A. Herzeg: Study conception and design, Protocol/project development, Data collection or management, Data analysis, Manuscript writing/editing

All authors contributed to the manuscript writing/editing. Study conception and design, material preparation, data collection and analysis were performed by Tiana Reinbach, Akos Herzeg. The first draft of the manuscript was written by Tiana Reinbach and Akos Herzeg and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Tab. 1

Estimates of the linear mixed model for increase in weight difference within twin pairs in relation to gestational age and groups (concordant, FFTS, sIUGR), SD: standard deviation

variables	estimates	P
Gestational age	3,98	<0,001
group	-52,3	<0,001
Gestational age x group	4,05	<0,001
Random slopes variance (SD)	3,27 (1,81)	<0,001
Residuals variance (SD)	8131,43 (90,37)	-

Tab. 2

Average values of the intertwin EWD of CC, TTTS, and sIUGR twin pairs. Data as mean values ± standard deviation. * Single-factor analysis of variance; The level of significance is P = 0.0042.

GA	Concordant twins		TTTS		sIUGR
	Mean ± SD	N	Mean ± SD	N	Mean ± SD	N	P*
12	4,00 ± 2,80	15	5,67 ± 4,31	12	7,50 ± 5,45	4	0,227
14	5,09 ± 4,72	11	3,67 ± 1,53	3	11,86 ± 6,26	7	0,024
16	11,85 ± 8,79	20	19,33 ± 9,08	9	31,44 ± 19,07	9	0,001
18	16,76 ± 13,82	21	52,27 ± 33,97	15	48,54 ± 24,87	13	<0,001
20	21,78 ± 18,74	37	71,94 ± 47,07	18	57,36 ± 34,12	11	<0,001
22	32,26 ± 19,71	31	99,86 ± 74,81	14	93,36 ± 52,61	11	<0,001
24	45,63 ± 42,33	27	190,50 ± 128,42	10	155,87 ± 87,43	15	<0,001
26	49,24 ± 51,08	21	142,89 ± 87,10	9	217,60 ± 99,52	10	<0,001
28	93,68 ± 64,78	31	237,60 ± 145,42	10	224,71 ± 132,97	14	<0,001
30	117,83 ± 61,91	36	273,36 ± 146,96	11	346,80 ± 172,85	5	<0,001
32	127,85 ± 133,30	40	279,78 ± 158,74	9	287,60 ± 209,88	10	0,002
34	129,83 ± 127,59	36	346,50 ± 272,90	6	401,36 ± 237,76	11	<0,001

Tab. 3,

Clinical parameters of the individual patient groups: concordant twins, TTTS, EO sIUGR, and LO sIUGR (n=154). Data as mean ± SD, median (IQA) or number (%), ICSI: intracytoplasmic sperm injection, IVF: in vitro fertilization, RDS: Prophylaxis of respiratory distress syndrome, GA: gestational age; * ANOVA, † Chi-square test, ‡ Kruskal-Wallis test

Patient group	Total (n=154)	Concordant (n = 84)	TTTS (n = 33)	EO sIUGR (n = 26)	LO sIUGR (n = 11)	P
Maternal age (years)	30,6 ± 4,5	30,3 ± 4,1	30,2 ± 5,2	31,6 ± 5,2	32,2 ± 4,0	0,349*
Gravidity	2 (1-2)	2 (1-3)	1 (1-2)	1 (1-2)	1 (1-2)	0,145^‡
Parity	0 (0-1)	0 (0-1)	0 (0-1)	0 (0-1)	0 (0-1)	0,093^‡
ICSI/IVF	15 (9,9%)	4 (4,8%)	5 (15,2%)	4 (16,0%)	2 (18,2%)	0,149^†
RDS	74 (55,2%)	30 (40,5%)	24 (85,7%)	15 (65,2%)	5 (55,6%)	<0,001^†
IUFD	8 (5,2%)	0 (0,0%)	6 (18,2%)¹	2 (7,7%)²	0 (0,0%)	0,001^†
GA at delivery	35 ± 3	36 ± 2	33 ± 4	34 ± 4	37 ± 1	<0,001*
Fetal indication for delivery	25 (19,4%)	6 (8,5%)	8 (30,8%)	7 (30,4%)	4 (40,0%)	0,007^†
Cesarean section	111 (81,6%)	58 (79,5%)	24 (82,8%)	19 (82,6%)	10 (90,9%)	0,825^†
Birth weight (g)	2112 ± 608	2342 ± 457	1824 ± 694	1735 ± 705	2095 ± 281	<0,001*
Birth percentile	16 (7-36)	20 (10 -39)	30 (10 - 50)	9 (3 – 20)	5 (2 – 9)	<0,001^‡
Neonatal intensive care	140 (56,9%)	61 (43,6%)	40 (85,1%)	27 (69,2%)	12 (60,0%)	<0,001^†
Duration (days)	8 (0-22)	0 (0 -17)	23 (9 - 53)	15 (0 – 30)	5 (0 – 15)	<0,001^‡
Neonatal death	5 (3,5%)	1 (1,2%)³	1 (3,0%)⁴	3 (11,5%)⁵	0 (0,0%)	0,066^†

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Timing of the onset of weight discordance in pathologic monochorionic twin pregnancies.

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Abstract

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Introduction

Material And Methods

Study sample

Definition of patient groups

Data collection and processing

Statistical analysis

Results

Comparison between artificial insemination and spontaneous conception

Discussion

Criticism

Abbreviations

Declarations

Author contributions:

References

Tables

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