First-trimester screening and small for gestational age in twin pregnancies: a single center cohort study.

doi:10.21203/rs.3.rs-4916119/v1

Objective: This study aimed to investigate the association between maternal factors and first-trimester biophysical and biochemical markers with small for gestational age (SGA) neonates in twin pregnancies (TwPs).

Methods: Single center retrospective cohort study of TwPs followed from January 2010 to December 2022 at a tertiary perinatal center, Lisbon, Portugal. Inclusion criteria consisted of 572 TwPs. Maternal and pregnancy characteristics, mean arterial pressure, pregnancy-associated plasma protein-A (PAPP-A), β-human chorionic gonadotropin (β-HCG), and uterine artery pulsatility index (UtA-PI) were analyzed. Univariable, multivariable logistic regression (LR) and receiver-operating characteristic curve analyses were performed. The main outcomes measures considered were: SGA <3^rd, <5^th and <10^th percentile, composite outcome of SGA concurrent with preterm birth (PTB) (<32, <34, and <36 weeks).

Results: TwPs affected with SGA <3^rd, <5^th or <10^th percentiles were 120/572 (20.9%), 157/572 (27.4%) and 190/572 (33.2%), respectively. SGA <3^rd percentile was associated with higher rate of PTB, 59.0% of cases <32 weeks, OR 6.4 (95%CI: 3.2-12.7, p<0.001). UtA-PI and PAPP-A were identified as significant independent risk factors associated with SGA, as well as with the composite outcome of SGA concurrent with PTB. A LR model was obtained for the composite outcome SGA <3^rd percentile and PTB <32 weeks, with an AUC of 0.765, a sensitivity rate of 70%, and a false positive rate of 20%.

Conclusion: SGA concurrent with prematurity significantly impacts TwPs, and the majority of pregnancies at risk for this outcome can be detected in the first trimester. However, larger datasets are necessary to develop robust predictive models.

Synopsis:

The association between first-trimester screening data and SGA concurrent with very preterm birth in twin pregnancies was determined in most of the cases.

twin pregnancies

small for gestational age

fetal growth restriction

preterm birth

first-trimester screening

aspirin prophylaxis.

In singletons, first-trimester screening data can moderately predict small for gestational age, but no predictive models exist this outcome in twins, despite the higher impact in this group. In this study, the association between first-trimester screening data and small for gestational age concurrent with very preterm birth in twin pregnancies was found using regression analysis, though large datasets are needed to develop well-fitted predictive models.

Fetal growth restriction (FGR) is one of the most significant causes of perinatal morbidity and mortality that significantly impacts Twin Pregnancies (TwPs) [1–2]. The chances of having a newborn that weighs < 1500 g is 10 times greater in TwPs than in singleton pregnancies, and at least 60% of all twins are born before the 37th week [3]. The incidence of FGR and small for gestational age (SGA) in twins depends on the definition of FGR and birthweight references adopted [4]. Previous studies have estimated the incidence of FGR to be approximately 19.7% and 10.5%, while the incidence of SGA < 10th percentile (customized for TwPs charts) is reported to be 8.6% and 6.8%, respectively, in monochorionic (MC) twins and dichorionic (DC) twins [5, 6]. Perinatal mortality rates were found to be 75.1/1000 and 33.0/1000 in MC twins and DC twins, respectively [7].

In singleton pregnancies, first-trimester screening for aneuploidies can be extended to predict SGA [8]. However, for TwPs, first-trimester screening performance for SGA or FGR is lacking, despite the higher incidence and deleterious impact in this group [9].

This study aimed to investigate the association between maternal factors and first-trimester biophysical and biochemical markers with SGA neonates in TwPs.

This is a single-center, retrospective cohort analysis of twin pregnancies followed at a tertiary perinatal center, the Maternity Dr. Alfredo da Costa, São José Local Health Unit, Lisbon, Portugal, between January 2010 and December 2022. Approval for the present study was granted by the Local Ethical Committees of Nova Medical Scholl (nº 81/2020/CEFCM) and ULSSJOSE (nº 950/2020). Verbal informed consent for anonymous data collection and publication was obtained from all subjects before their inclusion in the Twins Study Group database. Informed written consent was not sought before 2020 for the present study because of the retrospective nature and anonymous data collection. After 2020, written consent was obtained from all subjects for participation and publication.

Routine first-trimester screening for aneuploidies was performed by Fetal Medicine Foundation certified obstetricians. Gestational age was derived from the last menstrual period that was confirmed or corrected by the measurement of fetal crown–rump length of the larger twin in the first-trimester scan or from the day of oocyte retrieval in pregnancies after assisted reproductive techniques (ART). Chorionicity was established by ultrasonographic criteria—lambda and T-sign in dichorionic (DC) and monochorionic (MC) twins, respectively —and confirmed by examination of the delivered placenta by experienced obstetricians and histopathologists.

Maternal parameters (weight and height, conception method and ethnicity) and medical history (parity, cigarette smoking, chronic hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, previous PTB, FGR or preeclampsia (PE)) were included in the first-trimester screening. Maternal blood samples were collected at 10^+ 0-13^+ 6 weeks into tubes in our laboratory, and serum pregnancy-associated plasma protein-A (PAPP-A), and β-human chorionic gonadotropin (β-hCG) were obtained from two immunoassay systems: Kryptor (Thermo Fisher Scientific, Clinical Diagnostics, Brahms GmbH, Henningsdorf, Germany) and Cobas (Roche Diagnostics, Basel, Switzerland) and converted to multiples of the median (MoM) using Astraia® software. First-trimester uterine artery (UtA) dopplers were obtained according to the International Society of Ultrasound in Obstetrics and Gynecology recommendations [10]. UtA was visualized transabdominally along the side of the cervix at the level of the internal os and the mean pulsatility indices (PIs) of the left and right arteries were calculated and considered according to chorionicity [11]. Inclusion criteria for the study were two live fetuses at the first-trimester scan, and subsequent birth at ≥ 24 weeks gestation. Exclusion criteria were monoamniotic twins, chromosomal and major fetal structural abnormalities, single fetal demise before 24 weeks, abnormal umbilical cord (two vessels or velamentous insertions), TORCH infections, preterm deliveries related to COVID-19, twin-to twin transfusion syndrome (TTTS) or Twin anemia polycythemia sequence (TAPS) and lost to follow-up.

Because this was an observational study, obstetric interventions were conducted in accordance with clinical guidelines and followed individualized practices. In normally progressing gestations, we offered elective termination of pregnancy at 36–38 completed weeks of gestation and iatrogenic preterm deliveries were carried out based on maternal and/or fetal conditions. Hypertensive disorders of pregnancy (HDP) were defined according to the International Society for the Study of Hypertension in Pregnancy classification, diagnosis, and management recommendations for international practice [12]. FGR was defined according to “Consensus definition” in TwPs described by Khalil A et al [13]. SGA was defined as birthweight falling below the 10th, 5th, or 3rd percentile for each gestational age. To establish our own population birthweight percentiles (unpublished data), we analyzed all twins followed in our institution who had uncomplicated pregnancies (excluding maternal, obstetric and fetal diseases) and delivered two live newborns after 36 weeks between the years 1994 and 2002. Our twin birthweight population percentiles for each gestational age were adjusted for chorionicity and based on ultrasound fetal weight estimations between 20 and 35 weeks, as well as birthweight data after 36 weeks.

The evaluated outcomes were SGA in one or both twins per pregnancy, as well as the composite outcome of SGA concurrent with PTB (< 32, < 34 and < 36weeks).

Statistical analysis

The association of SGA with all demographic and clinical variables was analyzed using Mann-Whitney, Chi-square, or Fisher’s exact tests, as appropriate. For the multivariable models, all the variables that attained a p-value ≤ 0.25 in the univariable analysis were selected. Adjusted odds ratios (OR) were estimated with corresponding 95% confidence intervals (95% CI). Discriminative ability and calibration of these models were assessed by the area under the receiver-operating characteristic curve (AUC) and the Hosmer-Lemeshow (HL) goodness-of-fit test, respectively. Although a significance level of α = 0.05 was considered, several variables of clinical relevance were maintained in the final models despite having a p-value > 0.05.

Data analysis was performed using the Statistical Package for the Social Sciences for Windows (IBM Corp. Released 2021.Version 28.0).

Of the 1175 TwPs followed between January 2010 and December 2022 in our center, the dataset included 572 TwPs that met the inclusion criteria: 450 (78.7%) DC and 122 (21.3%) MC. Of these, 464 completed first-trimester serum biochemical screening, 390 underwent UtA-PI evaluation, and 371 had complete data with all biomarkers. Maternal and pregnancy characteristics stratified per birthweight percentiles are summarized in Table 1.

Overall, pregnancies affected with one or both infants classified as SGA <3^rd, <5^th or <10^th percentiles were 120/572 (20.9%), 157/572 (27.4%) and 190/572 (33.2%), respectively (Table 1). Newborns classified as SGA <3^rd, <5^th and <10^th percentiles accounted for 145/1142 (12.7%), 191/1142 (16.7%) and 247/1142 (21.6%), respectively.

Considering maternal and pregnancy characteristics, MC pregnancies exhibited similar incidence of SGA <3^rd and <10^th percentile compared to DC: 22.1% vs 20.7%, OR 0.9 (95%CI: 0.5-1.5, p = 0.725) and 39.3% vs 31.6%, OR 0.7 (95%CI: 0.5-1.0, p = 0.105), respectively (Table 1). Women with low body mass index (BMI) (<20Kg/m²) showed increased odds of SGA <3^rd and <10^th percentiles, 31.1% vs 19.5%, OR 1.8 (95%CI: 1.0-3.1, p=0.022), and 51.4% vs 30.5% OR 2.4 (95%CI: 1.4-3.9, p<0.001), respectively. Furthermore, women who reported smoking habits in the first trimester had increased odds of SGA in the subgroup >3^rd <10^th percentile, 24.1% vs 11.0%, OR 2.5 (95%CI: 1.3-5.0, p=0.005), but not to SGA <3^rd percentile: 20.4% vs 21.0%, OR 0.9 (95%CI: 0.5-1.9, p=0.908) (Table 1).

Within parous women, those with a previous history of SGA had increased odds of SGA <3^rd and <10^th percentile, 53.8% vs 16.7%, OR 5.8 (95%CI: 1.8-18.4, p=0.004) and 61.5% vs 25.8%, OR 4.6 (95%CI: 1.4-14.7, p=0.009). Additionally, women under aspirin prophylaxis revealed increased odds for SGA <5^th percentile, 39.7% vs 25.7%, OR 1.9 (95%CI: 1.1-3.1, p=0.012) (Supplementary Table 1).

In univariable analysis, women with high UtA-PI ≥95^th percentile (TwPs’ references) showed and increased odds of SGA <3^rd and SGA <5^th percentile, 54.2% vs 21.0 %, OR 4.4 (95%CI: 1.9-10.2, p<0.001) and 58.3% vs 26.8%, OR 3.8 (95%CI: 1.6-8.9, p<0.001), respectively (Table 2 and Supplementary Table 2). Additionally, women with low PAPP-A MoM (≤10^th percentile, corresponding to 0.50 MoM) also had increased odds of SGA <3^rd percentile, 34.8% vs 19.2% OR 2.2 (95%CI: 1.1-4.3, p<0.014) (Table 2).

The incidence of SGA <3^rd or <10^th percentile concurrent with PTB <32 weeks was found to be 4.0% and 4.9%, respectively, with more than half (71.8%) of premature births <32 weeks being associated with the presence of SGA <10^th percentile in one or both twins. Before 32 weeks, SGA <3^rd was present in 23 (59.0%) vs 97 (18.2%) cases, OR 6.4 (95%CI: 3.2-12.7, p<0.001); <34 weeks, in 40 (48.8%) vs 80 (16.3%) cases, OR 4.8 (95%CI: 2.9-8.0, p<0.001) and <36 weeks, in 73 (37.4%) cases vs 47 (12.5%) cases, OR 4.2 (95%CI: 2.7-6.4, p<0.001). Iatrogenic PTB <32, 34 and 36 weeks occurred in 46.2% (50.0% MC and 45.5% DC), 40.2% (47.7% MC and 38.1% DC) and 47.7% (62.5% MC and 41.7% DC), respectively. Among women with iatrogenic PTB <34 weeks, 30 (90.9%) had prenatal suspicion of FGR and 31 (93.9 %) had one or both SGA <10^th percentile. Conversely, the incidence found of early onset-PE/HELLP <34 weeks was 1.0% (unshown data).

Two single fetal demises occurred in two DC pregnancies, one at 25 weeks and another at 36 weeks. Neither fetus was suspected to be growth-restricted, although in the latter case, the surviving co-twin was SGA <3^rd percentile. Both neonatal and perinatal death rates were higher in the groups affected by SGA <5^th and <3^rd percentile, with observed incidences of 1.3% and 1.6%, and 1.7% and 2.1%, respectively; however without reaching statistical significance. Additionally, these groups experienced prolonged stays (≥ 8 days) in the neonatal care unit, particularly pronounced in MC twins, totaling 65.7% and 70.3%, p<0.001 in SGA <5^th and <3^rd percentiles, respectively (Table 3 and Supplementary Table 3).

In the multivariable LR analysis, the best association model was obtained for one or both SGA <3^rd percentile concurrent with to PTB <32 weeks, with an AUC 0.765, a sensitivity rate of 70% and a false positive rate of 20% (Table 4). Lowering the false positive rate to 10% resulted in a decrease in the detection rate to approximately 35%. We also performed a similar LR model with the same covariates but using UtA-PI references in singletons of our population and observed that the sensitivity lowers to 65% and 29% for the same false positive rates considered (unshown data).

UtA-PI and PAPP-A were important independent risk factors found to be associated with SGA as well the composite outcome of SGA concurrent with PTB. The highest odds (OR 6.4, 95%IC 2.5-16.4, p<0.001) were observed in women with UtA-PI ≥ 95th percentile for SGA <3^rd percentile concurrent with PTB <36 weeks (Table 4). In our cohort, there was no association between β-hCG levels and any of the evaluated outcomes (Table 2).

We found a significant incidence of pregnancies affected by one or both infants SGA (< 10th percentile) in this study, approximately one-third, using TwPs’ birthweight references. The incidence of FGR and SGA in twins depends on factors such as the definition of growth restriction, the birthweight references used, and the exclusion criteria applied [4]. In our study, we excluded velamentous cord insertions due to their frequent association with FGR, particularly in MC twins [15]. Perhaps for that reason, in this dataset, we found similar rate of SGA < 3rd percentile in MC and DC twins.

FGR, especially when diagnosed before term, is considered to be related to poor placental perfusion, frequently occurring alongside early-onset HDP, which predispose to iatrogenic PTB [14]. Very PTB (< 32 weeks) has a high association with FGR/SGA with a rate 8.0 times higher compared to early-onset HDP [11]. Considering first-trimester biomarkers, high UtA-PI achieved the highest odds for adverse outcomes. Indeed, almost half of the women with higher UtA-PI experienced PTB < 36 weeks concurrent with SGA < 3rd percentile. These findings highlight the clinical impact of different outcomes related to placental dysfunction in TwPs, with early FGR leading to PTB being the major manifestation.

First-trimester screening is relevant for stratifying high-risk pregnancies to establish prophylactic treatments that can reduce morbidity. In singletons, first-trimester screening for SGA < 3rd percentile and PTB < 32 weeks, utilizing a predictive model (with maternal factors, PAPP-A and UtA-PI), in a large dataset (57,131 women) achieved moderate performance (estimated AUC of 0.819, with a detection rate of 55% and 72% at false positive rates of 10% and 20%, respectively) [16]. In the case of singleton pregnancies, the use of aspirin for the prevention of preterm PE in high-risk patients is well established and is accompanied by a decrease in the risk of PTB and FGR [17]. In the ASPRE trial, use of aspirin reduced the overall incidence of SGA < 10th percentile by about 40% in newborns at < 37 weeks' gestation and by about 70% in newborns at < 32 weeks [18]. In our practice, we opted to prescribe aspirin exclusively to women with significant risk conditions for hypertensive disorders (12.8% under prophylaxis in this cohort). We cannot precisely estimate the potential reduction in the occurrence of adverse outcomes with this option, however, the incidence of SGA (< 5th percentile) was doubled in women under aspirin prophylaxis, likely due to inherent factors that cannot be mitigated. More importantly, most higher-risk women (78.2%), identified by the fitted LR model, were not under aspirin prophylaxis. Would the outcomes be different if a different approach was implemented and if we could correctly identify women at risk in the first-trimester?

Some societies recommend, by consensus, the use of aspirin to reduce preeclampsia in twin pregnancies [19, 20]. However, it is unclear if these women will also benefit in reduction in the incidence of FGR and related PTB and therefore there are no clear guidelines in this population for this particular outcome. A systematic review and meta-analysis showed that administering aspirin to women with TwPs reduced the risk of PE but not FGR. The overall quality of evidence is low, highlighting the need for randomized controlled trials to elucidate this question [21]. A multicentric clinical trial (ASPRE-T) is being conducted to clarify the use of aspirin for the prevention of PE in TwPs [22]. Although the primary outcome measurement is the incidence of PE requiring delivery < 37 weeks gestation, the iatrogenic PTB for FGR is a secondary outcome aimed to be analyzed. Given that FGR leading to PTB occurs more frequently than early-onset PE, its potential impact on this outcome may be clinically more significant. Thus, there remains hope to reduce the morbidity associated with TwPs through the institution of pharmacological prophylaxis that can optimize fetal growth and reduce the incidence of PTB associated with this condition [23–24].

Strengths and Limitations - Our small dataset does not allow us to develop a well-fitted predictive model for SGA. However, we believe that predictive models can be established with larger multicenter data. Also, we do not routinely measure PLGF in the first trimester, and this biomarker has demonstrated to be slightly superior to PAPP-A in improving predictive models [16]. Despite these limitations, to our knowledge, this is the first reported multivariable model associating SGA in TwPs with first-trimester screening data. We emphasize the importance of employing TwPs’ specific references for UtA Dopplers, fetal growth, and birthweight in clinical studies involving TwPs, as outlined in our methodology.

SGA concurrent with prematurity significantly impacts TwPs, and the majority of pregnancies at risk for this outcome can be detected in the first trimester. However, larger datasets are necessary to develop robust predictive models.

Acknowledgements

No acknowledgments to declare.

Conflicts of interest and Competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Authorship

All authors contributed to the study conception and design. Data collection was performed by Alexandra Queirós, Ana Bernardo, Cláudia Rijo, Ana Carocha, Leonor Ferreira, Ana Teresa Martins, Álvaro Cohen and Teresinha Simões. Statistical analysis was performed by Alexandra Queirós, Marta Alves and Ana Luís Papoila. The first draft of the manuscript was written by Alexandra Queirós and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethical approval

The present study was sought and granted approval by the Local Ethical Committees of Nova Medical School-Universidade Nova de Lisboa (No. 81/2020/CEFCM) and CHULC (reference number 950/2020). Both retrospective analyses before 2020 and prospective inclusions after 2020 were approved by the ethical committees, according to institutional policies and national laws.

Consent to participate and for publication

Verbal informed consent was obtained from all subjects for participation and publication of data collection and obstetric outcomes in this cohort. Written consent was not sought for the present study before 2020 due to its retrospective nature and anonymous data collection. After 2020, written consent was obtained from all subjects for participation and publication.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors used ChatGTP 3.5 only in order to improve language and readability. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the publication's content.

Funding

No funding was obtained for the present study.

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Table 1 Maternal and pregnancy characteristics grouped by neonate birthweight: pregnancies unaffected and affected with one or both neonate small for gestational age <10^th and <3^rd birthweight percentiles.
Total n =572	Unaffected n=382 (66.8%)	SGA <10^th n= 190 (33.2%)		SGA < 3^rd n= 120 (20.9%)
	Mean(SD) or n(%)	Mean(SD) or n(%)	OR (95%CI) p-value	Mean(SD) or n(%)	OR (95%CI) p-value
Maternal age (years)	32.6 (5.2)	33.0 (5.3)	0.797	33.0 (5.3)	0.405
Age ≥40 years	25 (6.5%)	13 (6.8%)	1.0 (0.5-2.0) 0.893	10 ( 8.3%)	1.3 (0.6-2.9) 0.403
BMI (Kg/m2)	24.7 (4.4)	23.7 (4.1)	0.002	23.7 (4.1)	0.076
BMI <20	36 (9.4%)	38 (20.0%)	2.4 (1.4-3.9) <0.001	23 (19.2%)	1.8 (1.1-3.1) 0.022
BMI ≥20<25	201 (52.6%)	95 (50.0%)	0.9 (0.6-1.2) 0.555	59 (49.2%)	0.8 (0.6-1.3) 0.524
BMI ≥25<30	102 (26.7%)	38 (20.0%)	0.6 (0.4-1.0) 0.079	24 (20.0%)	0.7 (0.4-1.2) 0.200
BMI ≥30	43 (11.3%)	19 (10.0%)	0.8 (0.4-1.5) 0.649	14 (11.7%)	1.1 (0.6-2.0) 0.743
Ethnicity
Caucasian	327 (85.6%)	166 (87.4%)	1.1 (0.7-1.9) 0.564	101 (84.2%)	0.8 (0.5-1.4) 0.470
African	46 (12.0%)	17 (8.9%)	0.7 (0.4-1.2) 0.266	12 (10.0%)	0.8 (0.4-1.7) 0.690
South Asian	8 (2.1%)	7 (3.7%)	1.7 (0.6-5.0) 0.275	7 (5.8%)	3.4 (1.2-9.6) 0.013
Mixed	1 (0.3%)	0 (0.0%)	0.480	0 (0.0%)	1.000
Nulliparous	230 (60.2%)	131 (68.9%)	1.4 (1.0-2.1) 0.041	80 (66.7%)	1.5 (1.0-2.3) 0.364
Parous with prior PTB	13/152 (8.5%)	9/59 (15.3%)	1.9 (0.7-4.7) 0.153	7/40 (17.5%)	2.2 (0.8-5.8) 0.146
Parous with prior SGA	5/152 (3.3%)	8/59 (13.6%)	4.6 (1.4-14.7) 0.009	7/40 (17.5%)	5.8 (1.8-18.4) 0.004
Parous with prior PE	5/152 (3.3%)	3/59 (5.1%)	1.5 (0.3-6.8) 0.689	3/40 (7.5%)	2.6 (0.6-11.7) 0.177
Method of conception
Spontaneous	236 (61.8%)	109 (57.4%)	0.8 (0.5-1.1) 0.310	70 (58.3%)	0.9 (0.6-1.3) 0.618
Ovulation inductions	15 (3.9%)	6 (3.2%)	0.7 (0.3-2.0) 0.645	3 (2.5%)	0.6 (0.2-2.1) 0.443
ART	131 (34.3%)	75 (39.5%)	1.2 (0.8-1.7) 0.224	47 (39.2%)	1.2 (0.8-1.8) 0.418
Chorionicity
Monochorionic diam.	74 (19.4%)	48 (25.3%)	0.7 (0.5-1.0) 0.105	27 (22.5%)	0.9 (0.6-1.5) 0.725
Dichorionic	308 (80.6%)	142 (74.7%)	0.7 (0.5-1.0) 0.105	93 (77.5%)	0.9 (0.6-1.5) 0.725
Smoker	30 (7.9%)	24 (12.6%)	1.6 (0.9-2.9) 0.066	11 (9.2%)	0.9 (0.5-1.9) 0.908
Chronic hypertension	17 (4.5%)	12 (6.3%)	1.4 (0.7-3.0) 0.338	8 (6.7%)	1.4 (0.6-3.3) 0.370
SLE/APS/Thrombophilia	11 (2.9%)	4 (2.1%)	0.7 (0.2-2.3) 0.783	3 (2.5%)	0.9 (0.3-3.4) 1.000
Aspirin prophylactic intake (started <20 weeks)	44 (11.5%)	29 (15.3%)	1.3 (0.8-2.2) 0.231	19 (15.8%)	1.3 (0.8-2.4) 0.257
1^st trimester Mean Arterial Pressure	85.4 (8.5)	86.0 (8.7)	0.824	86.4 (8.5)	0.582

ART- artificial reproductive techniques; APS- Antiphospholipid syndrome; β-hCG- β-human chorionic gonadotropin; BMI- body mass index; CI – confidence interval; OR -odds ratio; PE- preeclampsia; PTB- preterm birth; SGA- small for gestational age; SD- standard deviation; SLE- Systemic lupus erythematosus;

Table 2 First trimester serum biomarkers and uterine artery doppler grouped by neonate birthweight: pregnancies unaffected and affected with one or both neonate small for gestational age <10^th and <3^rd birthweight percentiles.
	Total	Unaffected	SGA <10^th		SGA < 3^rd
	n	n(%)	n(%)	OR (95%CI) p-value	n(%)	OR (95%CI) p-value
Uterine artery available data	390	254 (65.1%)	136 (34.8%)		90 (23.1%)
Uterine artery PI ≥ 90^th perc.	42	21 (8.3%)	21 (15.4%)	2.0 (1.1-3.8) 0.029	18 (20.0%)	2.8 (1.4-5.5) 0.001
Uterine artery PI ≥ 95^thperc.	24	10 (3.9%)	14 (10.3%)	2.8 (1.2-6.5) 0.013	13 (14.4%)	4.4 (1.9-10.2) < 0.001
Biomarkers available data	464	314 (67.2%)	150 (32.3%)		97 (20.8%)
PAPP-A MoM ≤ 10^th perc.	46	26 (8.3%)	20 (13.1%)	1.6 (0.9-3.0) 0.103	16 (16.5%)	2.2 (1.1-4.3) 0.014
β-hCG MoM ≤ 10^th perc.	46	28 (8.9%)	18 (11.8%)	1.3 (0.7-2.5) 0.332	13 (13.4%)	1.5 (0.8-3.1) 0.187

β-hCG - β-human chorionic gonadotropin; OR- odds ratio; PAPP-A - pregnancy-associated plasma protein-A; perc. – percentile; PI – pulsatility index; SGA – small for gestational age.

Table 3 Association of small for gestational age <10^th and <3^rd birthweight percentiles (one or both neonates per pregnancy) with obstetric and perinatal outcomes in MC and DC twin pregnancies
Total n=572	Unaffected n=382 (MC=74, DC=308)	SGA <10^th n= 190 ( MC= 48 , DC= 142 )		SGA < 3^rd n= 120 (MC=27, DC=93)
	Mean(SD) or n(%)	Mean(SD) or n(%)	OR (95%CI) p-value	Mean(SD) or n(%)	OR (95%CI) p-value
Prenatal suspicion of Fetal Growth Restriction (one or both fetus per pregnancy)
All twins	32 (8.4%)	120 (63.2%)	18.7 (11.7-29.9) < 0.001	92 (76.7%)	21.4 (12.9-35.4) <0.001
Monochorionic	5 (6.8%)	39 (81.3%)	59.8 (18.7-191.0) < 0.001	25 (92.6%)	50.0 (10.8-229.8) <0.001
Dichorionic	27 (8.8%)	81 (57.0%)	13.8 (8.2-23.1) < 0.001	67 (72.0%)	19.8 (11.3-34.6) <0.001
Fetal abnormal Doppler findings (one or both fetus per pregnancy)
All twins	28 (7.5%)	66 (34.7%)	6.7 (4.1-10.9) <0.001	53 (44.2%)	7.7 (4.7-12.6) <0.001
Monochorionic	8 (10.8%)	20 (41.7%)	5.8 (2.3-14.9) < 0.001	17 (63.0%)	12.9 (4.7-35.4) <0.001
Dichorionic	20 (6.7%)	46 (32.4%)	6.9 (3.8-12.3) <0.001	36 (38.7%)	6.7 (3.8-11.8) <0.001
Single fetal demise ≥ 24 weeks ^a
Dichorionic	1 (0.3%)	1 (0.5%)	2.1 (0.1-35.0) 0.532	1 (0.8%)	3.8 (0.2-62.4) 0.371
Gestational age at delivery (weeks)
Monochorionic	35.3 (1.5)	34.2 (1.6)	<0.001	33.9 (1.9)	<0.001
Dichorionic	36.2 (1.6)	34.3 (2.7)	<0.001	34.0 (2.7)	<0.001
Mean birthweight (g)
Monochorionic	2370 (323)	1816 (306)	<0.001	1684 (325)	<0.001
Dichorionic	2515 (346)	1872 (446)	<0.001	1788 (440)	<0.001
Birthweight discrepancy ≥ 25%
All twins	2 (0.5%)	37 (19.5%)	45 (10.7-189.9) <0.001	34 (28.3%)	34.8 (13.2-91.6) <0.001
Monochorionic	0 (0.0%)	7 (14.6%)	0.001^b	6 (22.2%)	26.5 (3.0-232.5) <0.001
Dichorionic	2 (0.7%)	30 (21.1%)	40.3 (9.4-171.4) <0.001	28 (30.1%)	37.4 (12.7-110.4) <0.001
PTB < 32 weeks
All twins	11 (2.9%)	28 (14.7%)	5.8 (2.8-11.9) <0.001	23 (19.2%)	6.4 (3.3-12.7) <0.001
Monochorionic	2 (2.7%)	4 (8.3%)	3.2 (0.5-18.6) 0.210	4 (14.8%)	8.0 (1.3-46.8) 0.021
Dichorionic	9 (2.9%)	24 (16.9%)	6.7 (3.0-14.9) <0.001	19 (20.4%)	6.2 (3.0-13.1) <0.001
PTB < 34 weeks
All twins	27 (7.1%)	55 (28.9%)	5.3 (3.2-8.8) <0.001	40 (33.3%)	4.8 (2.9-8.0) <0.001
Monochorionic	7 (9.5%)	12 (25.0%)	3.1 (1.1-8.8) 0.021	9 (33.3%)	4.2 (1.5-11.9) 0.013
Dichorionic	20 (6.5%)	43 (30.3%)	6.2 (3.5-11.1) <0.001	31 (33.3%)	5.0 (2.8-8.9) <0.001
PTB < 36 weeks
All twins	82 (21.5%)	113 (59.5%)	5.3 (3.6-7.8) <0.001	73 (60.8%)	4.2 (2.7-6.4) <0.001
Monochorionic	17 (23.0%)	39 (81.3%)	14.5 (5.8-35.9) <0.001	23 (85.2%)	10.8 (3.4-33.8) <0.001
Dichorionic	65 (21.1%)	74 (52.1%)	4.0 (2.6-6.2) <0.001	50 (53.8%)	3.5 (2.1-5.6) <0.001
Neonatal Death ^a
Dichorionic	4/763 (0.5%)	0/379 (0.0%)	0.397^b	4/239 (1.7%)	3.8 (0.8-17.0) 0.129
Perinatal Death ^a
Dichorionic	5/764 (0.6%)	1/379 (0.3%)	0.4 (0.01-2.9) 0.708	5/240 (2.1%)	3.8 (1.0-14.3) 0.078
Neonatal Care Unit admission ≥ 8 days
All twins	78/759 (10.2%)	177/379 (30.8%)	7.6 (5.5-10.5) <0.001	120/235 (51.0%)	5.9 (4.3-8.1) <0.001
Monochorionic	22/148 (14.8%)	58/96 (60.4%)	8.6 (4.7-16.2) <0.001	38/54 (70.3%)	11.2 (5.8-22.6) <0.001
Dichorionic	56/611 (9.2%)	119/283 (42.0%)	7.1 (5.0-10.3) <0.001	82/181 (45.3%)	5.5 (3.8-7.9) <0.001

a) all events in dichorionic pregnancies; b) The odds ratio could not be calculated due to zero counts in one of the groups

DC- Dichorionic; MC – Monochorionic; OR- odds ratio; PTB- preterm birth; SD- standard deviation; SGA- small to gestational age;

Table 4 Multivariable regression analyses for SGA and concurrent PTB in twin pregnancies.
Outcomes and independent variables	Adjusted OR (95%CI)	p-value	AUC (95%CI) Sensitivity to False Positive rate of 20%	Significance value
One or both SGA < 3^rdpercentile
PAPP-A MoM < 10^th percentile	2.1 (0.9-4.6)	0.050	0.582 (0.509-0.656) S 37%	0.826
UtA-PI ≥ 95^th percentile	5.3 (2.1-12.9)	<0.001	0.582 (0.509-0.656) S 37%	0.826
One or both SGA < 5^th percentile
Maternal Age ≥40 years	2.0 (0.9-4.7)	0.088	0.666 (0.604-0.728) S 45%	0.385
Nulliparas	1.7 (0.9-2.8)	0.053
BMI < 20 (Kg/m2)	1.9 (1.0-3.7)	0.049
PAPP-A MoM (continuous)	0.6 (0.4-1.0)	0.067
UtA-PI > 95^th percentile	4.8 (1.8-12.2)	<0.001
One or both SGA < 10^th percentile
Nulliparas	1.8 (1.1-2.9)	0.008	0.643 (0.584-0.702) S 39%	0.846
BMI < 20 (Kg/m2)	1.7 (0.9-3.2)	0.070
PAPP-A MoM (continuous)	0.7 (0.4-1.0)	0.124
UtA-PI > 95^th percentile	2.9 (1.2-6.8)	0.014
One or both SGA < 3^rd percentile and PTB < 32 weeks
Smoking habits	3.3 (0.9-12.1)	0.061	0.765 (0.650-0.881) S 70%	0.658
MAP (continuous)	1.0 (1.0-1.1)	0.031
PAPP-A MoM < 10^th percentile	3.2 (0.9-11.5)	0.066
UtA-PI ≥ 95^th percentile	6.0 (1.6-21.8)	0.006
One or both SGA < 3^rd percentile and PTB < 34 weeks
MAP (continuous)	1.0 (0.9-1.0)	0.124	0.665 (0.557-0.773) S 43%	0.773
PAPP-A MoM (continuous)	0.4 (0.1-0.9)	0.043
UtA-PI ≥ 95^th percentile	4.7 (1.6-13.4)	0.004
One or both SGA < 3^rd percentile and PTB < 36 weeks
PAPP-A MoM (continuous)	0.5 (0.3-0.9)	0.041	0.641 (0.555-0.727) S 40 %	0.468
UtA-PI ≥ 95^th percentile	6.4 (2.5-16.4)	<0.001	0.641 (0.555-0.727) S 40 %	0.468
One or both SGA < 10^th percentile and PTB < 32 weeks
Smoking habits	2.6 (0.7-8.8)	0.125	0.710 (0.590-0.830) S 50%	0.880
MAP (continuous)	1.0 (0.9-1.1)	0.053
PAPP-A MoM < 10^th percentile	2.6 (0.7-8.8)	0.120
UtA-PI ≥ 95^th percentile	4.7 (1.3-16.2)	0.014
One or both SGA < 10^th percentile and PTB < 34 weeks
BMI ≥ 30 (Kg/m2)	2.2 (0.9-5.2)	0.055	0.652 (0.561-0.744) S 44%	0.734
PAPP-A MoM (continuous)	0.5 (0.2-1.0)	0.066
UtA-PI > 95^th percentile	3.3 (1.2-9.4)	0.020
One or both SGA < 10^th percentile and PTB < 36 weeks
Nulliparas	2.3 (1.2-4.3)	0.005	0.669 (0.602-0.736) S 41%	0.223
Monochorionic	1.8 (0.9-3.4)	0.057
PAPP-A MoM (continuous)	0.6 (0.3-1.0)	0.054
UtA-PI > 95^th percentile	3.5 (1.4-8.9)	0.007

AUC- area under the receiver-operating characteristic curve; BMI- body mass index; MAP – mean arterial pressure; MoM- Multiple of the Median; OR- odds ratio; PAPP-A- Pregnancy-Associated Plasma Protein-A; PTB- Preterm Birth; SGA- Small for Gestational Age; UtA-PI – uterine artery pulsatility index.

First-trimester screening and small for gestational age in twin pregnancies: a single center cohort study.

Status:

Version 1

Abstract

What does this study adds to the clinical work

Introduction

Materials and Methods

Statistical analysis

Results

Discussion

Conclusions

Declarations

References

Tables

Status:

Version 1