Protocols for Monitoring of Multiple Pregnancies: A Literature Review

Charalampos Tsimpoukelis *¹, Sofoklis Stavros ², Despoina Mavrogianni ¹, Peter Drakakis ^1,2

1. First Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece.

2. Third Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Attikon Hospital, Athens, Greece.

Corresponding Author: Charalampos Tsimpoukelis, First Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece.

Copy Right: © 2023 Charalampos Tsimpoukelis, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received Date: April 13, 2023

Published Date: June 01, 2023

Abstract

Introduction

The incidence of multiple pregnancies has increased over the past decades, mainly due to the use of assisted reproduction methods and increased maternal age at childbirth. Indicatively in the United States, the birth rate of multiple pregnancies has increased dramatically since 1980, reaching a peak in 2014, with a slight decrease since then, reaching 33 per 1000 births in 2019. From 1980 to 2009, the twin birth rate rose 76%, with little fluctuation until 2019, when it was 32.1 per 1,000 births. The triplet and higher order multiple birth rate increased more than 400% from 1980 to 1998. In 2019, it stood at 0.87 per 1,000 births, a 55% decrease from the peak in 1998, due to fewer embryos being transferred during IVF and an increase in fetal reduction procedures.

In terms of the mechanisms of generation and risk factors of multiple pregnancies, there are differences between monozygotic and dizygotic twins. In monozygotic twins, depending on the period when the spontaneous division of the incipient developing embryo occurs, different combinations of amnionicity and chorionicity arise. Their creation is due to random non-hereditary factors. Their prevalence is relatively stable and is not affected by patient-specific factors, except for pregnancies resulting from IVF techniques, which appear to increase the risk of zygote cleavage. In contrast, dizygotic twins result from the independent fertilization of two ova during one ovulatory cycle. Their prevalence varies between populations. Risk factors for dizygotic twin pregnancies include black race, advanced maternal age, increased maternal weight and height, multiparity, family history of multiple pregnancies, high levels of follicle-stimulating hormone (FSH), and infertility treatment with techniques of multiple ovulation in combination with multiple embryo transfer.

Objectives-Methods: The aim of this paper is to review the issues and complications associated with twin and triplet pregnancies and to present an evidence-based approach to the management and monitoring of these pregnancies according to chorionicity and amnionicity.

A literature review was performed including studies up to June 2022. The following electronic databases were searched to identify articles for the systematic review: MEDLINE, PubMed-NCBI, Cochrane Library, Cochrane Central Register of Controlled Trials, EMBASE and Scopus. In addition, guidelines relevant to the topic of the work were searched in the following: ACOG, NICE, ISUOG, and HSOG.

Results: This paper first analyzed both the initial prenatal assessment and prenatal care in the second and third trimesters for singleton pregnancies and then reviewed twin and triplet pregnancies. In regard to multiple pregnancies, the way of diagnosis, determination of the gestational age and the chorionicity and amnionicity, and labeling of the fetuses was initially presented. Subsequently, a distinction was made between maternal, including preeclampsia and gestational diabetes mellitus, perinatal, and fetal complications of multiple pregnancies. In the latter, a further division was made into complications that characterize all multiple pregnancies (preterm birth, growth restriction and discordance, congenital anomalies), complications that occur exclusively in monochorionic multiple pregnancies [twin-twin transfusion syndrome (TTTS), twin anemia polycythemia sequence (TAPS), twin reversed arterial perfusion (TRAP), and selective fetal growth restriction (sFGR)], and complications which concern only monoamniotic multiple pregnancies (intertwin cord entanglement, conjoined twins). At the same time, reference was made to the management of the above complications. Then, special mention was made of how to deal with single fetal demise in twin and triplet pregnancies, and of the cases of multifetal pregnancy reduction and selective termination. Consequently, an attempt was made to record and present prenatal care in twin and triplet pregnancies as completely as possible. In more detail, the issue of education and promotion of pregnant women's health was initially touched upon.

Afterwards, screening of multiple pregnancies for fetal chromosomal and congenital anomalies, fetal growth restriction and discordance, preterm birth, and placental abnormalities was studied. Then, the ultrasound monitoring algorithms of twin and triplet pregnancies were described according to chorionicity and amnionicity. Finally, issues related to the birth of twins and triplets were listed, such as planning the timing and route of delivery.

In terms of ultrasound monitoring of twin pregnancies, women with an uncomplicated dichorionic twin pregnancy should have a first-trimester ultrasound examination, a second-trimester anomaly scan (including measurement of cervical length) and scans every 4 to 6 weeks thereafter. Uncomplicated monochorionic diamniotic twins should have a first-trimester ultrasound scan and then every 2 weeks after 16 weeks for early detection of TTTS, TAPS or sFGR. In addition to anatomy scan at 18 to 22 weeks of gestation, fetal echocardiography is performed at the same weeks for monochorionic but not dichorionic twins. Regarding monochorionic monoamniotic twins, there is insufficient evidence to suggest a different frequency of fetal growth monitoring compared to monochorionic diamniotic twins.

For antenatal fetal surveillance, NST and amniotic fluid volume determination or biophysical profile are performed weekly starting at 32 weeks in dichorionic twins and at 28 weeks in monochorionic diamniotic twins. Monochorionic monoamniotic twins are monitored more closely. It is common practice to hospitalize patients with monoamniotic twin pregnancies at the beginning of the third trimester (26 to 28 weeks) in order to intensively monitor fetal heart rates.

For uncomplicated dichorionic twin pregnancies, planned delivery is recommended from 37+0 to 38+6 weeks of gestation. Delivery of monochorionic diamniotic twins is recommended at 34+0 to 37+6 weeks. In contrast, for monochorionic monoamniotic pregnancies, delivery is planned between 32+0 and 34+0 weeks of gestation. Both chorionicity and amnionicity and fetal presentations at the onset of labor influence the choice of route of delivery in twin pregnancies.

Regarding ultrasound monitoring in triplet pregnancies, an ultrasound scan is performed in the first or early second trimester to ascertain chorionicity and amnionicity. Starting at 20 weeks, the ultrasound examination for triplet trichorionic triamniotic pregnancies is generally performed every three to four weeks to monitor the development of the fetuses. Because of the common chorionic sac, for monochorionic triamniotic and dichorionic triamniotic triplets, an ultrasound protocol similar to that commonly used to monitor monochorionic twin pregnancies is followed. In case of shared amniotic sac (monochorionic monoamniotic or dichorionic diamniotic triplets), experts recommend admitting these patients to the hospital at 26 weeks of gestation, to facilitate intensive monitoring of fetal heart rates. Ultrasound follow-up for these conditions is the same as for triplets with a common chorionic sac.

The timing of delivery of triplets is based on the type of amnionicity, regardless of lung maturity. Monoamniotic and diamniotic triplets are born between 32+0 and 32+6 weeks. For an uncomplicated trichorionic triamniotic or dichorionic triamniotic triplet pregnancy, planned delivery at 35 weeks of gestation is recommended. Regarding the monochorionic triamniotic triplet pregnancy, the time of delivery depends on the individual clinical scenario and the individual assessment of the physician. In all triplet pregnancies, cesarean delivery is recommended.

Conclusions-Discussion: Routine prenatal care of women with multiple pregnancies differs from routine prenatal care in singleton pregnancies in various aspects, such as recommendations for weight gain and micronutrient intake, routine prophylactic administration of low-dose aspirin for the prevention of preeclampsia in multiple pregnancies, choice of appropriate method for screening for chromosomal abnormalities, and frequency and goal of ultrasound monitoring. Although ultrasound measurement of cervical length is a common screening test to predict preterm delivery in singleton and twin pregnancies, short cervical length is not a sensitive test in triplets and its measurement is not recommended.

In contrast to singleton and twin pregnancies, there is no evidence of benefit from intervention to prevent preterm birth in women with triplets and short cervical length. Also, women with triplet pregnancies should undergo focused anatomic survey to screen for neural tube defects in the second trimester, since alpha-fetoprotein (AFP) screening has not been validated in triplets. Additionally, in triplet pregnancies, no serum marker or cell free fetal DNA (cffDNA) test for aneuploidy has been validated. Conversely, increased nuchal translucency has been validated as a screening test for trisomy 21 and trisomy 18, but not for trisomy 13.

Compared to singleton pregnancies, follow-up of twin and triplet pregnancies involves more frequent ultrasound examinations, which have an earlier onset and increased frequency, in case of fetuses with a common chorionic or amniotic sac, with the aim of early recognition of possible TTTS syndrome, TAPS sequence, and selective fetal growth restriction (sFGR).  Chorionicity and amnionicity determine also the timing of delivery. While cesarean delivery is recommended in all triplet pregnancies, chorionicity, amnionicity and presentations of both twins at the onset of labor influence the choice of delivery route in twin pregnancies.

Keywords

prenatal care, ultrasound, twin pregnancy, triplet pregnancy, multiple pregnancy, maternal complications, perinatal morbidity, fetal complications, monochorionic twins, twin-twin transfusion syndrome, twin anemia polycythemia sequence, selective fetal growth restriction, twin reversed arterial perfusion, monochorionic monoamniotic twins, conjoined twins, fetal demise, multifetal pregnancy reduction, selective termination, screening, follow-up of multiple pregnancies, timing of delivery, route of delivery.

Introduction

Definition of multiple pregnancy

A multiple pregnancy is defined as a pregnancy in which more than one embryo has implanted and is developing within the endometrial cavity. If the embryos are two, then it is characterized as a twin pregnancy, if it is three as a triplet, if it is four as a quadruplet, etc. However, in case one of the embryos involved implants outside the endometrial cavity, it is a heterotopic pregnancy, which constitutes an object of study of ectopic pregnancies. (Loutradis D. et al., 2018)

Mechanisms of multiple pregnancies

Zygosity refers to the genetic origin of embryos. More specifically, multiple pregnancy can occur in the following ways:

• From independent fertilization and implantation of more than one fertilized egg (dizygotic, trizygotic pregnancy, etc.), due to the rare phenomenon of multiple ovulation, while it is more frequent when it originates iatrogenically through induction of ovulation with stimulation of the ovaries, and multiple embryo transfer during in vitro fertilization.
• From spontaneous splitting of an incipient developing embryo into individual parts (monozygotic pregnancy).
• From the extremely rare case of simultaneous occurrence of the two aforementioned phenomena (mixed pregnancy), especially during in vitro fertilization, due to micromanipulations in the zona pellucida of the embryos and embryo transfer of more than one embryo (Loutradis D. et al., 2018) .

Chorionicity indicates the number of chorions and the composition of the placenta. Amnionicity refers to the number of amniotic cavities.

Dizygotic twin pregnancy

Dizygotic twins are not true twins in the strict sense, because they result from the fertilization of two eggs during one ovulatory cycle. Essentially, embryos are genetically like any other pair of siblings, so according to the law of probability they can be of the same or different sexes.

Dizygotic twin pregnancies are always dichorionic and diamniotic because each blastocyst creates its own chorionic and amniotic sac. The placentas are separate and recognizable from each other. However, many times they come together and present as one organ, with two chorionic layers separating them (Cunningham, 2018) .

Monozygotic twin pregnancy

On the other hand, monozygotic or identical twins, although they have essentially inherited the same genetic code, are usually not completely identical. That is, the division of a fertilized zygote does not necessarily result in an equal distribution of the protoplasmic material. Monozygotic twins may be discordant for genetic mutations, due to a postzygotic mutation, or they may have the same genetic disease but with marked variability in expression. Inactivation of an X chromosome in female fetuses can cause differential expression of X-linked traits or diseases. Furthermore, the phenomenon of monozygotic pregnancy is in a sense a teratogenic event and monozygotic twins have a higher incidence of often discordant malformations (Glinianaia et al., 2011) . For example, in a study of 926 monozygotic twins, the prevalence of congenital heart defects was 12 times the general population rate, but 68% of affected infants had a normal sibling (Pettit et al., 2013) . For any of these reasons, same-sex dizygotic twins may look more identical at birth than monozygotic twins, who are the same sex by genetics anyway. In rare cases, however, the karyotype or phenotype of a monozygotic twin pregnancy may be different due to somatic mutations or chromosomal aberrations. Most recorded cases describe postzygotic loss of the Y chromosome in one of 2 46,XY fetuses resulting in a phenotypically female fetus with Turner syndrome (45,X) and a male fetus (Cunningham, 2018 ) . A rare case of a 47, XXY zygote that has undergone postzygotic loss of the X chromosome in some cells and loss of the Y chromosome in other cells has also been reported. The phenotype of the resulting twins was one male and one female, both of whom had genetic mosaicism 46,XX/46,XY (Zech et al., 2008) .

In monozygotic twins, depending on the period when the separation will occur, different combinations of amnionicity and chorionicity arise. So, if separation occurs:

1. during the first 3 days (stage between 8 cells and blastocyst) monozygotic dichorionic diamniotic twins result. At this point, in which the differentiation of the trophoblast has not yet taken place, two choria and two amniotic sacs are observed. Two separate placentas or a single fused placenta may result.
2. during the time period of the first 4-8 days (early blastocyst stage) monochorionic diamniotic twins arise. The division results in the formation of a blastocyst with two separate embryoblasts (inner cell masses). Each embryo will form its own amnion within a common dermis and placenta.
3. during the first 9-12 days monochorionic monoamniotic twins are born. The differentiation of the chorion and the amnion is already complete. Division results in 2 embryos with a common placenta, a chorion and an amniotic cavity.
4. after day 13, monochorionic and monoamniotic twins are incompletely separated and share blood circulation and are classified as conjoined. Depending on the point of fusion, conjoined twins are divided into omphalopagus, thoracopagus, cephalopagus, and ischiopagus in order of frequency (Cunningham, 2018) .

Alternative mechanisms

Recently, there has been an alternative hypothesis, according to which the monozygotic pregnancy arises by fission at the postzygotic stage of the two cells. In this case, due to an alteration of the zygote-blastomere transition, the first zygotic division, instead of producing two blastomeres, gives rise to twin zygotes. In addition, monochorionicity and monoamnionicity do not depend on the cleavage of the embryos, but on the fusion of the membranes. (Herranz, 2015) . However, the data are not reliable to support either the traditional or the newly proposed model (Denker, 2015) .

It has long been accepted that monochorionicity unequivocally indicates monozygosity. Rarely, however, monochorionic twins may actually be dizygotic (Hackmon et al., 2009) . The mechanisms for this are theoretical, but in a review of 14 cases, almost all were conceived after ART procedures (Ekelund et al., 2008) .

Superfetation

In this case, there is an interval equal to or longer than one menstrual cycle between fertilizations. Ovulation and fertilization are required during an established pregnancy, which is theoretically possible, until the uterine cavity is obliterated by the fusion of the decidua capsularis with the genuine decidua parietalis. Although known to occur in mares, it is not known to occur spontaneously in humans. A case has been reported after ovarian hyperstimulation and intrauterine insemination in the presence of an undiagnosed tubal pregnancy (Lantieri et al., 2010) . Most authorities believe that the putative human cases of this phenomenon arise from markedly unequal development of twin fetuses of the same gestational age (Cunningham, 2018) .

Superfecundation

This condition refers to the fertilization of two eggs within the same menstrual cycle but not during the same intercourse, nor necessarily by sperm from the same man. In one case of this phenomenon the mother gave birth to a black newborn with blood type A and a white newborn with blood type O. The blood type of the mother and her husband was O (Harris, 1982 ) . More recent cases have been reported in paternity proceedings (Girela et al., 1997) . Considering that this phenomenon can also occur during IVF, women should be advised to avoid intercourse after embryo transfer (McNamara et al., 2016) .

Triplet pregnancy

A triplet pregnancy may have the following combinations of chorionicity and amnionicity in descending order of frequency:

• Trichorionic triamniotic triplets
• Dichorionic diamniotic triplets
• Dichorionic triamniotic triplets
• Monochorionic triamniotic triplets
• Monochorionic monoamniotic triplets

3.Epidemiology of multiple pregnancies

In 1980, the rate of multiple pregnancies in the U.S. amounted to 19.3 per 1000 births. Due to the use of assisted reproductive methods and the increased age of the mother at childbearing, the rate increased dramatically in the following decades, reaching the highest value in 2014 at 35.1 per 1000 births, with a slight decrease since then, rising to 33/1000 in 2019.

The frequency of spontaneous multiple pregnancies can be derived by the following calculation:

• Twin pregnancy 1: 80
• Triplet pregnancy 1: 80 ² =1 : 6 . 400
• Quadruple pregnancy 1: 80 ³ =1: 512,000 (Nathan et al., 2012)

Specifically, in the U.S., twin pregnancies account for approximately 3% of all pregnancies and 97% of multiple pregnancies. From 1980 to 2009, the rate of twin pregnancies increased 76% (from 18.9 to 33.2 per 1,000 births), was generally stable from 2009 to 2012, and then increased for 2013 and 2014 (33, 9). In 2019 it was 32.1 per 1,000 births, down 2% from the 2018 rate of 32.6 and 5% from the 2014 high (Martin et al., 2021).

Dizygotic twins are more common than monozygotic twins, accounting for approximately 70% and 30% of twins respectively (in the absence of assisted reproductive technology). The prevalence of dizygotic twins varies between populations. In contrast, the prevalence of monozygotic twins, whose generation is due to random non-hereditary factors, is relatively constant worldwide at 3 to 5 per 1000 births, and is not affected by patient-specific factors, except for pregnancies from in vitro fertilization (IVF) (Cunningham, 2018) . The distribution of the percentage of monozygotic twins according to chorionicity and amnionicity is:

• Diamniotic dichorionic twins: 25- 30 % of monozygotic twins
• Diamniotic monochorionic twins: 70-75 % of monozygotic twins
• Monoamniotic monochorionic twins: 1-2 % of monozygotic twins
• Conjoined twins: very rare (Gabbe, Niebyl and Simpson, 2017)

The rate of triplet and higher order multiple pregnancies increased in the US. more than 400% from 1980 (0.37 per 1000 births) to 1998 (1.93). In 2019 it was 0.87 per 1,000 births, a 6% decrease from 2017 (0.93) and a 55% drop from the 1998 peak, due to fewer embryos being transferred during IVF and an increase in fetal reduction techniques (Martin et al., 2021) .

Sex rates in multiple pregnancies

In humans, as the number of embryos per pregnancy increases, the percentage of male embryos decreases. It was found that the proportion of male fetuses in 31 million singleton births in the U.S. was 51.6%. For twins it was 50.9%, for triplets 49.5% and for quadruplets 46.5% (Strandskov HH, Edelen EW, and Siemens GJ, 1946) . Swedish data of 135 years reveal that the number of males per 100 female newborns was 106 among singleton pregnancies, 103 among twins and 99 among triplets (Fellman and Eriksson, 2010) . Females are even more dominant in twins from the late stages of segregation. For example, 68% of Siamese twin bullfighters are female. Two explanations were given. First, starting in the womb and continuing throughout the life cycle, mortality rates are lower in women. Second, female zygotes have a greater tendency to divide (Mutchinick et al., 2011) .

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