Abnormal Development - Twinning

Embryology - 1 Dec 2023        Expand to Translate
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Introduction

Historic drawing of twins by William Smellie (1697-1763)

While singleton human births are the most common, there are also several different forms of twinning (multiple pregnancy) that may arise in the early weeks (first two weeks) of development. The two major twinning forms are dizygotic (from two eggs fertilised by two different spermatazoa) and monozygotic (from one fertilised egg and a single spermatazoa). Higher multiple pregnancies (triplets, quadruplets, etc.) are generally dizygotic with ultrasound acting as the earliest diagnostic test for all multiple pregnancies.

Dizogotic twinning can be described following the normal developmental sequence, while monozygotic twinning requires a perturbation of developmental event(s) to occur in the first weeks following fertilisation. The later stages of monozygotic embryonic development may well follow the normal pattern of differentiation, though growth during the fetal period can be lower.

Twinning rate differences over time and between countries are thought due to variation in dizygotic twinning. Monozygotic twinning is thought to occur at a relatively constant rate of 3.5–4 per 1000 births across human populations, with assisted reproductive technologies possibly contributing to recent changes.

In addition to the zygosity, the additional twinning classifying terms refer to the type of placenta and fetal membranes, either separate or shared by the twins. Twinning has both a higher incidence of mortality in twins, due mainly to preterm delivery, and of incidence of birth defects. Single fetal mortality also occurs in 3.7 - 6.8% of all twin pregnancies, and there are more maternal risks involved with multiple pregnancies. As a positive, twins do appear to have a lower incidence of trisomy 21.

Week 2

Monozygotic twin embryos

Some Recent Findings

Longitudinal Doppler references for monochorionic twins and comparison with singletons "To construct monochorionic (MC) twin-specific longitudinal doppler ultrasound references for umbilical artery pulsatility index (UA-PI), middle cerebral artery (MCA) PI and peak systolic velocity (PSV) and ductus venosus (DV) PI derived from a strictly selected cohort of uncomplicated MC twins. The secondary aim of the study was to compare our findings with singleton reference charts. The study group comprised 150 uncomplicated MC twin pairs. Estimated centiles (3rd, 5th, 10th, 50th, 90th, 95th, 97th) of UA-PI, MCA-PI, MCA-PSV and DV-PI in function of the gestational age are presented. The comparison with singletons showed substantial differences, with higher UA-PI and lower MCA-PI and PSV median values in MC twins. Median DV PI values were similar to the values for singletons, while the upper centiles were higher in MC twins." doppler ultrasound | ultrasound Molecular Support for Heterogonesis Resulting in Sesquizygotic Twinning "Sesquizygotic multiple pregnancy is an exceptional intermediate between mono- zygotic and dizygotic twinning. We report a monochorionic twin pregnancy with fetal sex discordance. Genotyping of amniotic fluid from each sac showed that the twins were maternally identical but chimerically shared 78% of their paternal genome, which makes them genetically in between monozygotic and dizygotic; they are sesquizygotic. We observed no evidence of sesquizygosis in 968 dizygotic twin pairs whom we screened by means of pangenome single-nucleotide polymor- phism genotyping. Data from published repositories also show that sesquizygosis is a rare event. Detailed genotyping implicates chimerism arising at the juncture of zygotic division, termed heterogonesis, as the likely initial step in the causation of sesquizygosis." Early prenatal diagnosis of parapagus conjoined twins "Conjoined twinning occurs in 1/100 of monozygotic twins, 1/50,000 gestations and 1/250,000 live births. It is the consequence of a division event at the primitive streak stage of the human embryonic development, about 13-14 days after fertilisation, in monochorionic monoamniotic gestations. A healthy pregnant woman, Gravida 2 Para 1, was admitted into our Fetal Medicine Unit to perform the first trimester ultrasound. A diagnosis of conjoined parapagus twinning based on ultrasound features was made at 11 weeks of gestation, and the couple decided to terminate the pregnancy. The ultrasound showed two independent skulls and hearts, a shared spine below the thoracic level, and a shared stomach. The pathological findings were slightly different, showing two independent stomachs draining into a common duodenum. The karyotype was 46 XY. Early prenatal ultrasound may provide a window to counsel the family and to offer an early termination of pregnancy." Leftward Flow Determines Laterality in Conjoined Twins "Conjoined twins fused at the thorax display an enigmatic left-right defect: although left twins are normal, laterality is disturbed in one-half of right twins. Molecularly, this randomization corresponds to a lack of asymmetric Nodal cascade induction in right twins. We studied leftward flow at the left-right organizer (LRO) in thoracopagus twins in Xenopus, which displayed a duplicated, fused, and ciliated LRO. Cilia were motile and produced a leftward flow from the right LRO margin of the right to the left margin of the left twin. Motility was required for correct laterality in left twins, as knockdown of dynein motor dnah9 prevented Nodal cascade induction. Nodal was rescued by parallel knockdown of the inhibitor dand5 on the left side of the left twin. Lack of Nodal induction in the right twin, despite the presence of flow, was due to insufficient suppression of dand5. Knockdown of dand5 at the center of the fused LRO resulted in asymmetric Nodal cascade induction in the right twin as well. Manipulation of leftward flow and dand5 in a targeted and sided manner induced the Nodal cascade in a predictable manner, in the left twin, the right one, both, or neither. Laterality in conjoined twins thus was determined by cilia-driven leftward fluid flow like in single embryos, which solves a century-old riddle, as the phenomenon was already studied by some of the founders of experimental embryology." Nodal | frog

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: Twinning | Monozygotic Twinning

Twin-twin Transfusion Syndrome

Older papers

These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table. See also the Discussion Page for other references listed by year and References on this current page. Outcomes in twin pregnancies reduced to singleton pregnancies compared to ongoing twin pregnancies "Multifetal pregnancy reduction has been shown to improve outcomes in triplet and higher order multiple pregnancies. The data for fetal reduction of twin pregnancies is limited. The purpose of this study was to compare adverse pregnancy outcomes in ongoing twin pregnancies compared to twin pregnancies reduced to singletons. Fetal reduction of twin pregnancies decreases the risk of late preterm birth and birth weight less than the 10% but not the risks of more severe complications such as early preterm birth or birth weight less than the 5%." Trends and correlates of monozygotic twinning after assisted reproductive technology "Monozygotic twinning, associated with increased infant morbidity and mortality, is more common after assisted reproductive technology (ART) than in the general population. Although multiple factors have been proposed as contributors, studies seeking to define causality have been underpowered or inconclusive. We analyzed 392,136 pregnancies resulting from fresh, nondonor embryo transfers conducted between 2000 and 2011 and reported to the National ART Surveillance System. ...Monozygotic twin pregnancy incidence after ART has increased over the past decade. Day-5 transfer and assisted hatching are associated with increased monozygotic twinning risk." Assisted Reproductive Technology Birth weight in a large series of triplets "There was no effect of assisted reproductive techniques on triplet birth weight. At gestational age 24 to 40 weeks triplets gained on average 130 grams per week; boys weighed 110 grams more than girls and triplets of smoking mothers weighted 104 grams less than children of non-smoking mothers. Monozygotic triplets had lower birth weights than di- and tri-zygotic triplets and birth weight discordance was smaller in monozygotic triplets than in dizygotic and trizygotic triplets. The correlation in birth weight among monozygotic and dizygotic triplets was 0.42 and 0.32, respectively. In nearly two-thirds of families, the heaviest and the lightest triplet had a birth weight discordance over 15%." The impact of fetal gender on prematurity in dichorionic twin gestations after in vitro fertilization. "Fetal gender mix serves as risk factor for more significant prematurity in dichorionic-diamniotic twins after assisted reproduction with opposite sex twins at higher risk than same sex-twins." Increased prevalence of cardiovascular defects among 56,709 California twin pairs. "An increased prevalence was observed in twins compared to singletons in all 16 cardiovascular categories. Seven of the cardiovascular categories had at least double the prevalence in twins compared to singletons. Like-sex twins, as a proxy of monozygosity, had an increased prevalence of cardiovascular defects compared to unlike sex twins. Probabilities of concordance for flow lesions were higher among monozygotic than dizygotic twins." Maternal immunologic rejection: lessons from discordant dizygotic twin placentas. "We describe a series of dizygotic twin placentas where the more severe the chronic villitis, the more affected the placenta and fetus. Since the maternal environment was constant for each of these twins, differences in villitis severity appears to be attributable to differences in the ability of each placenta to induce a maternal immune response."

Dizygotic Twinning

Dizygotic twins (DZ, fraternal, non-identical) arise from separate fertilization events involving two separate oocyte (egg, ova) and spermatozoa (sperm). These twins may also implant at different sites within the uterus. Maternal factors such as genetic history, advanced age, increased parity, elevated FSH concentrations, maternal height (taller) and maternal body mass index (30>) increase the risk of dizygotic twins. There are also theories that suggest that non-in vitro fertilization dizygotic twins may have more in common with monozygotic mechanisms and not be due to purely twin ovulatory events.

Monoygotic Twinning

Monoygotic twins (MZ, identical) produced from a single fertilization event (one fertilised egg and a single spermatozoa, form a single zygote), these twins therefore share the same genetic makeup. Occurs in approximately 3-5 per 1000 pregnancies, more commonly with aged mothers. The later the twinning event, the less common are initially separate placental membranes and finally resulting in conjoined twins.

Week		Week 1 (GA week 3)							Week 2 (GA week 4)
Day	0	1	2	3	4	5	6	7	8	9	10	11	12	13	14
Cell Number	1	1	2	16	32	128				bilaminar
Event	Ovulation	Fertilization	First cell division	Morula	Early blastocyst	Late blastocyst Hatching	Implantation starts			X inactivation
Monoygotic Twin Type		Diamniotic Dichorionic			Diamniotic Monochorionic			Monoamniotic Monochorionic			Conjoined

Table based upon recent a recent twinning review.   Links: twinning

Sesquizygotic Twinning

Sesquizygotic twinning is a rare intermediate form of twinning, between mono-zygotic and dizygotic twinning, the twins can be maternally identical but chimerical for their paternal genome. Such a rare twinning event has been recently identified and published.

Conjoined Twinning

• Diprosopus - two faces are located on the same side of a single head. A form of parapagus (less than 1% of conjoined twins).
• Parapagus - side-by-side connection with a shared pelvis and variable cephalic sharing (28 % of conjoined twins).
• Ischiopagus - conjoined pelvis (6 –11 % of conjoined twins).
• Heteropagus - asymmetrical form of twinning when one of the twins monopolizes the placental blood at the expense of other fetus.

Both ischiopagus and pygopagus conjoined twins have a range of variable spinal abnormalities.

Conjoined twins ultrasound	Conjoined twins MRI	Conjoined twins after birth

Triplets

Triplet and higher birth rates for mothers 25 years of age and older: United States, 1980, 1990, 1998, and 2006.

Triplet birth incidence is rare (1 / 10,000 births) though this number increased (6 / 10,000 births) during the early stages of assisted reproductive technologies (ART) and has since dropped again with single embryo transfer (SET) policies. Triplets are often born premature and with a low birth weight. A recent large study in the Netherlands has characterised birth weight, zygosity and environmental effects

"There was no effect of assisted reproductive techniques on triplet birth weight. At gestational age 24 to 40 weeks triplets gained on average 130 grams per week; boys weighed 110 grams more than girls and triplets of smoking mothers weighted 104 grams less than children of non-smoking mothers. Monozygotic triplets had lower birth weights than di- and trizygotic triplets and birth weight discordance was smaller in monozygotic triplets than in dizygotic and trizygotic triplets. The correlation in birth weight among monozygotic and dizygotic triplets was 0.42 and 0.32, respectively. In nearly two-thirds of families, the heaviest and the lightest triplet had a birth weight discordance over 15%."

Twinning Prevalence

Twinning in Low and Middle Income Countries Map

USA Data 2012

A recent study of twinning in developed countries

• Twins constitute 2% - 4% of all births
• Rate of twining has increased by 76% between 1980 and 2009.
• Rate of preterm birth (<37 weeks) among twins is about 60%.
• Of all twin preterm births in the United States
  • roughly half are indicated
  • a third are due to spontaneous onset of labor
  • about 10% are due to preterm premature rupture of membranes.
• recent decline in neonatal morbidity (one or more of 5-minute Apgar score <4, neonatal seizures or assisted ventilation for ≥ 30 minutes) among twin gestations.
• ART twins are more likely to deliver at <37 weeks.

World Data 2003

The prevalence of spontaneous livebirth monozygotic twinning is relatively constant, with variability in dizygotic twinning around the world.

• Asia 6 in 1000
• Europe/USA 10-20 in 1000
• African-Americans 26 in 1000
• Africa 40 in 1000
• Japan 1 in 250
• Nigeria 1 in 11

Monozygotic conjoined twins - 1 in 100,000 births (more female)

United States of America - 2.7% of all confinements resulted in a multiple birth in 1996 (U.S. Census Bureau, 1999, p.80)

New Zealand - 1.6% in 1998 (Statistics New Zealand, 2000, p.70)

Australia - 1.5% in 1998 (ABS, see below)

Australian Data 2002

Data from the Year Book Australia (2002) looking at pregnancies (confinements) shows the number resulting in a singleton live birth has been declining while the number resulting in multiple births has been increasing. This has been attributed to increased number of births to older women and the increasing use of assisted conception technologies.

"While the number of confinements resulting in multiple births remains relatively low, there has been a steady increase since the 1970s."

Multiple Births

• 1980 - 1.0% (2,249 of 223,318; 2,219 twins, 30 triplets or higher)
• 1990 - 1.2% (3,168 of 259,435; 3,074 twins, 94 triplets or higher)
• 2000 - 1.6% (3,900 of 245,700; 3,800 twins, 100 triplets or higher)

"Among older women this trend is more pronounced. In 1980, there were 730 confinements resulting in multiple births to women aged 30 years and over, constituting 1% of all confinements among women over 30. By 2000, this number had increased to 2,300 (2%)."

Placenta

Monochorionic Twin Placenta Legend arteries - blue and green veins - red and yellow white star - large arterio-arterial anastomosis blue stars - several arterio-venous anastomoses green stars - veno-arterial anastomoses	Monochorionic Triamniotic Triplet Placenta A single placenta with marginal cord insertion.

Links: Placenta Development

Placental Membranes
Dichorionic diamniotic GA 13 week = 11 week	Monochorionic diamniotic GA 12 week = 10 week
Thick dividing membrane and "lambda" or twin peak sign at the junction with the placenta.	Thin dividing membrane and "T" sign at the junction with the placenta.

Links: placental membranes | ultrasound

Twin-twin Transfusion Syndrome

The abnormality of twin–twin transfusion syndrome (TTTS) can occur in both monochorionic and diamniotic twins that results from an unbalanced blood flow from one to the other in utero. Monozygotic twin pregnancies carry a 10-20% risk of twin-twin transfusion syndrome. Diagnosis of TTTS is generally by ultrasound: single placenta, same fetal sex, a “T-sign” and the amniotic fluid volume on either side of the dividing fetal membranes.

• Twin-to-twin transfusion syndrome, vein of galen malformation, and transposition of the great arteries in a pair of monochorionic twins: coincidence or related association? "The development of TTTS, VGM, and TGA in a single monochorionic pregnancy could be pure coincidence, but there might also be a causative link. We discuss the possible contribution of genetic factors, fetal flow fluctuations, vascular endothelial growth factors, and the process of twinning itself to the development of these congenital anomalies."

Fetoscopic Laser Therapy

Fetoscopic Laser Therapy also called fetoscopic selective laser photocoagulation (SLPC) has been used as a treatment for advanced stages of twin-to-twin transfusion syndrome.

Fetoscopic laser photocoagulation
Fetoscopic laser photocoagulation	Anastomoses ablation sites

Quintero Staging System

Quintero and others in 1999 established a sonographic and clinical parameter staging system (Quintero staging system) for TTTS.

• Stage I - The fetal bladder of the donor twin remains visible sonographically.
• Stage II = The bladder of the donor twin is collapsed and not visible by ultrasound.
• Stage III - Critically abnormal fetal Doppler studies noted. This may include absent or reversed end-diastolic velocity in the umbilical artery, absent or reverse flow in the ductus venosus, or pulsatile flow in the umbilical vein.
• Stage IV - Fetal hydrops present.
• Stage V - Demise of either twin.

This Quintero staging system efficacy has been recently suggested as not providing accurate information about prognosis. An alternative Children's Hospital of Philadelphia (CHOP) cardiovascular score, appears to also be "not of clinical use as a prognostic marker in TTTS".

Acardiac Twins

Historically called chorioangiopagus parasiticus. Acardia, also called twin reversed-arterial perfusion (TRAP) sequence, is an extreme form of twin-twin transfusion syndrome. In a twinned human fetal development where monozygotic twinning or higher multiple births have an artery-to-artery and a vein-to-vein anastomosis in the monochorial placenta.

The incidence of this condition is 1% of monochorionic twin pregnancies (approx. 1 of 35,000 pregnancies).

Premature Ovarian Failure

Both forms of twinning have been shown to be at higher risk of Premature Ovarian Failure (POF). The same study also showed that the menopausal ages were more concordant than for dizogotic twin-pairs, confirming that the timing of menopause has a heritable component.

Trisomy 21

A recent 2014 study of European data for the period 1990-2009 (14.8 million births 2.89% multiple births) showed the risk of trisomy 21 (Down Syndrome) per fetus/baby is lower in multiple than singleton pregnancies. The authors suggest that these estimates can be used for genetic counselling and prenatal screening.

Links: Trisomy 21

Additional Images

• 

  Historic drawing - Twinning in fish embryo

References

Books and Journals

Twin Research and Human Genetics "A quality peer-reviewed journal of the International Society for Twin Studies (ISTS). Founded in Rome in 1974, ISTS is an international, nonpolitical, nonprofit, multidisciplinary scientific organisation. Its purpose is to further research and public education in all fields related to twins and twin studies, for the mutual benefit of twins and their families and of scientific research in general."

Multiple Pregnancy: The Management of Twin and Triplet Pregnancies in the Antenatal Period. National Collaborating Centre for Women's and Children's Health (UK). London: RCOG Press; 2011 Sep. (NICE Clinical Guidelines, No. 129.) Bookshelf PMID 22855972

Reviews

Machin G. (2009). Non-identical monozygotic twins, intermediate twin types, zygosity testing, and the non-random nature of monozygotic twinning: a review. Am J Med Genet C Semin Med Genet , 151C, 110-27. PMID: 19363805 DOI.

Aston KI, Peterson CM & Carrell DT. (2008). Monozygotic twinning associated with assisted reproductive technologies: a review. Reproduction , 136, 377-86. PMID: 18577552 DOI.

Muggli EE & Halliday JL. (2007). Folic acid and risk of twinning: a systematic review of the recent literature, July 1994 to July 2006. Med. J. Aust. , 186, 243-8. PMID: 17391087

Prapas N, Kalogiannidis I, Prapas I, Xiromeritis P, Karagiannidis A & Makedos G. (2006). Twin gestation in older women: antepartum, intrapartum complications, and perinatal outcomes. Arch. Gynecol. Obstet. , 273, 293-7. PMID: 16283408 DOI.

Smith GC, Shah I, White IR, Pell JP & Dobbie R. (2005). Mode of delivery and the risk of delivery-related perinatal death among twins at term: a retrospective cohort study of 8073 births. BJOG , 112, 1139-44. PMID: 16045531 DOI.

Articles

Liao AW, Brizot Mde L, Kang HJ, Assunção RA & Zugaib M. (2012). Longitudinal reference ranges for fetal ultrasound biometry in twin pregnancies. Clinics (Sao Paulo) , 67, 451-5. PMID: 22666788 DOI.

Vela G, Luna M, Barritt J, Sandler B & Copperman AB. (2011). Monozygotic pregnancies conceived by in vitro fertilization: understanding their prognosis. Fertil. Steril. , 95, 606-10. PMID: 20522324 DOI.

Palmer JS, Zhao ZZ, Hoekstra C, Hayward NK, Webb PM, Whiteman DC, Martin NG, Boomsma DI, Duffy DL & Montgomery GW. (2006). Novel variants in growth differentiation factor 9 in mothers of dizygotic twins. J. Clin. Endocrinol. Metab. , 91, 4713-6. PMID: 16954162 DOI.

Search Pubmed

Search Pubmed: Twinning | Monozygotic Twinning | Diygotic Twinning | Twin-twin Transfusion Syndrome

Pubmed Books

• National Collaborating Centre for Women's and Children's Health (UK). Multiple Pregnancy: The Management of Twin and Triplet Pregnancies in the Antenatal Period. London: RCOG Press; 2011 Sep. (NICE Clinical Guidelines, No. 129.) Available from: http://www.ncbi.nlm.nih.gov/books/NBK83105/ "This guideline contains recommendations specific to twin and triplet pregnancies and covers the following clinical areas: optimal methods to determine gestational age and chorionicity; maternal and fetal screening programmes to identify structural abnormalities, chromosomal abnormalities and feto-fetal transfusion syndrome (FFTS), and to detect intrauterine growth restriction (IUGR); the effectiveness of interventions to prevent spontaneous preterm birth; and routine (elective) antenatal corticosteroid prophylaxis for reducing perinatal morbidity. The guideline also advises how to give accurate, relevant and useful information to women with twin and triplet pregnancies and their families, and how best to support them."

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

• International Society for Twin Studies
• Australian Twin Registry
• The Danish Twin Registry "The Danish Twin Registry (DTR) is one of the oldest twin registries in the world. It was established in the 1950's with the aim of studying causes of cancer and it comprises now twins born through more than 130 years."
• Berlin Twin Register
• Norwegian Twin Registry PMID 22947319
• United Kingdom - Department of Twin Research & Genetic Epidemiology "The Department of Twin Research and Genetic Epidemiology (DTR) encompasses the biggest UK adult twin registry of 12,000 twins used to study the genetic and environmental aetiology of age related complex traits and diseases."
• USA - National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry "It consists of 15,924 white male twin pairs born in the years 1917 to 1927 (inclusive), both of whom served in the armed forces, mostly during World War II."

Glossary Links

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Cite this page: Hill, M.A. (2023, December 1) Embryology Abnormal Development - Twinning. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Twinning

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© Dr Mark Hill 2023, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G