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Peer-reviewed

Research Article

Twin pregnancy and perinatal outcomes: Data from ‘Birth in Brazil Study’

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Department of Epidemiology and Quantitative Methods in Health, Sérgio Arouca National School of Public Health, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil

Roles Conceptualization, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing

Affiliation Medical School of Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Affiliation National Institute of Women, Children and Adolescents Health Fernandes Figueira, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil

Roles Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review & editing

Affiliation National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil

Roles Formal analysis, Investigation, Writing – original draft, Writing – review & editing

Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Writing – original draft, Writing – review & editing

• Ana Paula Esteves-Pereira, 
• Antônio José Ledo Alves da Cunha, 
• Marcos Nakamura-Pereira, 
• Maria Elisabeth Moreira, 
• Rosa Maria soares madeira Domingues, 
• Elaine Fernandes Viellas, 
• Maria do Carmo Leal, 
• Silvana Granado nogueira da Gama

• Published: January 11, 2021
• https://doi.org/10.1371/journal.pone.0245152
• Peer Review
• Reader Comments

Twin pregnancies account for 0.5–2.0% of all gestations worldwide. They have a negative impact on perinatal health indicators, mainly owing to the increased risk for preterm birth. However, population-based data from low/middle income countries are limited. The current paper aims to understand the health risks of twins, compared to singletons, amongst late preterms and early terms.

Data is from “Birth in Brazil”, a national inquiry into childbirth care conducted in 2011/2012 in 266 maternity hospitals. We included women with a live birth or a stillborn, and excluded births of triplets or more, totalling 23,746 singletons and 554 twins. We used multiple logistic regressions and adjusted for potential confounders.

Twins accounted for 1.2% of gestations and 2.3% of newborns. They had higher prevalence of low birth weight and intrauterine growth restriction, when compared to singletons, in all gestational age groups, except in the very premature ones (<34 weeks). Amongst late preterm’s, twins had higher odds of jaundice (OR 2.7, 95% CI 1.8–4.2) and antibiotic use (OR 1.8, 95% CI 1.1–3.2). Amongst early-terms, twins had higher odds of oxygen therapy (OR 2.7, 95% CI 1.3–5.9), admission to neonatal intensive care unit (OR 3.1, 95% CI 1.5–6.5), transient tachypnoea (OR 3.7, 95% CI 1.5–9.2), jaundice (OR 2.8, 95% CI 1.3–5.9) and antibiotic use (OR 2.2, 95% CI 1.14.9). In relation to birth order, the second-born infant had an elevated likelihood of jaundice, antibiotic use and oxygen therapy, than the first-born infant.

Although strongly mediated by gestational age, an independent risk remains for twins for most neonatal morbidities, when compared to singletons. These disadvantages seem to be more prominent in early-term newborns than in the late preterm ones.

Citation: Esteves-Pereira AP, da Cunha AJLA, Nakamura-Pereira M, Moreira ME, Domingues RMsm, Viellas EF, et al. (2021) Twin pregnancy and perinatal outcomes: Data from ‘Birth in Brazil Study’. PLoS ONE 16(1): e0245152. https://doi.org/10.1371/journal.pone.0245152

Editor: Andrew Sharp, University of Liverpool, UNITED KINGDOM

Received: August 7, 2020; Accepted: December 22, 2020; Published: January 11, 2021

Copyright: © 2021 Esteves-Pereira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The Birth in Brazil Study was funded by the National Council for Scientific and Technological Development (CNPq); National School of Public Health, Oswaldo Cruz Foundation (INOVA Project); and Foundation for supporting Research in the State of Rio de Janeiro (FAPERJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Twin births rates vary considerably around the world, according to country development, from less than 1% of all births in Asian South and Southeast [ 1 ] to more than 3% in the USA [ 2 ] and France [ 3 ]. Variations also exist according to race and ethnicity [ 1 , 2 ]. Multiple birth rates have been rising since the 1970s in developed countries [ 4 , 5 ]. Over three decades (1980–2009), the twin birth rate rose by 76% in USA, increasing more than 2% per year from 1980 through 2004 and reaching 3.3% of all births in 2009 [ 6 ]. The increasing maternal age after the emergence of new contraception and infertility treatments are the main causes of the increase in twin pregnancy rates [ 4 , 5 , 7 – 9 ].

In Brazil, according to the National Live Births Database (SINASC), there is also an increasing trend in twin birth rates, from 1.7% to 2.0% in the sixteen years since 2000 [ 10 ]. This trend was corroborated by a study in a Southern city of Brazil where multiple birth rates rose from 1.9% to 2.5% in the period 1994–2005 [ 11 ]. The prevalence of twin gestations is higher in the Brazilian regions with higher human development index (HDI). Moreover, mothers of twins are older and show higher levels of education [ 12 ].

Twin births have a negative impact on perinatal health indicators, since twins have a higher risk of perinatal mortality [ 12 – 14 ], especially due to higher preterm birth rates [ 5 ]. In low and middle income countries, early neonatal mortality is seven times higher among twins [ 14 ]. Even when we adjust these figures according to birth weight, the chance of early neonatal mortality in twins is three times higher than for single births. Several investigations have found that neonatal mortality and morbidity of the second twin are higher than the first [ 12 , 15 , 16 ]. Studies also point to the conflicting results on the safest mode of delivery for the second twin, particularly for non-cephalic second twins [ 16 – 18 ].

Moreover, maternal mortality and morbidity are higher in cases of twin births when compared with single pregnancies [ 13 , 19 , 20 ]. A large study conducted mainly in low- and middle- income countries has found that mothers of twins were three times more at risk of maternal near miss. The same group of women were considered four times more at risk of maternal mortality, particularly due to postpartum haemorrhage and hypertensive disorder [ 19 ].

In Brazil, as in several developing countries, surveys of twin pregnancies with country-specific data are limited. Most studies are hospital-based and consider a limited number of hospitals [ 21 ], or they are based on secondary data [ 11 , 12 ]. ‘Birth in Brazil’ was the first perinatal survey in Brazil to provide primary data comprising national and regional representative samples [ 22 ]. The study provides plentiful resource with which we can evaluate the magnitude of adverse outcomes in twin pregnancies in Brazil.

The objective of the current paper is to understand the health risks of giving birth to twins at different gestational ages. Subsequent analysis will explore the relationship between birth order and maternal and perinatal outcomes in cases of twin births.

Methodology

The present manuscript is based on data from ‘Birth in Brazil’, a nationwide population-based survey on gestation and delivery, performed between February 2011 and October 2012. The sample was selected in three stages. The first stage was to select hospitals with 500 or more births / year, stratified by the country's five macro-regions, location (capital or non-capital) and type of hospital (private, public and mixed). The second consisted of identifying the number of days needed to interview 90 puerperae (minimum of seven days in each hospital). The third consisted of selecting appropriate puerperae. 266 hospitals were sampled in total. Further details of sample design are available in Vasconcellos et al (2014) [ 23 ].

Inclusion and exclusion criteria

The study included 24,035 women who were admitted to maternity wards at the time of delivery, along with their newborns of any gestational age and weight, and stillbirths with birth weight ≥ 500 g and / or gestational age ≥ 22 weeks’ gestation. Of these, 23,746 had a single birth (23,746 newborns), 277 had twins (554 newborns) and 12 had triplets (36 newborns). For the present analysis, we have excluded deliveries of triplets. We thus sampled a total of 24,023 puerperae and 24,300 newborns.

Predictor variables

The main predictor variable was twin pregnancy, compared to single pregnancies, stratified into four gestational age groups: <34 weeks (preterm), 34–36 weeks (late preterm), 37 and 38 weeks (early term) and ≥39 weeks (full term). As a secondary predictor variable, we analysed the birth order of twin infants (first-born or second-born).

We analysed the following outcomes: low birthweight (<2500g); intrauterine growth restriction [IUGR] (below the tenth and third percentiles); resuscitation of the newborn in the delivery room (positive pressure ventilation, orotracheal intubation, cardiac massage or use of drugs); oxygen therapy (oxygen Hood, continuous positive airway pressure (CPAP) or mechanical ventilation); use of antibiotics at any time during hospitalisation; admission to the Neonatal Intensive Care Unit (NICU); transient tachypnoea of the newborn; hypoglycaemia in the first 48 hours of life; phototherapy in the first 72 hours of life (jaundice); severe neonatal outcomes; and severe maternal outcomes. The severe neonatal outcome included neonatal near misses, according to the WHO classification [ 24 ]. It also included early and late foetal and neonatal deaths. The severe maternal outcome included maternal near misses, according to the WHO classification [ 25 ], and maternal deaths occurring in the puerperal period. Appropriate birth weight for gestational age was assessed by Intergrowth-21st intrauterine growth curves, considering birth weight <10 th percentile as small for gestational age (SGA) and birth weight <3 th percentile as intrauterine growth restriction (IUGR) [ 26 ].

Covariables

We identified the following variables as potential confounding factors: macroregion (North, Northeast, South, Southeast, Midwest), type of payment for childbirth (public or private); maternal age (<20, 20–34, ≥35); years of maternal schooling (≤7, 8–10, 11–14, ≥15); and gestational age upon delivery (in gestational weeks).

Data collection

We collected data on the socioeconomic characteristics of the women (age, ethnicity, schooling, economic class, presence of a companion, and employment status) through face-to-face interviews with puerperal women. Data on obstetric history and maternal medical conditions were collected from maternal hospital records and prenatal cards. We recorded all neonatal outcomes from hospital records of newborns.

We gathered information on gestational age upon delivery primarily from results of ultrasound examinations, performed between seven and thirteen gestational weeks. We collected this information from both the original ultrasound examination and prenatal cards, maternal hospital and newborn records. 74% of women had gestational age at birth classified by this method and, in the absence of ultrasonographic estimates, gestational age was based on the information reported by the woman in the interview (23%) and, finally, on the date of the last menstrual period (1%) and the 50% percentile of weight for gestational age at birth (2%) [ 27 ].

Statistical analysis

Post-hoc calculations show that with a significance level of 5%, the twin sample (554 newborns) would have 80% power to detect an increased risk corresponding to an OR of ≥2 for neonatal outcomes, with a prevalence of 5%. However, gestational age categories of 34–36 weeks (with 248 newborns) and 37–38 weeks (with 164 newborns) would have 80% power to detect an increased risk corresponding to an OR of ≥2.5 and ≥3.0, respectively, for neonatal outcomes with a prevalence of 5%.

We analysed the differences in the characteristics of postpartum women, as well as absolute differences in neonatal outcomes according to twin births, using the χ2 test. Using multiple non-conditional logistic regressions, stratified by the four gestational age categories (<34, 34–36, 37 and 38, ≥39), we analysed neonatal outcomes associated with twin births in comparison to single births. We analysed neonatal outcomes associated with birth order by means of multiple non-conditional logistic regression. In both analyses, we estimated the odds ratios (OR), adjusted odds ratios (adj. OR) and their respective 95% confidence intervals.

For all outcomes, macro-region, type of birth payment, maternal age, maternal schooling years and gestational age, we performed adjusted analysis. Gestational age at delivery was used as an adjustment variable in the model in complete gestational weeks, as there was a higher proportion of twins than single births at lower gestational ages, even within the pre-determined categories. We accounted for the complex sample design in all statistical analyses. We adopted a significance level of 5% for all analyses. For this research, we used the statistical programme SPSS V.20.0.

Ethical considerations

This study was approved by the Research Ethics Committee of ENSP / FIOCRUZ under number 92/2010. Measures have been taken to ensure the privacy and confidentiality of data collected from participants. Informed consent was obtained prior to interviews with the use of an informed consent form.

Women giving birth to twins shared several defining characteristics, including higher usage of private healthcare services, older age (≥ 35 years), and a greater prevalence of hypertensive disorders (chronic and gestational arterial hypertension, preeclampsia and HELLP syndrome) when compared to single birth mothers.

Among women giving birth to twins, the onset of labour was mostly provider-initiated, with almost no labour induction performed. Caesarean sections were performed in 84% of twin births and, amongst them, 61.5% were elective (antepartum) CS. Gestational age ranges in twin births also differed significantly from figures observed in single births ( Table 1 and S1 Fig ). We detail the onset of labour and mode of birth in twin and singleton newborns, by gestational age groups, in S1 Table .

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https://doi.org/10.1371/journal.pone.0245152.t001

Newborn twins showed lower birthweights and a higher prevalence of restricted intrauterine growth, when compared to newborn single births. The results were independent of which percentile was considered (either tenth or third percentile) ( Table 2 ). Of the 277 pairs of twins, 21% (59 pairs) were of the same sex and 20% (55 pairs) showed a difference in birthweights that exceeded 20% (data nor shown).

https://doi.org/10.1371/journal.pone.0245152.t002

Newborn twins presented a larger risk of presenting neonatal outcomes, such as oxygen therapy, admission to neonatal intensive care unit, transient tachypnoea, jaundice and antibiotic use. Nevertheless, the absolute difference between twin and single newborns was more noticeable in late preterm infants ( Table 2 ).

Among late preterm infants, for every one-hundred infants born, around 48% of newborn twins showed neonatal near miss/foetal mortality/neonatal mortality, compared to 28% of the same outcomes among single newborns. Equally, 30% of twins showing signs of jaundice were subjected to phototherapy, compared to 11% in single newborns; 29% of twins were admitted to an intensive care unit (ICU), compared to 18% in single newborns; and antibiotics were used to treat 20% of newborn twins, compared to 12% in single newborns ( Table 2 ).

For early term infants, absolute differences between newborn twins and single-births were of a lesser magnitude, varying between 0.9% and 6.5%. Yet statistical significance was noted in a greater number of outcomes ( Table 2 ).

In cases of extreme prematurity, the difference in the application of supplemental oxygen between twins and single newborns was more telling: 91% vs. 76%, respectively. Meanwhile, the difference in levels of admission to an ICU was comparable to figures observed in late preterm infants. Although, the overall proportion of extremely premature infants admitted to an ICU was far greater ( Table 2 ).

In adjusted analysis, late preterm newborn twins showed a greater likelihood of being admitted to an ICU, receiving treatment with antibiotics, neonatal near miss, and undergoing phototherapy, with OR varying between 1.6 (CI 1.0–2.7) and 4.1 (CI 1.2–3.8). For early term infants, newborn twins were more likely to receive antibiotics, supplemental oxygen, phototherapy, to be admitted to an ICU, and to suffer from transient tachypnoea and hypoglycaemia, with OR varying between 2.5 (CI 1.1–5.6) and 6.2 (CI 1.9–20.0). Twin births were neither associated with maternal near miss nor maternal mortality ( Table 3 ).

https://doi.org/10.1371/journal.pone.0245152.t003

When analysing birth order in twins, we found that the second-born twin showed a greater prevalence of the outcomes studied in this research, compared to the first-born twin. After adjusting for confounding factors, second-born twins showed an elevated likelihood of requiring supplemental oxygen, treatment with antibiotics and phototherapy, than first-born twin ( Table 4 ).

https://doi.org/10.1371/journal.pone.0245152.t004

The twin pregnancy rate has increased in the last three decades due to available technologies facilitating assisted reproduction, and because more women of advanced age (≥ 35 years old) are becoming pregnant [ 7 – 9 ]. The proportion of twin pregnancies in this study was 1.15%, similar to results found in other studies in Brazil [ 12 ].

Twin pregnancies and births continue to present a challenge for health services. The risk of stillbirth is high, and the timing of delivery is important. Monochorionic twin pregnancies and dichorionic gestation, which often leads to early delivery, potentially increase the risk of neonatal complications [ 28 – 30 ]. Since the main objective of “Birth in Brazil” study was not to study twin births, it was not possible to determine whether the twin pregnancy was monochorionic or dichorionic. Neither was it possible to discern whether assisted reproductive technologies (ART) were applied during twin pregnancies. It was, however, possible to determine that the proportion of twins was higher in the private sector and in women >39 years, which increases the odds of twin pregnancy by ART. The same trend was observed in other studies in Brazil [ 12 , 31 ].

We found that the absolute difference between severe perinatal outcomes in twins compared to single born infants is higher during the late preterm period. The magnitude of this outcome reaches almost 50% of infants. The proportion of spontaneous and provider-initiated twin births was similar to single births in the late preterm; spontaneous births represented 60% of the total number of births. Thus, a possible explanation for the disparities of outcomes between twins and single born infants could be due to the higher prevalence of intrauterine growth restriction. Weight is a defining criterion for neonatal near miss and IUGR infants had greater occurrence of stillbirths. As for early term births, there was no significant increase in the chances of adverse perinatal outcomes of twins relative to single born infants. However, other neonatal outcomes—with the exception of resuscitation—were more prevalent in twins. These differences can be explained, in part, by the fact that 66% of births were provider-initiated, mainly prelabour caesarean, which increases the risk of respiratory morbidity of the newborn [ 32 ].

The optimal time of delivery for twin pregnancies is a highly debated topic [ 28 – 30 , 33 ]. A meta-analysis published in 2016 [ 30 ], which included 29,685 dichorionic and 5,486 monochronic pregnancies, showed that waiting for delivery beyond 37 weeks led to an additional 8.8/1,000 perinatal deaths in dichorionic twin pregnancies. For monochorionic twins, there was a non-significant trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks. This analysis supported the notion that delivery should be carried out at 37 weeks for dichorionic pregnancies, and at 36 weeks for uncomplicated monochorionic twins. However, other authors support the close monitoring of twin pregnancies so as to avoid late preterm deliveries without increasing risk of stillbirth [ 34 ]. In our study, most twins were delivered between 34 and 38 weeks of gestational age (74.4%) and had significantly more neonatal complications associated with the gestational age (jaundice, neonatal ICU admission, hypoglycaemia, need for oxygen, and use of antibiotics, among other morbidities).

Even though we collected our data before new recommendations regarding the timing of delivery of twins up to 38 weeks were emphasised in literature [ 30 , 35 ], only 8% of twins were born after 38 weeks.

In our data, the non-significant difference in the odds of adverse perinatal outcomes between twins and early term single born infants suggests that early term delivery is more beneficial to infant and mother than late preterm delivery.

The mode of delivery observed in this study was predominantly caesarean as an obstetric intervention. This procedure continues to draw controversy, especially when applied to a second twin not in the cephalic position [ 17 , 18 , 36 – 38 ]. In a randomised control trial published in 2013, planned caesarean did not result in an increase or decrease of perinatal mortality or serious neonatal morbidity [ 18 ]. In a cohort study conducted in Australia [ 38 ], when comparing planned caesarean section with planned vaginal delivery in twin pregnancies with the first cephalic foetus, there was no difference in perinatal mortality, Apgar score < 4, and asphyxia-related morbidity. However, before 36 weeks and 6 days, planned caesarean section resulted in higher neonatal morbidity and mortality. After 37 weeks, planned caesarean section resulted in less asphyixia-related morbidity, but no difference in mortality and morbidity < 28 days, and Apgar < 4 [ 38 ]. Similar results for preterm deliveries were found in a French study, in which planned caesarean was associated with increased composite neonatal mortality and morbidity [ 37 ]. In this study, no difference was found for term deliveries. We found that for early term infants, two thirds of twins were delivered by obstetric intervention, mainly via planned caesarean. Although we did not find differences regarding severe perinatal outcomes, some of the differences found for the other outcomes may be due to the effect of prelabour caesarean section, such as a greater likelihood of transient tachypnoea, need for oxygen therapy, and neonatal ICU admission.

Unlike other studies [ 13 , 19 , 20 ], we found no differences in severe maternal outcomes in twin pregnancies compared to single pregnancies. One hypothesis for this result is that twin pregnancies may receive more prenatal care than single pregnancies and are referred for delivery in specialised referral services. Moreover, Madar et al. [ 20 ] recently found that one fifth of the association between twin pregnancy and severe maternal outcomes may be mediated by caesarean delivery, yet caesarean rate was also high for single births in our sample. Recent findings from a French study verified that caesarean for the second twin and for both twins had higher risk of severe maternal morbidity compared to vaginal delivery for both twins [ 39 ], which also emphasizes the importance of reducing caesarean rates for twins in Brazil.

The twin pregnancy rate was similar to that found in other studies in Brazil. The proportion of caesarean sections was high, with 75% of newborns classified as late preterm and early term. Along with this came the inevitable greater occurrence of neonatal complications associated with these gestational ages. However, all neonatal complications were more frequent in twins at all gestational ages, when compared to single births. Caesarean delivery may be the cause for poorer outcomes observed in early term twins.

Supporting information

S1 fig. distribution of gestational age at birth in singleton and twin infants..

https://doi.org/10.1371/journal.pone.0245152.s001

S1 Table. Onset of labour and mode of birth in twin and singleton newborns by gestational age groups.

https://doi.org/10.1371/journal.pone.0245152.s002

https://doi.org/10.1371/journal.pone.0245152.s003

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• 10. Brasil (2018) Sistema de Informações sobre Nascidos Vivos. DATASUS: Ministério da Saúde.

Twin and Higher-order Pregnancies pp 411–424 Cite as

Research Studies in Twins and Multiple Pregnancy

• Janine R. Lam   ORCID: orcid.org/0000-0002-9878-838X 4 ,
• Becky Liu 5 ,
• Kate Murphy 4 &
• Asma Khalil 5  
• First Online: 01 January 2022

580 Accesses

This chapter outlines the key research priorities for the health of twins and multiples from the Global Twins and Multiples Priority Setting Partnership. These priorities are considered significant by families of twins and multiples and clinicians and researchers who work with twins and multiples. The top ten and 89 priorities from five key areas are discussed: antenatal care, intrapartum and postpartum care, neonatal and paediatric health, child psychiatry and development, and parental and family health. Existing findings and future directions for research are outlined.

• Postnatal depression
• Perinatal morbidity and mortality
• Growth restriction
• Neonatal unit admission

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Key Reading

Lam JR, Liu B, Bhate R, Fenwick N, Reed K, Duffy JMN, et al. Research priorities for the future health of multiples and their families: The Global Twins and Multiples Priority Setting Partnership. Ultrasound Obstet Gynecol. 2019;54(6):715–21. https://doi.org/10.1002/uog.20858 .

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Lam, J.R., Liu, B., Murphy, K., Khalil, A. (2021). Research Studies in Twins and Multiple Pregnancy. In: Khalil, A., Lewi, L., Lopriore, E. (eds) Twin and Higher-order Pregnancies. Springer, Cham. https://doi.org/10.1007/978-3-030-47652-6_28

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Study of obstetric and perinatal outcome of twin pregnancy

International Journal of Reproduction, Contraception, Obstetrics and Gynecology

Background: Multifetal pregnancy constitutes a significant portion of high-risk pregnancies. This is due to the increasing obstetric and perinatal morbidity and mortality rates associated with it. Maternal and perinatal outcome of twin pregnancies has been evaluated in this study.Methods: Total 30 patients with twin pregnancy and having gestational age more than 28 weeks were included in this observational study.Results: Incidence of twins in the study was found to be 2%. Twin pregnancies were more common in multiparous women aged between 20 and 30 years. Most common foetal presentation was vertex- vertex presentation. Most common maternal complication was preterm labour seen in 67% women, followed by anaemia seen in 50% women. Most of the women were delivered by caesarean section (63.3%). Most common perinatal complication was birth hypoxia (41.6%). Other perinatal complications were jaundice, septicemia, intrauterine growth restriction. 71% of the neonates had birth weight less th...

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Objective: To study the epidemiology, role of regular antenatal care influence of chorionicity maternal and perinatal outcome, maternal and fetal complication and plan of management in cases of twin pregnancy in our institute during study period of Jan. 2017 to Sep. 2018 Method: The study was conducted in the Department of Obstetrics and Gynecology of JLN Medical College & Associated group of hospitals, Ajmer (Raj.). 100 cases of twin pregnancy that register in Zanana Hospital during period of Jan 2017 to Sep 2018 were studied and data regarding feto-maternal outcome and the mode of delivery were collected and analyzed. Result: In our study we observed that incidence of twin pregnancy was 1:45.4, with the mean age of the patients ranging between 21-30years. Antenatal diagnosis was made in 92% cases and in 8% of cases diagnosed after delivery of first baby. Out of 100 cases 48% were primigravida and 27% were second gravida, 41% were below the gestation age of 37 weeks while 59% above it. In 51% cases presentation of both twin was vertex-vertex and in remaining 24% vertex-breech being the commonest presentation. The incidence of operative delivery was 46% and vaginal delivery 54%. The incidence of monozygotic twins was 6% and of dizygotic twins 93%.In present study total perinatal mortality morbidity was 26% and higher for second twin (29%) as compared to first twin (23%) and more in monozygotic twin (45%) than in dizygotic twins (24%), more in males (22.12%) than in females (18%). The incidence of anemia was 19%, PIH 15% accidental hemorhage 6% and cord prolapsed 3% respectively, preterm was pain 42% PROM 14%. Post partum hemorrhage occurred in 10% of cases and anemia in post partum stage was 12%. Conclusion: As we know twin pregnancy is associated with a high risk in mother as well as foetus, this warrants need of early antenatal diagnosis and vigilant care during antenatal as well as intrapartum and postpartum period to reduce complications.

Clarence Samuel

Background: Twin pregnancy is a high-risk pregnancy with increased incidence in the past few years. They are associated with much higher rates of maternal and perinatal morbidity and mortality as compared to singleton pregnancies. Material and methods: This was a prospective case control study conducted at Department of Obstetrics and Gynaecology, BNMCC, Government Medical College, Amritsar from February 2019 to August 2020. 100 cases of twin pregnancies (cases) and 100 singleton pregnancies (controls) delivered at our hospital were recruited in the study. After history taking, patients were subjected to examination and relevant investigations as per the protocol. Various feto-maternal parameters were recorded and the data was analysed statistically. Results: The incidence of twin pregnancies was 1.75% with majority patients belonging to 21-25 years age group. Most of the patients in our study were multigravida. Iatrogenic conception was seen in 8% of twin pregnancies. Mean gestational age of presentation was 33.3 weeks in twin pregnancies as compared to 36.4 weeks in singleton pregnancies. DCDA was the most common type of placentation seen in 64% of twin pregnancies. Preterm labour (62%), anaemia (59%) and malpresentation (35%) were the major complications in twin pregnancies which were significantly higher as compared to singletons. Other complications like PROM (23%), hypertensive disorders (17%), PPH (11%), hyperemesis (5%) were also more common in twin pregnancies. Significantly higher rates of LSCS (62%) were found in twin pregnancies as compared to 42% in singleton pregnancies. Low birth weight babies were seen in 89% of twin pregnancies as compared to 21% of singleton pregnancies. Complications associated with prematurity and low birth weight were the main causes of neonatal morbidities and mortality in cases of twin pregnancies. Perinatal mortality in our study was 19% in first twin and 26% in second twin which was significantly higher as compared to 12 % in singletons. Conclusion: Twin pregnancies are associated with significant feto-maternal morbidity and mortality. Frequent antenatal visits, early detection of high-risk cases, timely referral, and early hospitalization with good neonatal care set up are necessary to improve the maternal and neonatal outcomes associated with twin pregnancies.

Sanjivani wanjari

Background: A normal delivery is what every woman wishes to have. The objective of this study was to find out the maternal and neonatal outcome and background characteristics of women delivering vaginally in a tertiary care center in Chennai, South India.Methods: For this one-year study, with power above 80%, Parturition records were selected by computerized random numbers, for a calculated sample size. Salient demographic features such as age, residential background and religion were noted. Details of obstetric history, past and current, delivery and baby details and admission to NICU were analyzed. Acceptance of postpartum contraception was noted.Results: A total of 338 women delivered vaginally. Majority of 63%, were from urban background. Late referrals were 19.2% of women,38.5% women had antenatal complications. Primigravida were 49.7%. Nearly 91.4% of women delivered naturally. Previous pregnancy loss was noted in 14.8%. Term deliveries were in 72% of women, and 2.7% of women ...

wairimu njoroge

Objective:The incidence of twin pregnancy has increased largely over the past 30 year. Prevention of preterm labour is the major challenge in the management of multiple pregnancy.Within the last decade a substantial reduction in perinatal mortality has been achieved through advances in neonatal care. Intervention to decrease the neonatal mortality rates in multiple gestations should be directed towards reducing the incidence of low-birth weight infants. However there is still scope of further improvement of perinatal mortality and both maternal & perinatal morbidity. Material and methods:This prospective observational study was conducted under the department of Obstetrics &Gynaecology, in a tertiary care hospital of West Bengal. Independent variables of interest studied were gestational age, preterm delivery and mode of delivery.Dependent variables of interest were preeclampsia, premature rupture of membranes, post partum hemorrhage, birth weight, perinatal morbidity and mortality. The singleton mother admitted immediately after the twin was taken as control. Results: Incidence of twin gestation is higher in multigravida (86.6%)Anaemia was found in 39 (52.0%) mothers with twin gestation. The incidence of pre-eclampsia, preterm labour and postpartum haemohhragw were 14.7%,65.3% and 12% respectively. Prematurity and low birth weight is the most common cause of high perinatal mortality. The mean birth weight of first twin was 1.99 kg. and that of second twin was 1.89 kg. Regarding neonatal complications 32% developed transient tachypnea and 12.7% developed birth asphyxia compared to only 16% and 4% respectively in the singleton group. There was 17.3% perinatal mortality in the twin pregnancy group compared to only 5.3% among singleton mothers. Perinatal mortality is comparatively less, when fetus was delivered in cephalic presentation (4.2% and 13.8% in 1st and second baby repectively) compared to 35.7% and 32.3% in case of breech presentation.With the increase in delivery interval between the first and second twin the incidence of perinatal mortality is gradually increasing. Conclusion: Inspite of advances in obstetric and neonatology, perinatal mortality in twin pregnancy is alarmingly high. Gestational age, presentation, mode of delivery and birth weight are the significant determinants of perinatal outcome.

Jayshree Vaman

Background: The purpose was to determine whether AFI&lt;5 cm after preterm premature rupture of the membranes (PPROM) is associated with an increased risk of maternal and perinatal morbidity.Methods: We performed a prospective case control study of 161 singleton pregnancies complicated by preterm prelabour rupture of the membranes (PPROM) in whom AFI was assessed. Patients were categorized in two groups on the basis of amniotic fluid index- AFI&lt;5 cm or AFI ≥ 5 cm. Categorical data were tested for significance with the χ2 and Fisher exact tests. All 2-sided p values &lt; 0.05 were considered significant.Results: Both groups were similar with respect to selected demographics, gestational age atrupture of the membranes, gestational age at the delivery, birth weight. Both groups were similar with respect to maternal chorio-amnionitis, abruption, mode of delivery, early onset neonatal sepsis and NICU stay. Patients with AFI&lt;5 cm demonstrated greater frequency of C/S delivery for no...

BACKGROUND: Multiple gestations are becoming a problem of increasing dimensions with a dramatic increase in numbers in the last decade due to pregnancy at older age and widespread use of assisted reproductive technology Objectives:To study the incidence of vaginal delivery versus caesarean section in twin pregnancy in primigravida. To study maternal and fetal outcome in twin pregnancy among primigravida. METHODS: A Prospective observational study carried out in the Department of Obstetrics and Gynaecology, Sri Venkateswara Medical College, Tirupati conducted over one year from October 2017 to September 2018. RESULTS: In one year, total of 11,242 deliveries were conducted and amongst them 48 were twin pregnancies in primigravida, giving an incidence of 4.26%. Incidence of twin pregnancy in primigravida is more common in the age group of 21-25 years (62.5 %). Preeclampsia was found to be the most common medical disorder (70.8%)., followed by anemia in 13 cases (27.1%). LSCS was the most common mode of delivery for 31 patients (64.6%), followed by vaginal delivery in 17 patients(35.4%). In majority of cases, indication for LSCS was 1st twin non cephalic presentation. Perinatal mortality rate of monchorionic pregnancy was 4.6% and dichorionic pregnancy was 3.48% CONCLUSION : Twin pregnancy is a high risk pregnancy with increased incidence of antenatal and intrapartum complications like anemia, preeclampsia, gestational diabetes milletus, polyhydramnios, premature rupture of membranes, antepartum haemorrhage, post-partum hemorrhage, preterm labour, cord prolapse and fetal complications like prematurity, low birth weight, IUGR, discordant growth, NICU admissions etc.

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A Retrospective Study of Maternal and Fetal Outcomes of Twin Pregnancy

Department of Obstetrics and Gynecology, Krishna Institute of Medical Sciences, Karad, Maharashtra-415110

Corresponding Author E-mail:  [email protected]

DOI : https://dx.doi.org/10.13005/bpj/2365

Objective: This study was aimed to study the prevalence of twin pregnancy in a tertiary care hospital in Karad and to evaluate the various factors that influence maternal, fetal, and neonatal outcomes of twin gestation. Methods: This retrospective study was conducted at a tertiary care hospital in Karad, Maharashtra, for a period of two years. All women admitted with twin pregnancy (>28 weeks gestation) were considered for study. Maternal data including age, gestational age, parity, mode of conception, maternal interventions, mode of delivery, fetal death, intrauterine fetal growth restriction (IUGR), twin to twin transfusion, neonatal intensive care unit (NICU) admissions, birth asphyxia, low birth weight (LBW) and respiratory distress were recorded and analyzed Results: Incidence rate of twin pregnancy was 1.9%. Most women (56.48%) were aged 21-30 years and have completed 34-36 weeks of gestation (48.15%) with average gestational age of 34.97±2.35 weeks. Malpresentations (37.96%) followed by preterm labour (35.1%) was most common maternal complication. Cesarean section (62.04%) was most frequent mode of delivery. Most neonates had LBW (92.34%) and required NICU admissions (19.6%). Total rate of neonatal mortality is 3.34%. Birth asphyxia (42.85%) was the most frequent cause of  neonatal mortality. Conclusion: Twin gestation necessitates special attention as there is increased risk of maternal and perinatal morbidity and mortality. Early detection and anticipation of complications of twin gestation can greatly improve the maternal and fetal outcomes.

Cesarean section; Gestational age; Infant; Low birth weight; Obstetric labor

Introduction

Globally, in the last two decades, with advances in assisted reproductive technology (ART), older maternal age and widespread use of ovulation inducers, the incidence of twin gestation has witnessed a steep increase 1 . In India, the occurrence of twin gestation is approximately 1% of all gestations but accounts for 10% of perinatal mortality. There is 2.5-fold increased risk of maternal mortality in twin gestation than in singleton pregnancies 2 . The incidence of twins varies with ethnicity and geographical distribution 3 .

Twin gestation has increased risk of maternal and fetal morbidity and mortality. The maternal complications commonly observed in twin gestation are anemia, gestational diabetes mellitus (GDM), pre-eclampsia, pregnancy induced hypertension, antepartum hemorrhage, preterm labor, premature rupture of membrane (PROM), placental abruption and polyhydramnios. The combination of increased plasma volume, anemia and hypertensive disorders during pregnancy contributes to the risk of pulmonary edema, which further leads to maternal  morbidity and mortality 4 . Consequently, these complications account for repeated antenatal admissions, longer hospital stays and blood transfusions 5 .

The main causes of adverse neonatal outcomes in multiple pregnancies are related to low birth weight (LBW), intrauterine fetal demise (IUD), intrauterine growth restriction (IUGR), twin transfusion syndrome (TTTS), congenital malformations, birth asphyxia and neonatal death 6 . All these factors contribute to higher perinatal complications observed in multifetal gestations which is five to six times greater compared to singleton pregnancy 7 .

In India, there is disparity in the prevalence of twin pregnancy and their complications reported in the literature [8,9,10] . Considering the difference in incidence of twin pregnancies, this study was undertaken to study the prevalence of twins, to examine the high-risk factors associated with twin pregnancies and also to determine the maternal and fetal outcomes in twin gestations.

Materials and methods

Study design

This observational retrospective study was carried out at the Department of Obstetrics and Gynaecology in a tertiary care hospital, Karad, Maharashtra, extended over a period of two years from October 2016 to October 2018. Ethical clearance was obtained by the Institutional Ethical Committee. The study population considered in our study was women admitted with years from October 2016 to October 2018. Ethical clearance was obtained by the Institutional Ethical Committee. The study population considered in our study was women admitted with twin pregnancy.

Selection criteria

Inclusion criteria included all women admitted during antenatal period or during labor with twin gestation after 28 weeks gestation. Women with gestational age less than 28 weeks and with chronic medical illness namely diabetes mellitus, chronic obstructive pulmonary disease (COPD), bronchial asthma and coronary artery diseases were excluded from the study.

Data collection

Using a pre-designed structured proforma, data on maternal and neonatal data were collected from the labor room delivery data entry register and detailed information related to mode of delivery and neonatal outcome was gathered from hospital records. Maternal data consists of maternal age, duration of pregnancy (gestational age), parity, mode of conception, maternal interventions and mode of delivery. Fetal data consisted of fetal death, IUGR, twin to twin transfusion, NICU admissions, birth asphyxia (indexed by Apgar scores of <7 at one minute and five minutes), LBW, septicemia, respiratory distress. Early neonatal deaths occurring after discharge were not captured in the dataset.

Definitions

Gestational age was calculated from the first day of the last menstrual period (LMP) and the date of delivery expressed in weeks. Preterm labor was determined as onset of labor less than 37 weeks of gestation. IUGR was determined as below the 10 th percentile for gestational age using an ultrasound. LBW was defined as birth weight < 2500 g and very low birth weight was defined as less than 1500 g.

Twin pregnancy is associated with increased risk of maternal and fetal morbidity and mortality. Early detection and anticipation of complications of twin gestation can greatly improve maternal and fetal outcomes.

Statistical analysis

Data related to the maternal and fetal outcomes were analyzed by R software and was presented in percentages and mean ± standard deviation.

Out of 5492 deliveries 108 (1.9%) subjects had twin gestation. The distribution of maternal demographic data is shown in Table 1. Large numbers of women (56.48%) with twin gestation were between 21-30 years of age. The average age is 29.11±4.68 years. Twin gestation was observed most in multiparous women (51.85%). Most women have completed 34-36 weeks of gestation (48.15%) with average gestational age of 34.97±2.35 weeks.

Table 1: Maternal demographic data

Malpresentations (37.96%) followed by preterm labor (35.1%) was the most common maternal complication in this study. Interventions such as antenatal corticosteroids and cervical cerclage were performed during the antenatal period. 16 pregnancies (14.8%) were conceived by ART and the rest were conceived spontaneously (85.2%). Cesarean section (62.04%) was the most frequent mode of delivery.

Table 2: Antepartum complications and interventions during pregnancy.

ART- Assisted reproductive technology, C- Cesarean, PROM- Premature rupture of membrane

Fetal complications associated with twin gestation are mentioned in the Table 3. One fetal death (37.5%) in twin pregnancy was the most common complication compared to both fetal death. Most neonates had LBW (92.34%) and required NICU admissions (19.6%). Neonatal mortality in this study was due to birth asphyxia, septicemia, pulmonary hemorrhage and disseminated intravascular coagulation (DIC) listed in the table below. Among this, birth asphyxia (42.85%) was the most frequent cause of neonatal mortality. The total rate of neonatal mortality is 3.34%.

Table 3: Foetal complications of pregnancy

IUGR- Intrauterine growth restriction, NICU- Neonatal intensive care unit, LBW- Low birth weight, RDS-Respiratory distress syndrome, DIC-Disseminated intravascular coagulation

There is substantial difference in the prevalence rate of twin gestations and their complications observed throughout the years. Despite the advancements in obstetric care, twin gestation is still a high-risk pregnancy. Hence, this research was aimed to study the prevalence of twins and examine the high-risk factors associated with twin pregnancies

The incidence rate of twinning was 1.9% in this study. The is complying with the incidence rate (1.9%) reported by Upreti et al. [9] and but contradicting with Smitha et al. [11] (1.64%). The high incidence of twin pregnancy in this study could be due to increased use of ART and also referral of cases to this tertiary care centre for better management. The distribution of age shows most women had twin gestations in their twenties. The number of primigravida and multigravida with twin gestation were almost equal in this study, similar to Bangal et al.  7 . The mean gestational age in this study is similar to a study by Vanaja et al. 12  with 35 weeks.

Intrapartum management of twin gestation is greatly determined by their presentation in labor 13 . The most frequent maternal complication in this study seemed to be malpresentation at delivery. Sarojini et al. [14] have observed 42.7% of patients had malpresentation which is comparable to our study. Malpresentation affects the mode of delivery and the outcome of pregnancy 15 . As for the other complications, preterm labor rate is 35.1%. Preterm delivery is one of the most pressing problems that leads to perinatal morbidity and mortality in obstetric practice 16 . For those patients who were at a risk of delivering before 34 weeks of gestation were given antenatal steroids. An increased incidence of twin gestation in recent years exists due to ART. In this study, ART was reported to be responsible for 14.8% of twin gestation. Dubey et al. 17  have observed a rate of 13.4% of twin gestation due to ART.

There is a rising trend in cesarean section in twin gestation over the last decade 18 . The rate of cesarean section in this study was also high at 62.04%. This is consistent with Chaudary et al. 19  who reported cesarean section rate of 67.4%. On the contrary, Arora et al. 20  reported cesarean section rate of 20.32% which is much lower than our study. The reason for high rate of cesarean section in this study is due to malpresentation and fetal distress.

The ratio of one fetal death to both fetal deaths is 3:2. One fetal death was more common in the current study. The incidence of LBW was higher in this study. The increased LBW could be due to poor maternal nutritional status and younger age 21 . The neonatal mortality rate reported in this study is 3.34%, which is due to various factors like birth asphyxia, septicemia, pulmonary hemorrhage and DIC. Birth asphyxia (42.85%) was the most common reason for neonatal deaths. However, this is higher when compared to Sheela et al. 22  who  reported rate of birth asphyxia of 13.3%. NICU admissions were required in 19.6% of the neonates due to LBW and prematurity. This is in contrast with Nandmer et al. 23  who reported much higher rate of NICU admission (50%).

The findings of the study highlight the necessity of appropriate treatment protocols for counselling, routine antenatal check-ups, early maternal admission and appropriate care throughout intrapartum and immediate postpartum periods.

However, there were a few limitations in this study such as there were no information regarding the chorionicity of the pregnancy which could be linked to perinatal outcomes and early neonatal deaths occurring after discharge were not captured in the dataset.

Twin gestation necessitates special attention as they contribute to maternal and fetal morbidity and mortality. Regardless of its simplicity and limitations, this research adds to the existing literature by providing the Indian data findings on the prevalence of twin pregnancy and maternal and fetal outcomes in twin gestation. Further studies on the subject would be appropriated, particularly to determine whether specialized obstetric and neonatal care would mitigate the incidence of certain complications and thus enhance maternal and perinatal outcomes.

Acknowledgement

Conflict of interest

Authors have no conflict of interests.

Funding sources

The study was not funded by any government or private organization

• Daftary SN, Desai SV. Multiple fetal gestations. In: Daftary SN, Desai SV, eds. Textbook of Selected Topics in Obstetrics and Gynaecology-2, for Postgraduates and Practitioners. 19th ed. New Delhi: BI Publications Pvt Ltd. 2004:52-72.
• National Institute for Health and Clinical Excellence. Multiple pregnancy. The management of twin and triplet pregnancies in the antenatal period. NICE clinical Guideline. 2011. Available from: http://guidance.nice.org.uk/cg129
• Blondel B, Kaminski M. Trends in the occurrence, determinants, and consequences of multiple births . Semin Perinatol 2002; 26: 239-49. CrossRef
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• Bangal VB, Patel SM, Khairnar DN. Study of maternal and fetal outcomes in twin gestation at tertiary care teaching hospital. Int J Biomed Adv Res 2012; 3(10): 758-62. CrossRef
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• Asalkar M, Kasar B, Dhakne S, Panigrahi PP. Study of perinatal outcome in twin gestation in rural referral hospital in Maharashtra (India): a cross sectional study. Int J Reprod Contracept Obstet Gynecol 2017; 6: 5074-80. CrossRef
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Physical Activity Patterns of Women with a Twin Pregnancy-A Cross-Sectional Study

Affiliations.

• 1 Students Scientific Association, 1st Department of Obstetrics and Gynecology, First Faculty of Medicine, Medical University of Warsaw, 02-015 Warsaw, Poland.
• 2 The Center of Postgraduate Medical Education, 2nd Department of Obstetrics and Gynecology, 01-813 Warsaw, Poland.
• 3 1st Department of Obstetrics and Gynecology, First Faculty of Medicine, Medical University of Warsaw, 02-015 Warsaw, Poland.
• PMID: 34360017
• PMCID: PMC8345556
• DOI: 10.3390/ijerph18157724

Background: No specific physical activity guidelines are available for women in multiple pregnancy. Aim of the study was to assess the knowledge and experience of women regarding physical activity during their latest twin pregnancy.

Methods: A cross-sectional study including women after a twin delivery was conducted in Poland. A questionnaire was distributed in 2018 via web pages and Facebook groups designed for pregnant women.

Results: 652 women filled out the questionnaire completely. Only 25% of women performed any physical exercises during twin gestation. The frequency of preterm delivery was similar in physically active and non-active participants. 35% of the respondents claimed to have gained information on proper activity from obstetricians during antenatal counselling while 11% claimed to be unable to identify the reliable sources of information. 7% of women admitted to feel discriminated by social opinion on exercising during a twin pregnancy.

Conclusions: The population of women with a twin gestation is not sufficiently physically active and is often discouraged from performing exercises during gestation. Therefore, it is crucial to inform obstetricians to recommend active lifestyle during a twin gestation and to provide reliable information on physical activity to pregnant women. Further research on this topic is necessary in order for obstetric providers to counsel women on appropriate exercise with a twin pregnancy.

Keywords: physical activity; pregnancy; preterm delivery; twin pregnancy.

• Cross-Sectional Studies
• Infant, Newborn
• Pregnancy, Twin*
• Pregnant Women
• Premature Birth*

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Gestational diabetes mellitus and adverse pregnancy outcomes: systematic review and meta-analysis

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• Peer review
• Wenrui Ye , doctoral student 1 2 ,
• Cong Luo , doctoral student 3 ,
• Jing Huang , assistant professor 4 5 ,
• Chenglong Li , doctoral student 1 ,
• Zhixiong Liu , professor 1 2 ,
• Fangkun Liu , assistant professor 1 2
• 1 Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
• 2 Hypothalamic Pituitary Research Centre, Xiangya Hospital, Central South University, Changsha, China
• 3 Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China
• 4 National Clinical Research Centre for Mental Disorders, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• 5 Department of Psychiatry, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Correspondence to: F Liu liufangkun{at}csu.edu.cn
• Accepted 18 April 2022

Objective To investigate the association between gestational diabetes mellitus and adverse outcomes of pregnancy after adjustment for at least minimal confounding factors.

Design Systematic review and meta-analysis.

Data sources Web of Science, PubMed, Medline, and Cochrane Database of Systematic Reviews, from 1 January 1990 to 1 November 2021.

Review methods Cohort studies and control arms of trials reporting complications of pregnancy in women with gestational diabetes mellitus were eligible for inclusion. Based on the use of insulin, studies were divided into three subgroups: no insulin use (patients never used insulin during the course of the disease), insulin use (different proportions of patients were treated with insulin), and insulin use not reported. Subgroup analyses were performed based on the status of the country (developed or developing), quality of the study, diagnostic criteria, and screening method. Meta-regression models were applied based on the proportion of patients who had received insulin.

Results 156 studies with 7 506 061 pregnancies were included, and 50 (32.1%) showed a low or medium risk of bias. In studies with no insulin use, when adjusted for confounders, women with gestational diabetes mellitus had increased odds of caesarean section (odds ratio 1.16, 95% confidence interval 1.03 to 1.32), preterm delivery (1.51, 1.26 to 1.80), low one minute Apgar score (1.43, 1.01 to 2.03), macrosomia (1.70, 1.23 to 2.36), and infant born large for gestational age (1.57, 1.25 to 1.97). In studies with insulin use, when adjusted for confounders, the odds of having an infant large for gestational age (odds ratio 1.61, 1.09 to 2.37), or with respiratory distress syndrome (1.57, 1.19 to 2.08) or neonatal jaundice (1.28, 1.02 to 1.62), or requiring admission to the neonatal intensive care unit (2.29, 1.59 to 3.31), were higher in women with gestational diabetes mellitus than in those without diabetes. No clear evidence was found for differences in the odds of instrumental delivery, shoulder dystocia, postpartum haemorrhage, stillbirth, neonatal death, low five minute Apgar score, low birth weight, and small for gestational age between women with and without gestational diabetes mellitus after adjusting for confounders. Country status, adjustment for body mass index, and screening methods significantly contributed to heterogeneity between studies for several adverse outcomes of pregnancy.

Conclusions When adjusted for confounders, gestational diabetes mellitus was significantly associated with pregnancy complications. The findings contribute to a more comprehensive understanding of the adverse outcomes of pregnancy related to gestational diabetes mellitus. Future primary studies should routinely consider adjusting for a more complete set of prognostic factors.

Review registration PROSPERO CRD42021265837.

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Introduction

Gestational diabetes mellitus is a common chronic disease in pregnancy that impairs the health of several million women worldwide. 1 2 Formally recognised by O’Sullivan and Mahan in 1964, 3 gestational diabetes mellitus is defined as hyperglycaemia first detected during pregnancy. 4 With the incidence of obesity worldwide reaching epidemic levels, the number of pregnant women diagnosed as having gestational diabetes mellitus is growing, and these women have an increased risk of a range of complications of pregnancy. 5 Quantification of the risk or odds of possible adverse outcomes of pregnancy is needed for prevention, risk assessment, and patient education.

In 2008, the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study recruited a large multinational cohort and clarified the risks of adverse outcomes associated with hyperglycaemia. The findings of the study showed that maternal hyperglycaemia independently increased the risk of preterm delivery, caesarean delivery, infants born large for gestational age, admission to a neonatal intensive care unit, neonatal hypoglycaemia, and hyperbilirubinaemia. 6 The obstetric risks associated with diabetes, such as pregnancy induced hypertension, macrosomia, congenital malformations, and neonatal hypoglycaemia, have been reported in several large scale studies. 7 8 9 10 11 12 The HAPO study did not adjust for some confounders, however, such as maternal body mass index, and did not report on stillbirths and neonatal respiratory distress syndrome, raising uncertainty about these outcomes. Other important pregnancy outcomes, such as preterm delivery, neonatal death, and low Apgar score in gestational diabetes mellitus, were poorly reported. No comprehensive study has assessed the relation between gestational diabetes mellitus and various maternal and fetal adverse outcomes after adjustment for confounders. Also, some cohort studies were restricted to specific clinical centres and regions, limiting their generalisation to more diverse populations.

By collating the available evidence, we conducted a systematic review and meta-analysis to quantify the short term outcomes in pregnancies complicated by gestational diabetes mellitus. We evaluated adjusted associations between gestational diabetes mellitus and various adverse outcomes of pregnancy.

This meta-analysis was conducted according to the recommendations of Cochrane Systematic Reviews, and our findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (table S16). The study was prospectively registered in the international database of prospectively registered systematic reviews (PROSPERO CRD42021265837).

Search strategy and selection criteria

We searched the electronic databases PubMed, Web of Science, Medline, and the Cochrane Database of Systematic Reviews with the keywords: “pregnan*,” “gestatio*” or “matern*” together with “diabete*,” “hyperglycaemia,” “insulin,” “glucose,” or “glucose tolerance test*” to represent the exposed populations, and combined them with terms related to outcomes, such as “pregnan* outcome*,” “obstetric* complicat*,” “pregnan* disorder*,” “obstetric* outcome*,” “haemorrhage,” “induc*,” “instrumental,” “caesarean section,” “dystocia,” “hypertensi*,” “eclampsia,” “premature rupture of membrane,” “PROM,” “preter*,” “macrosomia,” and “malformation,” as well as some abbreviated diagnostic criteria, such as “IADPSG,” “DIPSI,” and “ADIPS” (table S1). The search strategy was appropriately translated for the other databases. We included observational cohort studies and control arms of trials, conducted after 1990, that strictly defined non-gestational diabetes mellitus (control) and gestational diabetes mellitus (exposed) populations and had definite diagnostic criteria for gestational diabetes mellitus (table S2) and various adverse outcomes of pregnancy.

Exclusion criteria were: studies published in languages other than English; studies with no diagnostic criteria for gestational diabetes mellitus (eg, self-reported gestational diabetes mellitus, gestational diabetes mellitus identified by codes from the International Classification of Diseases or questionnaires); studies published after 1990 that recorded pregnancy outcomes before 1990; studies of specific populations (eg, only pregnant women aged 30-34 years, 13 only twin pregnancies 14 15 16 ); studies with a sample size <300, because we postulated that these studies might not be adequate to detect outcomes within each group; and studies published in the form of an abstract, letter, or case report.

We also manually retrieved reference lists of relevant reviews or meta-analyses. Three reviewers (WY, CL, and JH) independently searched and assessed the literature for inclusion in our meta-analysis. The reviewers screened the titles and abstracts to exclude ineligible studies. The full texts of relevant records were then retrieved and assessed. Any discrepancies were resolved after discussion with another author (FL).

Data extraction

Three independent researchers (WY, CL, and JH) extracted data from the included studies with a predesigned form. If the data were not presented, we contacted the corresponding authors to request access to the data. We extracted data from the most recent study or the one with the largest sample size when a cohort was reported twice or more. Sociodemographic and clinical data were extracted based on: year of publication, location of the study (country and continent), design of the study (prospective or retrospective cohort), screening method and diagnostic criteria for gestational diabetes mellitus, adjustment for conventional prognostic factors (defined as maternal age, pregestational body mass index, gestational weight gain, gravidity, parity, smoking history, and chronic hypertension), and the proportion of patients with gestational diabetes mellitus who were receiving insulin. For studies that adopted various diagnostic criteria for gestational diabetes mellitus, we extracted the most recent or most widely accepted one for subsequent analysis. For studies adopting multivariate logistic regression for adjustment of confounders, we extracted adjusted odds ratios and synthesised them in subsequent analyses. For unadjusted studies, we calculated risk ratios and 95% confidence intervals based on the extracted data.

Studies of women with gestational diabetes mellitus that evaluated the risk or odds of maternal or neonatal complications were included. We assessed the maternal outcomes pre-eclampsia, induction of labour, instrumental delivery, caesarean section, shoulder dystocia, premature rupture of membrane, and postpartum haemorrhage. Fetal or neonatal outcomes assessed were stillbirth, neonatal death, congenital malformation, preterm birth, macrosomia, low birth weight, large for gestational age, small for gestational age, neonatal hypoglycaemia, neonatal jaundice, respiratory distress syndrome, low Apgar score, and admission to the neonatal intensive care unit. Table S3 provides detailed definitions of these adverse outcomes of pregnancy.

Risk-of-bias assessment

A modified Newcastle-Ottawa scale was used to assess the methodological quality of the selection, comparability, and outcome of the included studies (table S4). Three independent reviewers (WY, CL, and JH) performed the quality assessment and scored the studies for adherence to the prespecified criteria. A study that scored one for selection or outcome, or zero for any of the three domains, was considered to have a high risk of bias. Studies that scored two or three for selection, one for comparability, and two for outcome were regarded as having a medium risk of bias. Studies that scored four for selection, two for comparability, and three for outcome were considered to have a low risk of bias. A lower risk of bias denotes higher quality.

Data synthesis and analysis

Pregnant women were divided into two groups (gestational diabetes mellitus and non-gestational diabetes mellitus) based on the diagnostic criteria in each study. Studies were considered adjusted if they adjusted for at least one of seven confounding factors (maternal age, pregestational body mass index, gestational weight gain, gravidity, parity, smoking history, and chronic hypertension). For each adjusted study, we transformed the odds ratio estimate and its corresponding standard error to natural logarithms to stabilise the variance and normalise their distributions. Summary odds ratio estimates and their 95% confidence intervals were estimated by a random effects model with the inverse variance method. We reported the results as odds ratio with 95% confidence intervals to reflect the uncertainty of point estimates. Unadjusted associations between gestational diabetes mellitus and adverse outcomes of pregnancy were quantified and summarised (table S6 and table S14). Thereafter, heterogeneity across the studies was evaluated with the τ 2 statistics and Cochran’s Q test. 17 18 Cochran’s Q test assessed interactions between subgroups. 18

We performed preplanned subgroup analyses for factors that could potentially affect gestational diabetes mellitus or adverse outcomes of pregnancy: country status (developing or developed country according to the International Monetary Fund ( www.imf.org/external/pubs/ft/weo/2020/01/weodata/groups.htm ), risk of bias (low, medium, or high), screening method (universal one step, universal glucose challenge test, or selective screening based on risk factors), diagnostic criteria for gestational diabetes mellitus (World Health Organization 1999, Carpenter-Coustan criteria, International Association of Diabetes and Pregnancy Study Groups (IADPSG), or other), and control for body mass index. We assessed small study effects with funnel plots by plotting the natural logarithm of the odds ratios against the inverse of the standard errors, and asymmetry was assessed with Egger’s test. 19 A meta-regression model was used to investigate the associations between study effect size and proportion of patients who received insulin in the gestational diabetes mellitus population. Next, we performed sensitivity analyses by omitting each study individually and recalculating the pooled effect size estimates for the remaining studies to assess the effect of individual studies on the pooled results. All analyses were performed with R language (version 4.1.2, www.r-project.org ) and meta package (version 5.1-0). We adopted the treatment arm continuity correction to deal with a zero cell count 20 and the Hartung-Knapp adjustment for random effects meta models. 21 22

Patient and public involvement

The experience in residency training in the department of obstetrics and the concerns about the association between gestational diabetes mellitus and health outcomes inspired the author team to perform this study. We also asked advice from the obstetrician and patients with gestational diabetes mellitus about which outcomes could be included. The covid-19 restrictions meant that we sought opinions from only a limited number of patients in outpatient settings.

Characteristics of included studies

Of the 44 993 studies identified, 156 studies, 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 involving 7 506 061 pregnancies, were eligible for the analysis of adverse outcomes in pregnancy ( fig 1 ). Of the 156 primary studies, 133 (85.3%) reported maternal outcomes and 151 (96.8%) reported neonatal outcomes. Most studies were conducted in Asia (39.5%), Europe (25.5%), and North America (15.4%). Eighty four (53.8%) studies were performed in developed countries. Based on the Newcastle-Ottawa scale, 50 (32.1%) of the 156 included studies showed a low or medium risk of bias and 106 (67.9%) had a high risk of bias. Patients in 35 (22.4%) of the 156 studies never used insulin during the course of the disease and 63 studies (40.4%) reported treatment with insulin in different proportions of patients. The remaining 58 studies did not report information about the use of insulin. Table 1 summarises the characteristics of the study population, including continent or region, country, screening methods, and diagnostic criteria for the included studies. Table S5 lists the key excluded studies.

Search and selection of studies for inclusion

Characteristics of study population

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Associations between gestational diabetes mellitus and adverse outcomes of pregnancy

Based on the use of insulin in each study, we classified the studies into three subgroups: no insulin use (patients never used insulin during the course of the disease), insulin use (different proportions of patients were treated with insulin), and insulin use not reported. We reported odds ratios with 95% confidence intervals after controlling for at least minimal confounding factors. In studies with no insulin use, women with gestational diabetes mellitus had increased odds of caesarean section (odds ratio 1.16, 95% confidence interval 1.03 to 1.32), preterm delivery (1.51, 1.26 to 1.80), low one minute Apgar score (1.43, 1.01 to 2.03), macrosomia (1.70, 1.23 to 2.36), and an infant born large for gestational age (1.57, 1.25 to 1.97) ( fig 2 and fig S1). In studies with insulin use, adjusted for confounders, the odds of an infant born large for gestational age (odds ratio 1.61, 95% confidence interval 1.09 to 2.37), or with respiratory distress syndrome (1.57, 1.19 to 2.08) or neonatal jaundice (1.28, 1.02 to 1.62), or requiring admission to the neonatal intensive care unit (2.29, 1.59 to 3.31) were higher in women with than in those without gestational diabetes mellitus ( fig 3) . In studies that did not report the use of insulin, women with gestational diabetes mellitus had increased odds ratio for pre-eclampsia (1.46, 1.21 to 1.78), induction of labour (1.88, 1.16 to 3.04), caesarean section (1.38, 1.20 to 1.58), premature rupture of membrane (1.13, 1.06 to 1.20), congenital malformation (1.18, 1.10 to 1.26), preterm delivery (1.51, 1.19 to 1.93), macrosomia (1.48, 1.13 to 1.95), neonatal hypoglycaemia (11.71, 7.49 to 18.30), and admission to the neonatal intensive care unit (2.28, 1.26 to 4.13) (figs S3 and S4). We found no clear evidence for differences in the odds of instrumental delivery, shoulder dystocia, postpartum haemorrhage, stillbirth, neonatal death, low five minute Apgar score, low birth weight, and infant born small for gestational age between women with and without gestational diabetes mellitus in all three subgroups ( fig 2, fig 3, and figs S1-S4). Table S6 shows the unadjusted associations between gestational diabetes mellitus and adverse outcomes of pregnancy.

Findings of meta-analysis of association between gestational diabetes mellitus and adverse outcomes of pregnancy after adjusting for at least minimal confounding factors, in studies in patients who never used insulin during the course of the disease (no insulin use). NA=not applicable

Findings of meta-analysis of association between gestational diabetes mellitus and adverse outcomes of pregnancy after adjusting for at least minimal confounding factors, in studies where different proportions of patients were treated with insulin (insulin use). NA=not applicable

Subgroup, meta-regression, and sensitivity analyses

Subgroup analyses, based on risk of bias, did not show significant heterogeneity between the subgroups of women with and without gestational diabetes mellitus for most adverse outcomes of pregnancy ( table 2 and table 3 ), except for admission to the neonatal intensive care unit in studies where insulin use was not reported (table S7). Significant differences between subgroups were reported for country status and macrosomia in studies with (P<0.001) and without (P=0.001) insulin use ( table 2 and table 3 ), and for macrosomia (P=0.02) and infants born large for gestational age (P<0.001) based on adjustment for body mass index in studies with insulin use (table S8). Screening methods contributed significantly to the heterogeneity between studies for caesarean section (P<0.001) and admission to the neonatal intensive care unit (P<0.001) in studies where insulin use was not reported (table S7). In most outcomes, the estimated odds were lower in studies that used universal one step screening than those that adopted the universal glucose challenge test or selective screening methods ( table 2 and table 3 ). Diagnostic criteria were not related to heterogeneity between the studies for all of the study subgroups (no insulin use, insulin use, insulin use not reported). The subgroup analysis was performed only for outcomes including ≥6 studies.

Subgroup analysis according to country status, diagnostic criteria, screening method, and risk of bias for adverse outcomes of pregnancy in women with gestational diabetes mellitus compared with women without gestational diabetes mellitus in studies with no insulin use

Subgroup analysis according to country status, diagnostic criteria, screening method, and risk of bias for adverse outcomes of pregnancy in women with gestational diabetes mellitus compared with women without gestational diabetes mellitus in studies with insulin use

We applied meta-regression models to evaluate the modification power of the proportion of patients with insulin use when sufficient data were available. Significant associations were found between effect size estimate and proportion of patients who had received insulin for the adverse outcomes caesarean section (estimate=0.0068, P=0.04) and preterm delivery (estimate=−0.0069, P=0.04) (table S9).

In sensitivity analyses, most pooled estimates were not significantly different when a study was omitted, suggesting that no one study had a large effect on the pooled estimate. The pooled estimate effect became significant (P=0.005) for low birth weight when the study of Lu et al 99 was omitted, however (fig S5). We found evidence of a small study effect only for caesarean section (Egger’s P=0.01, table S10). Figure S6 shows the funnel plots of the included studies for various adverse outcomes (≥10 studies).

Principal findings

We have provided quantitative estimates for the associations between gestational diabetes mellitus and adverse outcomes of pregnancy after adjustment for confounding factors, through a systematic search and comprehensive meta-analysis. Compared with patients with normoglycaemia during pregnancy, patients with gestational diabetes mellitus had increased odds of caesarean section, preterm delivery, low one minute Apgar score, macrosomia, and an infant born large for gestational age in studies where insulin was not used. In studies with insulin use, patients with gestational diabetes mellitus had an increased odds of an infant born large for gestational age, or with respiratory distress syndrome or neonatal jaundice, or requiring admission to the neonatal intensive care unit. Our study was a comprehensive analysis, quantifying the adjusted associations between gestational diabetes mellitus and adverse outcomes of pregnancy. The study provides updated critical information on gestational diabetes mellitus and adverse outcomes of pregnancy and would facilitate counselling of women with gestational diabetes mellitus before delivery.

To examine the heterogeneity conferred by different severities of gestational diabetes mellitus, we categorised the studies by use of insulin. Insulin is considered the standard treatment for the management of gestational diabetes mellitus when adequate glucose levels are not achieved with nutrition and exercise. 179 Our meta-regression showed that the proportion of patients who had received insulin was significantly associated with the effect size estimate of adverse outcomes, including caesarean section (P=0.04) and preterm delivery (P=0.04). This finding might be the result of a positive linear association between glucose concentrations and adverse outcomes of pregnancy, as previously reported. 180 However, the proportion of patients who were receiving insulin indicates the percentage of patients with poor glycaemic control in the population and cannot reflect glycaemic control at the individual level.

Screening methods for gestational diabetes mellitus have changed over time, from the earliest selective screening (based on risk factors) to universal screening by the glucose challenge test or the oral glucose tolerance test, recommended by the US Preventive Services Task Force (2014) 181 and the American Diabetes Association (2020). 182 The diagnostic accuracy of these screening methods varied, contributing to heterogeneity in the analysis.

Several studies have tried to pool the effects of gestational diabetes mellitus on pregnancy outcomes, but most focused on one outcome, such as congenital malformations, 183 184 macrosomia, 185 186 or respiratory distress syndrome. 187 Our findings of increased odds of macrosomia in gestational diabetes mellitus in studies where insulin was not used, and respiratory distress syndrome in studies with insulin use, were similar to the results of previous meta-analyses. 188 189 The increased odds of neonatal respiratory distress syndrome, along with low Apgar scores, might be attributed to disruption of the integrity and composition of fetal pulmonary surfactant because gestational diabetes mellitus can delay the secretion of phosphatidylglycerol, an essential lipid component of surfactants. 190

Although we detected no significant association between gestational diabetes mellitus and mortality events, the observed increase in the odds of neonatal death (odds ratio 1.59 in studies that did not report the use of insulin) should be emphasised to obstetricians and pregnant women because its incidence was low (eg, 3.75% 87 ). The increased odds of neonatal death could result from several lethal complications, such as respiratory distress syndrome, neonatal hypoglycaemia (3.94-11.71-fold greater odds), and jaundice. These respiratory and metabolic disorders might increase the likelihood of admission to the neonatal intensive care unit.

For the maternal adverse outcomes, women with gestational diabetes mellitus had increased odds of pre-eclampsia, induction of labour, and caesarean section, consistent with findings in previous studies. 126 Our study identified a 1.24-1.46-fold greater odds of pre-eclampsia between patients with and without gestational diabetes mellitus, which was similar to previous results. 191

Strengths and limitations of the study

Our study included more studies than previous meta-analyses and covered a range of maternal and fetal outcomes, allowing more comprehensive comparisons among these outcomes based on the use of insulin and different subgroup analyses. The odds of adverse fetal outcomes, including respiratory distress syndrome (P=0.002), neonatal jaundice (P=0.05), and admission to the neonatal intensive care unit (P=0.005), were significantly increased in studies with insulin use, implicating their close relation with glycaemic control. The findings of this meta-analysis support the need for an improved understanding of the pathophysiology of gestational diabetes mellitus to inform the prediction of risk and for precautions to be taken to reduce adverse outcomes of pregnancy.

The study had some limitations. Firstly, adjustment for at least one confounder had limited power to deal with potential confounding effects. The set of adjustment factors was different across studies, however, and defining a broader set of multiple adjustment variables was difficult. This major concern should be looked at in future well designed prospective cohort studies, where important prognostic factors are controlled. Secondly, overt diabetes was not clearly defined until the IADPSG diagnostic criteria were proposed in 2010. Therefore, overt diabetes or pre-existing diabetes might have been included in the gestational diabetes mellitus groups if studies were conducted before 2010 or adopted earlier diagnostic criteria. Hence we cannot rule out that some adverse effects in newborns were related to prolonged maternal hyperglycaemia. Thirdly, we divided and analysed the subgroups based on insulin use because insulin is considered the standard treatment for the management of gestational diabetes mellitus and can reflect the level of glycaemic control. Accurately determining the degree of diabetic control in patients with gestational diabetes mellitus was difficult, however. Finally, a few pregnancy outcomes were not accurately defined in studies included in our analysis. Stillbirth, for example, was defined as death after the 20th or 28th week of pregnancy, based on different criteria, but some studies did not clearly state the definition of stillbirth used in their methods. Therefore, we considered stillbirth as an outcome based on the clinical diagnosis in the studies, which might have caused potential bias in the analysis.

Conclusions

We performed a meta-analysis of the association between gestational diabetes mellitus and adverse outcomes of pregnancy in more than seven million women. Gestational diabetes mellitus was significantly associated with a range of pregnancy complications when adjusted for confounders. Our findings contribute to a more comprehensive understanding of adverse outcomes of pregnancy related to gestational diabetes mellitus. Future primary studies should routinely consider adjusting for a more complete set of prognostic factors.

What is already known on this topic

The incidence of gestational diabetes mellitus is gradually increasing and is associated with a range of complications for the mother and fetus or neonate

Pregnancy outcomes in gestational diabetes mellitus, such as neonatal death and low Apgar score, have not been considered in large cohort studies

Comprehensive systematic reviews and meta-analyses assessing the association between gestational diabetes mellitus and adverse pregnancy outcomes are lacking

What this study adds

This systematic review and meta-analysis showed that in studies where insulin was not used, when adjusted for confounders, women with gestational diabetes mellitus had increased odds of caesarean delivery, preterm delivery, low one minute Apgar score, macrosomia, and an infant large for gestational age in the pregnancy outcomes

In studies with insulin use, when adjusted for confounders, women with gestational diabetes mellitus had increased odds of an infant large for gestational age, or with respiratory distress syndrome or neonatal jaundice, or requiring admission to the neonatal intensive care unit

Future primary studies should routinely consider adjusting for a more complete set of prognostic factors

Ethics statements

Ethical approval.

Not required.

Data availability statement

Table S11 provides details of adjustment for core confounders. Supplementary data files contain all of the raw tabulated data for the systematic review (table S12). Tables S13-15 provide the raw data and R language codes used for the meta-analysis.

Contributors: WY and FL developed the initial idea for the study, designed the scope, planned the methodological approach, wrote the computer code and performed the meta-analysis. WY and CL coordinated the systematic review process, wrote the systematic review protocol, completed the PROSPERO registration, and extracted the data for further analysis. ZL coordinated the systematic review update. WY, JH, and FL defined the search strings, executed the search, exported the results, and removed duplicate records. WY, CL, ZL, and FL screened the abstracts and texts for the systematic review, extracted relevant data from the systematic review articles, and performed quality assessment. WY, ZL, and FL wrote the first draft of the manuscript and all authors contributed to critically revising the manuscript. ZL and FL are the study guarantors. ZL and FL are senior and corresponding authors who contributed equally to this study. All authors had full access to all the data in the study, and the corresponding authors had final responsibility for the decision to submit for publication. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: The research was funded by the National Natural Science Foundation of China (grants 82001223 and 81901401), and the Natural Science Foundation for Young Scientist of Hunan Province, China (grant 2019JJ50952). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Natural Science Foundation of China and the Natural Science Foundation for Young Scientist of Hunan Province, China for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: The dissemination plan targets a wide audience, including members of the public, patients, patient and public communities, health professionals, and experts in the specialty through various channels: written communication, events and conferences, networks, and social media.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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Montfoort, Aafke Philomena Anna van. "Prevention of twin pregnancies in IVF by single embryo transfer." [Maastricht] : Maastricht : Universitaire Pers Maastricht ; University Library, Universiteit Maastricht [host], 2007. http://arno.unimaas.nl/show.cgi?fid=8686.

Denbow, Mark. "Interfetal transfusion along placental vascular anastomoses in monocorionic twin pregnancies." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271116.

Momberg, Zoe. "Accuracy of ultrasound beyond 14 weeks to determine chorionicity of twin pregnancies." Master's thesis, University of Cape Town, 2014. http://hdl.handle.net/11427/22023.

Martins, Yolanda Maria dos Santos. "Into the heart monochorionic twin pregnancies - from the placenta to the hemodynamic compromise." Dissertação, Faculdade de Medicina da Universidade do Porto, 2009. http://hdl.handle.net/10216/53771.

Martins, Yolanda Maria dos Santos. "Into the heart monochorionic twin pregnancies - from the placenta to the hemodynamic compromise." Master's thesis, Faculdade de Medicina da Universidade do Porto, 2009. http://hdl.handle.net/10216/53771.

Tortschanoff, Sonja. "Incidence and importance of double ovulations and twin pregnancies of warmblood mares in Switzerland /." [S.l.] : [s.n.], 2002. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

Hermann, Catherine. "Outcome of Cervical Cerclage in Twin Pregnancies for Treatment of Ultrasound Detected Short Cervix." Thesis, The University of Arizona, 2018. http://hdl.handle.net/10150/626853.

Cloete, Alrese. "Birth order, delivery and concordance of mother-to-child transmission of Human Immunodeficiency Virus in twin pregnancies." Master's thesis, University of Cape Town, 2013. http://hdl.handle.net/11427/3040.

Sebire, Neil James. "Prenatal diagnosis and management of multiple pregnancies : the role of the 10-14 week ultrasound examination." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391612.

Barrelet, Frédéric. "The incidence of twins in thoroughbred pregnancies and their management : a two season study in 1091 mares /." [S.l.] : [s.n.], 1988. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

Đorđe, Ilić. "Analiza problema višeplodnih trudnoća nastalih vantelesnom oplodnjom." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2015. http://www.cris.uns.ac.rs/record.jsf?recordId=90376&source=NDLTD&language=en.

Nunes, Joana Maria Sousa. "Monochorionicity in twin pregnancies, crown-rump length and birthweight discordancy: the trio of influence." Dissertação, 2017. https://repositorio-aberto.up.pt/handle/10216/104439.

Nunes, Joana Maria Sousa. "Monochorionicity in twin pregnancies, crown-rump length and birthweight discordancy: the trio of influence." Master's thesis, 2017. https://hdl.handle.net/10216/104439.

Costa, Maria João Alcaide. "Perinatal outcomes, risk perception and psychological adjustment in twin and singleton pregnancies: does assisted reproduction technologies makes the difference?" Master's thesis, 2016. http://hdl.handle.net/10316/37156.

"Maternal serum alpha-fetoprotein and total beta-human chorionic gonadotrophin in twin pregnancies during mid-trimester: their implications for adverse pregnancy outcomes." 1997. http://library.cuhk.edu.hk/record=b5889300.

MacLaughlin, Severence Michael. "The impact of the periconceptional environment (in vivo and ex vivo) on feto-placental development in the sheep." 2006. http://hdl.handle.net/2440/58187.

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A Review of Research Progress of Pregnancy with Twins with Preeclampsia

1 Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China

2 Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China

Haitao Shen

3 Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China

Preeclampsia has a significant long-term effect on the health of both mothers and babies. Preeclampsia-related pregnancy complications increase the morbidity and mortality of pregnant women and their fetuses by 5–8%. The recent advancement of assisted reproductive technology, combined with a rise in the number of elderly pregnant women, has resulted in pregnancy incidence with twins. Twins pregnant women have a 2–3 times greater risk of developing preeclampsia than singleton pregnant women, and it happens sooner and progresses faster. It is more severe and may appear in an atypical way. End-organ damage, such as renal failure, stroke, cardiac arrest, pulmonary edema, placental abruption, and cesarean section, are related maternal complications. Fetal growth retardation, stillbirth, and premature delivery with obstetric signs are all fetal complications. According to studies, all multiple pregnancies can take low-dose aspirin (60–150 mg) to minimize the risk of preeclampsia. To improve pregnancy outcomes and reduce the inherent risk of pregnancy with twins, twins should be handled as a high-risk pregnancy and treated differently than singletons. The literature on twin pregnancy with preeclampsia is the subject of this review. It will examine the current state of research on preeclampsia in pregnancy with twins, including the occurrence, diagnosis, and pathophysiological process. Moreover, the effect of pregnancy with twins on the perinatal outcome and pregnancy management of pregnancy with twins, including blood pressure management and preeclampsia prevention and treatment, is examined in this literature review. The goal is to figure out what kind of diagnosis and care you may need.

Introduction

With the implementation of China’s “two child” policy, the incidence of multiple pregnancies, especially twins, is growing year after year. Multiple pregnancies become more common as assisted reproductive technology becomes more widely used and the increasing age of conception rises. 1 On the other hand, women with multiple pregnancies have a higher rate of pregnancy complications, fetal malformations, perinatal morbidity, and mortality than women with single pregnancies, which has become a challenging issue in maternal and fetal medicine. Preeclampsia is 2–3 times more common in twin pregnancies than in singleton pregnancies, and it develops sooner, progresses quicker, and is more severe, as well as presenting in an atypical manner. 2 The incidence rate of maternal diseases, including terminal organs such as cardiac arrest, stroke, renal failure, lung injury, and others, are more likely to cause placental abruption and pathological cesarean section. 3 Fetal growth restriction, stillbirth, and premature delivery are all examples of fetal complications. Given the preceding evidence, preeclampsia literature focusing on multiple pregnancies is relatively scarce. Our goal is to review the literature on Preeclampsia in twin pregnancy, find out the gap in evidence, and comprehensively understand the pathophysiology of Preeclampsia in twin pregnancy. We must fully comprehend the physiology of twins as well as the pathophysiology of Preeclampsia. The aim is to increase the birth population’s efficiency, customized twin pregnancy management, pay attention to early pregnancy, and do a good job in twin pregnancy management to find out the potential diagnosis and care in the future. It is important to reduce the global prevalence of perinatal outcomes, morbidity, and mortality among women.

The Incidence of Preeclampsia in Pregnancy with Twins

In recent years, there has been widespread use of assisted reproductive technology, owing primarily to a rise in the number of elderly women. As a result, the number of twin pregnancies is growing on an annual basis. Preeclampsia, gestational diabetes mellitus, premature birth, fetal growth restriction, pathological surgical delivery, and other perinatal complications are more common in women with twin pregnancies when compared to singletons. 4 According to the literature, Preeclampsia accounts for 2–5% of pregnancy complications. Preeclampsia is described as an increase in blood pressure and proteinuria after 20 weeks of gestation. 5 Preeclampsia symptoms include headache, dizziness, nausea, vomiting, epigastric discomfort, and others. Preeclampsia progresses to the more severe condition known as eclampsia. Eclampsia is a convulsion or coma that cannot be explained by other causes other than Preeclampsia. The etiology is yet to be determined. Eclampsia is a severe complication of Preeclampsia that may cause significant maternal and neonatal complications. Currently, there is no effective preventive treatment except the termination of pregnancy. The existing therapy aims to control the disease and extend the gestational period. According to reports, Preeclampsia is responsible for about 14% of maternal deaths. 6 Preeclampsia is thought to be associated with long-term cardiovascular disease, 7 particularly in early-onset Preeclampsia and recurrent Preeclampsia, increasing cardiovascular disease risk. 8–10 Preeclampsia is currently classified into early-onset and late-onset Preeclampsia based on the 34-week gestation period. Early-onset preeclampsia is characterized by small gestational weeks, long distance from full-term, and maternal and neonatal complications. 11 However, early-onset and late onset have different occurrence rates, clinical manifestations, and risk factors. Early-onset Preeclampsia is thought to be linked to the likelihood of fetal intrauterine growth restriction, resulting in extreme vascular endothelial damage. In contrast, late-onset Preeclampsia is linked to maternal weight gain and neonatal weight gain. 12–14 Multiple pregnancies are an independent risk factor for Preeclampsia. 15 , 16

Preeclampsia was slightly more common in twin pregnancies than in singleton pregnancies. Preeclampsia was 3.50 times higher in dizygotic twins than in monozygotic twins and 2.61 times higher in monozygotic twins. Furthermore, twins are two to three times more likely than singletons to develop extreme hypertension. 17 Preeclampsia occurs at an earlier gestational age in twin pregnancies, and the incidence is substantially higher than in singleton pregnancies. 18 There is a clear connection between adverse pregnancy outcomes and twin pregnancies; 19 it may be because twin pregnancies have a larger placental size, exposing the maternal to a larger area of placental perfusion damage. 15 The overall peripheral resistance of the uterus and placenta increases as the twins develop. The placenta’s angiogenic factors may harm the functionality of the vascular endothelium in the dynamic process. 20 The incidence of Preeclampsia is significantly higher in triplets 20 than that of triplets experiencing reduction. 21 These findings further confirm the pathogenicity of placental tissue. 22 Preeclampsia is also more common in IVF twins than in naturally born twins, according to research. Preeclampsia increases the risk of preterm birth, surgical delivery, and low birth weight in in-vitro twins. 23 Studies have shown that, as opposed to fresh embryos, frozen embryo transfer increases the risk of preeclampsia and preterm delivery in pregnancies with assisted reproductive technology that uses autologous eggs. 24

Diagnosis and Pathophysiology of Preeclampsia in Pregnancy with Twins

Preeclampsia in twin pregnancies and singleton pregnancies is currently diagnosed using the same diagnostic criteria. The following is the current definition of Preeclampsia: after 20 weeks of pregnancy, systolic blood pressure and diastolic blood pressure increase to ≥ 140mmHg and ≥ 90mmHg respectively, on two or more consecutive occasions (interval ≥ 4h), and when the patient’s blood pressure is elevated and one or more of the following abnormalities occur at the same time:(1) Proteinuria (24-hour urine total protein content ≥ 300 mg or ≥ 1 +); (2) Dysfunction of important organs of the mother’s body, such as abnormal renal function (creatinine < 90 umol/L), liver damage (elevated transaminase or epigastric discomfort), neurological and hematological abnormalities. 25 This study aims to conduct a literature review on Preeclampsia, with a focus on twin pregnancies. The aim is to identify evidence gaps that can direct potential diagnosis and care of twin pregnancies. As a result, it is important to better understand the pathophysiology of Preeclampsia in twin pregnancies. 6 Although most pathophysiological studies on Preeclampsia have been conducted in singleton pregnancy, their effect would be amplified in pregnancy with twins due to greater placental mass and stronger inflammatory response. According to research, the possibility of Preeclampsia is a dose-dependent condition that is greatly influenced by the quality of the placenta and the number of fetuses. 23

The abnormal condition of elderly women, obesity, diabetes, chronic hypertension, antiphospholipid syndrome, chronic kidney disease, and lupus erythematosus all raise the risk of Preeclampsia. Endothelial dysfunction has been recorded in these cases, increasing the risk of Preeclampsia. 26 In previous studies, excessive placental anti-angiogenic factors and soluble FMS including tyrosine kinase 1 (sflt1), were found to antagonize vascular growth factor (VEGF) and placental growth factor (PlGF), causing extensive endothelial dysfunction in these women. 20 , 27–29 The single nucleotide polymorphism (rs4769613) near the Flt1 site on fetal chromosome 13 was found to be significantly associated with Preeclampsia in a large clinical genome-wide association study. 30 , 31 The amount of Flt1 in the blood of pregnant women with chronic hypertension and diabetes mellitus increased significantly.

Meanwhile, PLGF levels in the blood of obese pregnant women were found to be substantially lower. 32 The mechanism of Flt1 upregulation in the placenta is still unknown. Flt1 precursor mRNA produced sflt1 after alternative splicing and only contained the Flt1 extracellular ligand binding region. It does not, however, produce intracellular or transmembrane regions. 33 Increased placental mass and circulating levels and soluble FMS like tyrosine kinase-1 can increase the risk of Preeclampsia in multiple pregnancies (sFlt-1).

Endothelial dysfunction may lead to a vascular condition that affects the entire body. The widespread use of assisted reproductive technology has increased the number of elderly twin births, which has increased in maternal primary diseases. Endothelial dysfunction can result from increased cardiac output and systemic total peripheral resistance in chronic hypertension patients. 34 Sympathetic neuropathy is caused by insulin resistance and a high insulin level. Endothelial cell damage from abnormal renal tubular sodium absorption will increase the risk of Preeclampsia. 34 In the first three months of pregnancy, a lack of trophoblast penetration and inadequate remodeling of the uterine spiral artery, combined with decreased uterine placental perfusion, may result in poor perfusion and stress of placental syncytiotrophoblast cells, which releases a series of mediators that cause endothelial dysfunction and clinical manifestations. 35 It is true that the exact mechanism by which endothelial dysfunction leads to systemic vascular disease is unknown. Insufficient vascular remodeling, which is the secret to systemic vascular dysfunction, may be caused by irregular matrix metalloproteinases (MMPs) and increased extracellular collagen deposition. 36 Vascular instability persists after preeclampsia symptoms have vanished clinically, suggesting that it may be linked to long-term cardiovascular disease risk.

A growing number of studies have looked into the connection between immune abnormalities and Preeclampsia in recent years. The expression of the histocompatibility complex is one of the most important factors (MHC). HLA-C molecules expressed in trophoblast interact with killer Ig like receptors (KIR) expressed by maternal natural killer cells in normal pregnancy. Normal placenta formation necessitates maternal KIR to recognize allogeneically HLA-C of the father. 37 According to the findings, some HLA-C molecular groups’ expression frequency and some KIR haplotypes appears to be higher in preeclampsia patients. 38 Preeclampsia risk rises as the father’s antigen exposure decreases, as in the case of nulliparous women, short-term cohabitation, and paternity, 39 indicating the role of the immune system in pathogenesis. 39 , 40 Placental tissue has the characteristics of secreting T cells and some other cytokines, of which type 2 helper T cell factor (such as anti-inflammatory IL-10) is the main factor. 41 An unbalanced T cells’ distribution distinguishes Preeclampsia, especially T helper cell 1 and its associated cytokines IFN and TNF. 42 This immune factor imbalance can result in fetal adnexal dysplasia, followed by maternal inflammation and endothelial dysfunction. Complement activation, on the other hand, is linked to the pathogenesis of Preeclampsia. 43 , 44 The complement-activated fragment BB, a marker of alternative pathways, was measured by the researchers and found that women with higher BB levels were four times more likely to develop Preeclampsia before 20 weeks of gestation. All of this suggests that complement activation plays a role in the onset and development of Preeclampsia. 45 In animal models, angiogenic factor imbalance appears to occur before complement activation. 46 Complement activation could play a larger role in the development of Preeclampsia. 47 Formalized paraphrase According to some studies, atypical hemolytic uremic syndrome (aHUS) with excessive activation of the complement replacement pathway is similar to severe preeclampsia syndrome (HELLP syndrome). 47 , 48 Inhibiting complement activation has been shown in studies to prevent the increase of sflt1 in pregnant mice. 49 If this hypothesis is confirmed in twins, dichorionic twins with high placental immunogenicity have a higher risk of Preeclampsia than monozygotic twins. However, the available data do not appear to support the increased risk of Preeclampsia in twins. 50

Presently, the ratio of Preeclampsia increased to 1.65 for women with a body mass index between 25 kg/m2 and 30 kg/m2, and 6.04 for women with body mass index ≥ 40 kg/m2. The precise underlying mechanism is uncertain. 51 At the moment, the impact of genetic factors on the onset of Preeclampsia is also worth considering. The risk of Preeclampsia in nulliparous mothers or sisters with a preeclampsia family history is 2 to 5 times higher than in nulliparous mothers without a preeclampsia family history. A study of preeclampsia sisters revealed that the fetal inheritance of the mother’s stox1 missense mutation at 10q22 resulted in the development of Preeclampsia. Paternal homologous gene inheritance, on the other hand, does not result in Preeclampsia during pregnancy. Preeclampsia is more likely in mothers who have a trisomy 13 fetus. According to research, the sFlt-1 and Flt-1 genes linked to Preeclampsia, are also found on chromosome 13. 3 ( Figure 1 )

The pathogenesis of twin preeclampsia, from the characteristics of twin, twin placenta area is larger, produce more anti angiogenic substances, assisted reproductive technology is widely used, old age, obesity and maternal primary disease increase, immune disorders, the role of genetic factors, from many aspects reveals the mechanism of the occurrence and development of twin preeclampsia.

Despite these well-known facts, the literature on multiple pregnancies in Preeclampsia is limited when compared to singleton pregnancies. Women who have multiple pregnancies are typically excluded from studies or included in undifferentiated singleton studies. The focus of these patients has created new challenges. It is critical to include this population in future research in order to improve perinatal outcomes and reduce the incidence rate and mortality of women worldwide. These women are known to be at a higher risk of many obstetric complications, particularly Preeclampsia. Furthermore, their pregnancy process differs from that of singletons. Based on evidence of multiple births, it is more appropriate to investigate specific guidelines and pathophysiological processes.

Influence of Preeclampsia on Perinatal Outcome of Twins Pregnant Women

One of the most common pregnancy complications is Preeclampsia. It has far-reaching consequences for mothers’ and infants’ short- and long-term health, including maternal organ dysfunction, which includes renal failure, liver involvement, neurological or hematological complications, uterine placental dysfunction, and fetal growth restriction. 5 Preeclampsia is a common cause of maternal and fetal death and morbidity around the world. 52 Many identified risk factors are thought to be linked to the etiology of Preeclampsia, but the specific etiology remains unknown. Preeclampsia is more common in older women, obese mothers, diabetic mothers, and mothers with pre-pregnancy hypertension. Preeclampsia is also linked to the mother’s and offspring’s long-term cardiovascular disease development. 7 Preeclampsia significantly increased the risk of adverse pregnancy outcomes in the offspring, including cesarean section, placental abruption, SGA, preterm birth, and 5-minute Apgar score < 7. Furthermore, numerous studies have found a link between an adverse intrauterine environment for the fetus and adult diseases like coronary atherosclerotic heart disease, hypertension, obesity, type 2 diabetes, and so on. 53 The level of understanding and management of Preeclampsia has improved as current research on the disease progresses. Previously, most research focused on singleton pregnancies. Only a few studies, particularly those with a higher level of evidence on Preeclampsia’s long-term effect on the offspring of twin pregnancies, have looked into the link between twin pregnancies and Preeclampsia.

The findings of various studies on the impact of Preeclampsia on twin pregnancies’ perinatal outcomes are neither conclusive nor consistent. Common risk factors such as maternal age, parity, body mass index (BMI), diabetes, smoking, socioeconomic status (education level is an indicator), and in vitro fertilization (IVF) were evaluated by Laine et al 54 in a statistical analysis of women who gave birth in Norway from 1999 to 2014. The findings showed that the risk of Preeclampsia in twin pregnancies was higher than previously thought, and that the prevalence of Preeclampsia in twin pregnancies was three to four times that of singleton pregnancies. Sibai et al 55 discovered a trend that complemented Laine’s findings. However, the risk of Preeclampsia from twin pregnancies was estimated to be lower than in Laine’s study (AOR 2.48, 95% CI 1.82 to 3.38). Only 8 out of 92 articles in another large meta-analysis listed multiple births as a risk factor for Preeclampsia, confirming the lack of research into the relationship between twin pregnancies and Preeclampsia. 56

The study discovered that the risk of hypertension in twins increased following natural pregnancy or assisted reproductive technology, but after assisted reproductive technology pregnancy (risk difference, 1.73 percentage points every five years; confidence interval, 95%, 1.35–2.11 percentage points every five years) was higher than that in twins after natural pregnancy (risk difference, 0.75 percentage points; confidence interval, 95%, 1.35–2.11 percentage points every five years); The confidence interval was 95%, 0.61–0.89 percentage points every five years). 57 Twin pregnancy has more severe Preeclampsia. 58

When chorionic factors of twins are considered, some studies have found that women with dizygotic chorionic twins (DC) have an increased risk of Preeclampsia compared to monozygotic ones chorionic twins (MC). Bartnik et al looked at 233 dizygotic chorionic twins (DC) and 79 monozygotic chorionic twins (MC) twins. It was discovered that the risk of Preeclampsia was three to four times higher in dizygotic chorionic twins (DC) pregnancy. 59 Sparks et al discovered that the risk of Preeclampsia doubled in women carrying dizygotic chorionic twins. 60 However, Savvidou et al discovered no difference in preeclampsia risk between monozygotic and dizygotic chorionic twins. 61 The risk of preterm PE in DC and MC twins is comparable to and significantly higher than in singleton pregnancies. 18 GDM has a greater influence on MCDA twin pregnancy, manifested as maternal hypertensive disorder complicating pregnancy and SGA. 62 In the twins with Preeclampsia, map (mean arterial pressure) was significantly higher than that in the twins without Preeclampsia (P < 0.02, one tailed), while the level of Doppler PI (Doppler pulse index) was significantly lower. (P < 0.01, two-tailed). 63 Twin pregnancy had a lower mid-term Doppler PI level than singleton pregnancy. 64 The study found no difference in the incidence of hypertension during pregnancy between women with and without gestational diabetes after adjusting for mother’s age, in vitro fertilization treatment, race, and pre-pregnancy body mass index 65 The incidence of hypertensive disorders complicating pregnancy (Preeclampsia and gestational hypertension) was comparable between the two groups, but the incidence of severe Preeclampsia was higher in twin pregnancy (8 cases (5.9%) than in twin pregnancy (0 case, P = 0.057) 66 Compared with preeclampsia singletons, twins had higher mean birth weight, lower small for gestational age (SGA) and fewer births < 34 weeks and < 32 weeks. The incidences of placental weight < 10% (AOR 0.49, 95% CI 0.33–0.71), fetal vascular pathology (AOR 0.28, 95% CI 0.20–0.39) and fetal vascular perfusion pathology (AOR 0.65, 95% CI 0.45–0.93) was significantly reduced. The findings support the hypothesis that MVM has little to do with the pathogenesis of HDP in twin pregnancy, and that other placental or non-placental factors are to blame for the increased risk. 67 In terms of perinatal mortality, there was no difference. 68 The risk of PE was higher in twin pregnancies with chronic hypertension than in singleton pregnancies (P < 0.01). The risk of PE was higher in twin pregnancies with chronic hypertension than in singleton pregnancies (P < 0.01). The gestational age of twin pregnancy with PE was earlier (P < 0.001), and SGA was more. 69 When comparing mothers and neonates of twin pregnancies complicated to mothers and neonates of singleton pregnancies complicated by severe Preeclampsia, there does not appear to be a difference in morbidity and mortality. 70 ( Table 1 )

Summary of Studies on the Clinical Features of Twins

Abbreviations : DC, dichorionic; GDM, gestational diabetes mellitus; HDP, hypertensive disorders in pregnancy; MAP, mean arterial pressure; MVM, maternal vascular malperfusion; MC, monochorionic; MCDA, monochorionic diamniotic twin; PI, pulse index; PE, preeclampsia; SGA, small for gestational age.

Because the burden associated with multiple pregnancies increases, the increased risk of Preeclampsia in twin pregnancies could be due to different pathophysiological progress. It differs from other risk factors that may remain unchanged during pregnancy as the pregnancy progresses. Preeclampsia may be caused by an oversized placental volume or an insufficient placental blood supply. 71 The total peripheral resistance of the uterus and placenta increases as the twins grow, and the angiogenic factors released by the placenta may harm vascular endothelial function in the dynamic process. 20

Preeclampsia Management During a Twin Pregnancy

Preeclampsia patients can improve their perinatal outcomes by managing their pregnancies. Previous studies only looked at singleton pregnancies or only included a small number of twin pregnancies, so preeclampsia patients with twin pregnancies have no way of knowing what kind of pregnancy management they should expect. The primary advice is to prevent Preeclampsia. Antiplatelet drugs, particularly aspirin, are effective and safe in preventing Preeclampsia in women at moderate or high risk in at least 75 randomized controlled trials. 72 , 73 According to meta-analyses, women at high risk of Preeclampsia who started taking aspirin between 12 and 16 weeks of pregnancy had a 53% lower relative risk of pregnancy (95% confidence interval: 35% to 66%) 74–76

In the United States, the Society of Obstetricians and Gynecologists recommends that women with a history of recurrent Preeclampsia or severe illness requiring delivery use low-dose aspirin as a preventive measure 34 weeks prior. 5 However, such stringent precautions have little effect on the overall health consequences of Preeclampsia. Moreover, public health publications have recommended low-dose aspirin prophylaxis for all women with twins pregnancies. 5 , 77 As a result, the potential benefits of low-dose aspirin for women with twin pregnancies must be emphasized. Low-dose aspirin has been shown to prevent Preeclampsia’s onset and progression by promoting the invasion and migration of trophoblast cells into the uterine artery, interfering with cytokine production and promoting the production of the angiogenic protein placental growth factor (PlGF). As a result, inhibition of apoptosis and early uterine artery remodeling may help to prevent the onset and progression of Preeclampsia. 78

When comparing twins and singletons, it was discovered that a high carbohydrate diet combined with a lack of protein, iron, and other micronutrients can cause preeclampsia. 79 To further optimize pregnant mothers and children’s health, it is critical to determine the appropriate maternal nutrition or micronutrient supplement.

Analysis of maternal characteristics, maternal mean arterial pressure, uterine artery pulsatility index, and serum biochemical indicators are currently the most commonly used screening methods for early detection of Preeclampsia (PAPP-A and/or PlGF), which can be measured as early as 11–13 weeks of gestation. The severity of maternal antiangiogenesis in preeclampsia patients in the third trimester of pregnancy may be more accurate than elevated blood pressure in predicting the occurrence of preeclampsia complications. 80 , 81 In pregnant women with Preeclampsia within 34 weeks, the sFlt-1/PlGF ratio was 85, which could predict premature delivery within two weeks, and the risk ratio was 15.2. 80 The sFlt-1/PlGF ratio < 38 had a high negative predictive value (99.3%) for complications within 1 week. 82 Furthermore, other research has found that patients with Preeclampsia but normal angiogenesis have no adverse maternal or neonatal complications. 83 Regardless of the development of Preeclampsia, the remaining delivery time of patients with sflt1/PlGF ratio < 38 was significantly shorter and the preterm birth rate was higher. 84 The sflt1/PlGF ratio was 38 in 90% of women suspected or diagnosed with Preeclampsia, which is rather stable. 85 A recent randomized control trial found that using preeclampsia measurement in the treatment of women with suspected Preeclampsia can significantly improve postpartum outcomes. 86 A larger cohort study is needed to confirm whether twins and singletons are consistent with the same probability value in the prediction of preeclampsia needs.

Preeclampsia can currently be treated with a number of medications (eg methyldopa, hydralazine, magnesium sulfate). 87 PreeclampsiaThe severity of the symptoms determines preeclampsia treatment. It is critical to consider timely delivery in clinical work in order to assess and reduce the incidence rate of maternal and perinatal diseases. The most important factors are gestational age, the progression of maternal disease, and the health of the fetus. Women with Preeclampsia should be delivered as soon as possible after 37 weeks of pregnancy, according to most national guidelines, 88 , 89 and the risk of mothers after delivery can be significantly reduced. However, the best delivery time for women with late preterm Preeclampsia (34–37 weeks gestation) is unknown because the severity of maternal disease progression must be balanced against the importance of fetal management (including abnormal fetal heart rate requiring emergency delivery, worsening growth restriction, stillbirths, etc.). 90 The current standard of care is to have an expectant treatment before 37 weeks of pregnancy. Serious complications could arise if the clinical situation changes, so the delivery should be scheduled ahead of time. On a global scale, these recommendations are still used by countries. 91 Due to its unique complications, twin pregnancies in combination with a singleton strategy are ideal, based on the situation and analysis.

In the last decade, our understanding of the pathophysiology of Preeclampsia has advanced significantly. One of the fundamental mechanisms of maternal systemic vascular dysfunction is endothelial dysfunction caused by placental antiangiogenic factors. Imbalance is becoming more widely used in clinical practice to investigate clinical treatment options from the perspective of maternal angiogenesis. Preeclampsia is currently a special risk factor for future cardiovascular disease in women. Furthermore, hypertension, hyperlipidemia, and diabetes are the most closely monitored conditions. Women with a history of Preeclampsia are given lifestyle recommendations. However, it is still unclear how to improve these women’s cardiovascular health. 92 To further refine treatment strategies and programs, more research is needed to develop appropriate strategies for monitoring and intervening with these women and conducting differential treatment analyses of singletons and twins. The clinical treatment strategy of regulating angiogenesis imbalance is expected to lower the risk of complications and lengthen the gestational period. In addition, elucidating pathophysiology and developing accurate detection and prevention methods can help preeclampsia women reduce their risk of cardiovascular disease.

Preeclampsia risk is significantly higher in twin pregnancies than in singleton pregnancies. Its complications appear sooner, progress more quickly, and the condition becomes more serious. On the other hand, women with twin pregnancies are usually either not grouped with singleton pregnancies in the study or are excluded entirely. In today’s obstetric clinical work, the management of these patients has presented a unique challenge. The major contradiction that obstetric staff will have to resolve in the future is to improve perinatal outcomes while simultaneously lowering the incidence rate and mortality of women around the world. The pregnancy process for twins is different from that of a singleton pregnancy, as is the pathophysiological process of Preeclampsia. The treatment of twin pregnancies must be separated from treatment guidance to improve the perinatal outcome of twin pregnancies and carry out accurate twin pregnancy management.

Funding Statement

This work was supported by the Natural Science Foundation of Liaoning Province (No. 2020-MS-03), the Science Foundation of Liaoning Education Department (FWZR2020012) and the 345 Talent Project of Shengjing hospital.

Statement of Ethics

This article does not contain any studies with human or animals performed by any of the authors.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

The authors declare no conflicts of interest in this work.

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Pelvic girdle pain during pregnancy is common, but can be relieved

by University of Gothenburg

Acupuncture and transcutaneous electrical nerve stimulation (TENS) are two interchangeable treatments to relieve pelvic girdle pain during pregnancy. Both treatments also alleviate the pregnant woman's concern about pain, according to a thesis from the University of Gothenburg.

More than 1 in 2 pregnant women are affected by pelvic girdle pain to some degree. Pelvic girdle pain often makes it difficult to walk. For 1 in 10 women with more severe pain, there could be residual symptoms more than ten years after giving birth.

"Pelvic girdle pain, can be caused by various changes in the body due to pregnancy, and it is important to identify such pain at an early stage in order to offer treatment," emphasizes physiotherapist Annika Svahn Ekdahl, the author of the thesis.

"Pregnant women are often told that it's not surprising they have pains in their back or pelvis, for example, and that it's something related to pregnancy. But when your whole life is affected by the pain, it becomes a problem. Then it is no longer normal," she says.

Comparing acupuncture and TENS

The thesis compares the effect of two different treatments: acupuncture and transcutaneous electrical nerve stimulation (TENS). In the study, 113 pregnant women were randomly selected to receive either 10 acupuncture sessions with a physiotherapist or daily at-home TENS treatment over five weeks. The treatments were found to give equivalent results.

"Both treatments reduced the participants' pain intensity and concern related to pain, while also helping them maintain their physical activity. This is remarkable because pelvic girdle pain often leads to reduced physical activity," says Annika Svahn Ekdahl.

Pain and anxiety

The participants in both groups had improved their functional status over time and about half of them achieved the general recommendations for physical activity three years after giving birth.

"At the same time, we found that some women still experienced persistent pelvic pain. "The concern women felt about their problems was also related to how well they were able to cope with everyday life," says Annika Svahn Ekdahl.

"One interesting finding is that concern about pain is a major problem, in addition to the actual pain. Concern relating to pain seems to be a significant factor in women's functional status."

When asked about their expectations coming into a meeting with a physiotherapist, pregnant women with pelvic pain expressed that they want advice tailored to them. They want expert help to deal with their specific situation.

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