Difference between revisions of "Abnormal Development - Twinning"

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{| class="wikitable mw-collapsible mw-collapsed"
{{Historic Twinning links}}
! [[Embryology_History|'''Historic Embryology''']] - Twinning 
| [[Paper - Description of two young twin embryos with 17-19 paired somites|1915 Twin embryos 17-19 somites]] | [[Paper - Direct proof of the monozygotic origin of human identical twins|1922 Monozygotic origin identical twins]] | [[Paper - Human monochorial twin embryos In separate amnions|1927 Separate amnions]] | [[Paper - Early human twins with peculiar relations to each other and the chorion|1942 Twin chorion]] | [[Paper - The observed embryology of human single-ovum twins and other multiple births|1955 Twins and multiple birth]]
| Carnegie Embryos: {{CE7170a}} {{CE7545}} 9009a and b 9123 8505a 8505b 5542B 5935A 5621A
[[File:Monozygotic twin embryos.jpg|thumb|Monozygotic twin embryos]]  
[[File:Monozygotic twin embryos.jpg|thumb|Monozygotic twin embryos]]  
==Some Recent Findings==
==Some Recent Findings==

Revision as of 16:28, 27 November 2017

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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.[1] 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.[2][3]

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,[4] and there are more maternal risks involved with multiple pregnancies. As a positive, twins do appear to have a lower incidence of trisomy 21.[5]

Abnormality Links: abnormal development | abnormal genetic | abnormal environmental | Unknown | teratogens | ectopic pregnancy | cardiovascular abnormalities | coelom abnormalities | endocrine abnormalities | gastrointestinal abnormalities | genital abnormalities | head abnormalities | integumentary abnormalities | musculoskeletal abnormalities | limb abnormalities | neural abnormalities | neural crest abnormalities | placenta abnormalities | renal abnormalities | respiratory abnormalities | hearing abnormalities | vision abnormalities | twinning | Developmental Origins of Health and Disease |  ICD-11
Historic Embryology  
1915 Congenital Cardiac Disease | 1917 Frequency of Anomalies in Human Embryos | 1920 Hydatiform Degeneration Tubal Pregnancy | 1921 Anencephalic Embryo | 1921 Rat and Man | 1966 Congenital Malformations

Week 2

Historic Embryology - Twinning 
1915 Twin embryos 17-19 somites | 1916 Conjoined Twins | 1922 Monozygotic origin identical twins | 1927 Separate amnions | 1942 Twin chorion | 1955 Twins and multiple birth
Carnegie Embryos: 8505a 8505b 7170a 7545 9009a and b 9123 5542B 5935A 5621A
Monozygotic twin embryos

Some Recent Findings

  • Leftward Flow Determines Laterality in Conjoined Twins[6] "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 Development
  • Outcomes in twin pregnancies reduced to singleton pregnancies compared to ongoing twin pregnancies[7] "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[3] "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[8] "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%."
  • The impact of fetal gender on prematurity in dichorionic twin gestations after in vitro fertilization.[9] "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.[10] "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.[11] "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."
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<pubmed limit=5>Twinning</pubmed>

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.[12] 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.[13]

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


Implantation starts X inactivation
Follicle 001 icon.jpg Early zygote.jpg Human embryo day 2.jpg Human embryo day 3.jpg Human embryo day 5.jpg CSt3.jpg Week2 001 icon.jpg Macaque Xi at interphase 02.jpg

Twin Type








Table based upon recent a recent twinning review.[14]   Links: twinning

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.[15]

Both ischiopagus and pygopagus conjoined twins have a range of variable spinal abnormalities.[16]

Conjoined twins 02.jpg Conjoined twins 03.jpg Conjoined twins 01.jpg
Conjoined twins ultrasound[17] Conjoined twins MRI[17] Conjoined twins after birth[18]


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 [8]

"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[1]

USA Data 2012

A recent study of twinning in developed countries[19]

  • 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.[14]

  • 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%)." [20]


Monochorionic twin placenta Monochorionic Triamniotic Triplet Pregnancy
Monochorionic Twin Placenta[21]


  • 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[22]

A single placenta with marginal cord insertion.

Links: Placenta Development

Placental Membranes
Ultrasound twinning 01.jpg Ultrasound twinning 02.jpg
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: Placenta Membranes | Ultrasound

Twin-twin Transfusion Syndrome

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? [23] "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.[24][25]

Quintero Staging System

Quintero and others in 1999 established a sonographic and clinical parameter staging system for TTTS.[26]

  • 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.[27][28] An alternative Children's Hospital of Philadelphia (CHOP) cardiovascular score, appears to also be "not of clinical use as a prognostic marker in TTTS".[29]

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.[30]

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).[31] 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 [5] 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


  1. 1.0 1.1 21980404</pubmed>| PLoS One.
  2. <pubmed>24373946</pubmed>
  3. 3.0 3.1 <pubmed>24770255</pubmed>
  4. <pubmed>22752835 </pubmed>
  5. 5.0 5.1 <pubmed>24495335</pubmed>
  6. <pubmed>28190730</pubmed>
  7. <pubmed>26071922</pubmed>
  8. 8.0 8.1 <pubmed>21453554</pubmed>| BMC Pediatr.
  9. <pubmed>20534177</pubmed>| Reprod Biol Endocrinol.
  10. <pubmed>19353581</pubmed>
  11. <pubmed>18598117</pubmed>
  12. <pubmed>18024802</pubmed>
  13. <pubmed>19252194</pubmed>
  14. 14.0 14.1 Hall JG. (2003). Twinning. Lancet , 362, 735-43. PMID: 12957099 DOI. Cite error: Invalid <ref> tag; name "PMID12957099" defined multiple times with different content
  15. <pubmed>21129567</pubmed>
  16. <pubmed>15278384</pubmed>
  17. 17.0 17.1 <pubmed>22567498</pubmed>| PMC3335527 | Case Rep Obstet Gynecol.
  18. <pubmed>22953266</pubmed>
  19. <pubmed>22713495 </pubmed>
  20. Australian Bureau of Statistics Year Book Australia 2002
  21. <pubmed>23050183</pubmed>| PMC3462376 | Case Rep Pediatr.
  22. <pubmed>15819977</pubmed>| PMC1082912 | Reprod Health.
  23. <pubmed>16808639</pubmed>
  24. <pubmed>23395141</pubmed>
  25. <pubmed>22378622</pubmed>
  26. <pubmed>10645517</pubmed>
  27. <pubmed>18044824</pubmed>
  28. <pubmed>19283655</pubmed>
  29. <pubmed>20582931</pubmed>
  30. <pubmed>10072652</pubmed>
  31. <pubmed>17065173</pubmed>| Hum Reprod.

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


<pubmed>19363805</pubmed> <pubmed>18577552</pubmed> <pubmed>17391087</pubmed> <pubmed>16283408</pubmed> <pubmed>16045531</pubmed>


<pubmed>20522324</pubmed> <pubmed>16954162</pubmed>

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."

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Cite this page: Hill, M.A. (2021, April 16) Embryology Abnormal Development - Twinning. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Twinning

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