Talk:Abnormal Development - Twinning

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Cite this page: Hill, M.A. (2021, April 11) Embryology Abnormal Development - Twinning. Retrieved from


Wen SW, Miao Q, Taljaard M, Lougheed J, Gaudet L, Davies M, Lanes A, Leader A, Corsi DJ, Sprague AE & Walker M. (2020). Associations of Assisted Reproductive Technology and Twin Pregnancy With Risk of Congenital Heart Defects. JAMA Pediatr , , . PMID: 32091547 DOI.

Associations of Assisted Reproductive Technology and Twin Pregnancy With Risk of Congenital Heart Defects

Abstract IMPORTANCE: The extent to which assisted reproductive technology is associated with increased risk of congenital heart defects independent of its known association with twinning remains uncertain. OBJECTIVE: To assess the extent to which assisted pregnancy is associated with increased risk of congenital heart defects independent of its known association with twinning. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study linked records of congenital heart defect diagnoses with assisted reproductive technology cycles in 507 390 singleton or twin pregnancies (10 149 assisted pregnancies and 497 241 nonassisted pregnancies), including singleton and twin early pregnancy losses, stillbirths, and live births (follow-up to 1 year of age) in Ontario, Canada, between April 1, 2012, and October 31, 2015. Statistical analysis was performed from January 1, 2017, to September 9, 2019. EXPOSURES: Assisted reproductive technology and its 2 subtypes: intracytoplasmic sperm injection and in vitro fertilization without intracytoplasmic sperm injection. MAIN OUTCOMES AND MEASURES: The main outcome was congenital heart defects (prevalence and relative risk measured as odds ratios [ORs]). Mediation analysis was performed to assess the extent to which the association between assisted reproductive technology and congenital heart defects was mediated by twinning. RESULTS: Of 507 390 mother-infant pairs with singleton or twin pregnancies evaluated, the prevalence of congenital heart defects in assisted pregnancies (223 [2.2%]) was higher than that in nonassisted pregnancies (6057 [1.2%]; crude OR, 1.82; 95% CI, 1.59-2.09). The strength of the association between assisted pregnancy and congenital heart defects decreased after adjusting for several risk factors simultaneously (adjusted OR, 1.70; 95% CI, 1.48-1.95). Further mediation analysis indicated that most of the association between assisted pregnancy and congenital heart defects was mediated by twinning (adjusted OR, 1.68; 95% CI, 1.44-1.92), and the natural direct association of assisted pregnancy with congenital heart defects among singleton pregnancies was 1.09 (95% CI, 0.93-1.25). Mediation of twinning accounted for 87.3% of the association. CONCLUSIONS AND RELEVANCE: Our study results suggest that the association between assisted reproductive technology and congenital heart defects may be mediated by twinning. PMID: 32091547 DOI: 10.1001/jamapediatrics.2019.6096


Casati D, Pellegrino M, Cortinovis I, Spada E, Lanna M, Faiola S, Cetin I & Rustico MA. (2019). Longitudinal Doppler references for monochorionic twins and comparison with singletons. PLoS ONE , 14, e0226090. PMID: 31809530 DOI.

Longitudinal Doppler references for monochorionic twins and comparison with singletons.

Abstract OBJECTIVES: To construct monochorionic (MC) twin-specific longitudinal Doppler 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. METHODS: A retrospective evaluation was made of all consecutive uncomplicated MC twin pregnancies referred to our Unit from 2010 to 2018. Fortnightly serial examinations were performed of UA-PI, MCA-PI, MCA-PSV and DV-PI, according with the clinical protocol, from 20 to 37 weeks of gestation. We included cases with at least four ultrasound examinations, delivery at our hospital and complete neonatal follow up. A two-step method was used to trace the estimated centile curves: estimation of the median was performed with appropriate fractional polynomials by a multilevel model and estimation of the external centiles through the residuals (quantile regression). The comparison with singletons was made by plotting the references derived from the present study on the referred charts commonly used for singletons. RESULTS: 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. CONCLUSIONS: This study sets out MC twin-specific longitudinal references for UA-PI, MCA-PI, MCA-PSV and DV-PI derived from the largest series of uncomplicated MC twin pregnancies presently available. The comparison with singleton reference values underscores the deviation from physiology that is intrinsic to these unique pregnancies and supports the need for MC twin-specific charts. PMID: 31809530 PMCID: PMC6897428 DOI: 10.1371/journal.pone.0226090


Early prenatal diagnosis of parapagus conjoined twins

Clin Pract. 2018 Mar 28;8(2):1039. doi: 10.4081/cp.2018.1039. eCollection 2018 Mar 28.

Melo Â1, Dinis R1, Portugal A1, Sousa AI1, Cerveira I1.


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. KEYWORDS: Monozygotic twinning; termination of pregnancy; ultrasound PMID: 29657701 PMCID: PMC5890089 DOI: 10.4081/cp.2018.1039


Leftward Flow Determines Laterality in Conjoined Twins

Curr Biol. 2017 Feb 20;27(4):543-548. doi: 10.1016/j.cub.2016.12.049. Epub 2017 Feb 9.

Tisler M1, Thumberger T1, Schneider I1, Schweickert A1, Blum M2.


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 [1-3]. Molecularly, this randomization corresponds to a lack of asymmetric Nodal cascade induction in right twins [4]. We studied leftward flow [5, 6] at the left-right organizer (LRO) [7, 8] 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 [9, 10] 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, including Dareste [11], Fol and Warynsky [12], and Spemann and Falkenberg [13] (reviewed in [14]). Copyright © 2017 Elsevier Ltd. All rights reserved. KEYWORDS: Xenopus; cilia; conjoined twin; dand5; laterality; left-right asymmetry; left-right organizer; leftward flow; nodal flow; pitx2 PMID 28190730


Outcomes in twin pregnancies reduced to singleton pregnancies compared to ongoing twin pregnancies

Am J Obstet Gynecol. 2015 Jun 10. pii: S0002-9378(15)00601-8. doi: 10.1016/j.ajog.2015.06.018. [Epub ahead of print]

Gupta S1, Fox NS2, Feinberg J3, Klauser CK2, Rebarber A2.


OBJECTIVE: 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. STUDY DESIGN: This is a retrospective cohort study comparing dichorionic diamniotic twin pregnancies with dichorionic diamniotic twin pregnancies reduced to singleton gestations between 11-24 weeks gestation in a single Maternal Fetal Medicine practice over a 9 year period. Adverse pregnancy outcomes >24 weeks were compared with p<0.05 used for significance. RESULTS: 501 ongoing twin pregnancies and 63 twin pregnancies reduced to singletons were included. Patients with reductions to singletons had a significantly lower risk of preterm delivery before 37 weeks gestation (10% vs. 43%, p<0.001) but no difference in the risk of preterm delivery before 34 weeks or 28 weeks gestation. Patients with reductions to singletons also had a lower risk of infant birth weight less than the 10% (23% vs. 49%, p<0.001), but no difference in the risk of infant birth weigh less than the 5%. There was no difference in the risk of fetal demise after 24 weeks gestation. CONCLUSION: 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%. Copyright © 2015 Elsevier Inc. All rights reserved. KEYWORDS: multifetal pregnancy reduction; selective reduction; twin pregnancy

PMID 26071922

Epidemiology of twinning in the National Birth Defects Prevention Study, 1997 to 2007

Birth Defects Res A Clin Mol Teratol. 2015 Feb;103(2):85-99. doi: 10.1002/bdra.23325. Epub 2014 Oct 31.

Dawson AL1, Tinker SC, Jamieson DJ, Hobbs CA, Rasmussen SA, Reefhuis J; National Birth Defects Prevention Study.


BACKGROUND: Our objective was to evaluate associations between twinning and maternal demographic factors and periconceptional exposures among infants with and without orofacial clefts. METHODS: We used data from the National Birth Defects Prevention Study; 228 twins and 8242 singletons without birth defects (controls), and 117 twins and 2859 singletons with orofacial clefts, born 1997 to 2007, were included in the analyses. Because of the occurrence of twinning due to the use of assisted reproductive technologies, logistic regression models were computed to estimate odds ratios and 95% confidence intervals for each exposure, stratified by fertility treatment use. To evaluate factors by zygosity, we used sex-pairing data and a simulation approach to estimate the zygosity of like-sex twin pairs for unassisted conceptions. RESULTS: Among control mothers who did not use fertility treatments, predictors of twinning included non-Hispanic black maternal race (adjusted odds ratio, 1.6; 95% confidence interval, 1.0-2.4), and tobacco smoking (adjusted odds ratio, 1.6; 95% confidence interval, 1.1-2.4). Among control mothers who used fertility treatments, older maternal age, higher income, and state of residence were associated with twinning. Associations were generally stronger among mothers of dizygotic (estimated) twins than monozygotic (estimated) twins. Results for mothers of infants with isolated orofacial clefts were similar to those of controls. CONCLUSION: We observed an increased twinning frequency with increasing maternal age, but factors such as maternal race/ethnicity and socioeconomic status may also contribute. Among women receiving fertility treatments, factors associated with twinning suggested a relation with treatment specifics (e.g., treatment type and number of embryos implanted) and availability of insurance coverage. Birth Defects Research (Part A) 103:85-99, 2015 © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc. KEYWORDS: ART; IVF; clomiphene citrate; orofacial clefts; twinning

PMID 25359509

Prenatal diagnosis and management of mono amniotic twins

Curr Opin Obstet Gynecol. 2015 Apr;27(2):159-64. doi: 10.1097/GCO.0000000000000160.

Ishii K1.


PURPOSE OF REVIEW: The purpose of this article is to investigate the perinatal outcomes of monoamniotic twins under current standards of prenatal management involving intensive fetal surveillance. RECENT FINDINGS: The incidence of perinatal mortality in monoamniotic twins has fallen over the last 2 decades. Umbilical cord entanglement has long been considered one of the main causes of poor outcome among monoamniotic twins; however, new evidence shows that it appears to be less important than prematurity and congenital anomalies. If intensive fetal surveillance is provided, the risk of perinatal mortality is acceptably low regardless of setting. In uncomplicated monoamniotic twin pregnancies, delivery at around 33 weeks of gestation might reduce the risk of neonatal adverse events without increasing the risk of perinatal death. SUMMARY: Perinatal outcome in monoamniotic twins improved if intensive fetal surveillance was performed under either outpatient or inpatient management. Planned delivery in uncomplicated monoamniotic twin pregnancies can be considered at around 33 weeks of gestation.

PMID 25689237

Twin Res Hum Genet. 2015 Mar 5:1-7. [Epub ahead of print]

=Insights From Twin Research: Conference at Royal Childrens Hospital, Melbourne, Australia / Twin Studies

Timing of Monozygotic Splitting and Commentary; Gestational Diabetes; ICOMBO'S Post-Partum Depression Study; Photographs of Conjoined Twins / Human Interest: Rare Quadruplets; Mistaken Identity on the Soccer Field; Prenatal Laser Surgery on Triplets; Twins Born to Prince and Princess of Monaco.

Segal NL1.


Highlights from a conference, 'Healthier Kids: Insights From Twin Research', held in Melbourne, Australia on December 5, 2014, are summarized. In addition to informative and exciting presentations and discussions of recent findings, three key themes emerged: (1) results from twin research have important implications for non-twins, (2) researchers from diverse disciplines should be encouraged to participate actively in twin research, and (3) investigators, twins and families need to work more collaboratively. Next, papers and studies concerning the biological bases of monozygotic (MZ) twinning, gestational diabetes and post-partum depression are reviewed. Finally, general interest reports of rare quadruplets, mistaken identity, prenatal laser surgery and a royal twin birth are provided. KEYWORDS: zygotic splitting

PMID 25740114


Prevalence and risk of Down syndrome in monozygotic and dizygotic multiple pregnancies in Europe: implications for prenatal screening

BJOG. 2014 Jun;121(7):809-19; discussion 820. doi: 10.1111/1471-0528.12574. Epub 2014 Feb 4.

Boyle B1, Morris JK, McConkey R, Garne E, Loane M, Addor MC, Gatt M, Haeusler M, Latos-Bielenska A, Lelong N, McDonnell R, Mullaney C, O'Mahony M, Dolk H.


OBJECTIVE: To determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome. DESIGN: Population-based prevalence study based on EUROCAT congenital anomaly registries. SETTING: Eight European countries. POPULATION: 14.8 million births 1990-2009; 2.89% multiple births. METHODS: DS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases. MAIN OUTCOME MEASURES: Relative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome. STATISTICAL ANALYSIS: Poisson and logistic regression stratified for maternal age, country and time. RESULTS: Overall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53-0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25-0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23-1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50-0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27-0.59]). CONCLUSIONS: The risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening. © 2014 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists. KEYWORDS: Concordance; Down syndrome; monozygotic and dizygotic pregnancies; multiple births; pregnancy outcomes; twins PMID 24495335 [PubMed - indexed for MEDLINE] PMCID: PMC4234000

Impact of monozygotic twinning on multiple births resulting from in vitro fertilization in the United States, 2006-2010

Am J Obstet Gynecol. 2014 May;210(5):468.e1-6. doi: 10.1016/j.ajog.2013.12.034. Epub 2013 Dec 25.

Gee RE1, Dickey RP2, Xiong X3, Clark LS4, Pridjian G5. Author information


OBJECTIVE: To determine the contribution of monozygotic twining to in vitro fertilization multiple births. STUDY DESIGN: We performed a retrospective analysis of the incidence of monozygotic twining in multiple births resulting from fresh embryo transfers using 2006-2010 data from the Society for Reproductive Technology Clinic Outcome Reporting System. RESULTS: The number of embryos transferred were fewer than the number of births in 0.5% (223/40950) of twin, 29% (659/2289) of triplet, and 64% (43/67) of quadruplet births resulting from transfer of fresh embryos from 2006 to 2010. In 2010, 37% of triplets and 100% of quadruplet births occurred when fewer than 3 and fewer than 4 embryos respectively were transferred. CONCLUSION: Monozygotic twinning plays a key role in the development of triplet and quadruplet pregnancies achieved through in vitro fertilization. Copyright © 2014 Mosby, Inc. All rights reserved. KEYWORDS: IVF, monozygotic twining, quadruplet birth, singleton birth, triplet birth, twin birth

PMID 24373946

Trends and correlates of monozygotic twinning after assisted reproductive technology

Obstet Gynecol. 2014 May;123 Suppl 1:6S. doi: 10.1097/01.AOG.0000447243.23572.6a.

Kanter JR1, Boulet S, Kawwass JF, Jamieson DJ, Kissin D.


INTRODUCTION: 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 evaluated trends of monozygotic twinning in ART and its association with patient and treatment factors. METHODS: We analyzed 392,136 pregnancies resulting from fresh, nondonor embryo transfers conducted between 2000 and 2011 and reported to the National ART Surveillance System. We examined trends of monozygotic twin pregnancies (defined as those in which number of fetal heart tones on first trimester ultrasound exceeded number of embryos transferred) using the Cochrane-Armitage test and subsequently compared monozygotic twins with (1) singleton pregnancies (one fetal heart) and (2) other multiple-gestation pregnancies (more than one fetal heart but not more than number of embryos transferred). Modified Poisson regression models were used to estimate adjusted risk ratios (aRRs) for monozygotic twinning association with assisted hatching for both comparison groups, stratified by day-3 and day-5 transfer. RESULTS: Incidence of monozygotic twinning after ART increased from 2000 to 2011 (P<.001 for trend), with greater incidence in day-5 (1.72%) than day-3 (0.48%) embryo transfers. Monozygotic twinning was associated with assisted hatching among day-3 embryo transfers when compared with both singleton (aRR 2.19, confidence interval [CI] 1.93-2.48) and other multiple-gestation (aRR 2.27, CI 2.00-2.57) pregnancies and among day-5 embryo transfers when compared with other multiple-gestation pregnancies (aRR 1.18, CI 1.05-1.32). CONCLUSIONS: 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.

PMID 24770255

The incidence of monozygotic twinning in assisted reproductive technology: Analysis based on results from the 2010 Japanese ART national registry

J Assist Reprod Genet. 2014 Apr 11. [Epub ahead of print]

Nakasuji T1, Saito H, Araki R, Nakaza A, Nakashima A, Kuwahara A, Ishihara O, Irahara M, Kubota T, Yoshimura Y, Sakumoto T.


PURPOSE: To assess the incidence of monozygotic twinning (MZT) among cases undergoing assisted reproductive technology (ART) treatment. METHODS: We performed a retrospective observational study and analyzed the data of patients who were registered in the national ART registry system of Japan from January to December 2010; only the data of patients with single embryo transfer (ET) were included. RESULTS: Of 30,405 pregnancies, 425 resulted in MZT following fresh and frozenthawed ET. The MZT incidence among women undergoing ART was 1.4 %. Multiple logistic regression analysis indicated that cases undergoing fresh and frozen-thawed ET, blastocyst transfer had a significantly increased MZT rate (P < 0.01). Assisted hatching (AH) and frozen-thawed ET and maternal age did not significantly affect the MZT incidence. Of 8510 fresh ET pregnancies, 104 resulted in MZT. Multiple logistic regression analysis indicated that blastocyst transfer significantly increased the MZT rate in cases undergoing fresh ET. Ovarian stimulation, intracytoplasmic sperm injection, AH, and maternal age did not significantly affect the MZT incidence. CONCLUSIONS: Blastocyst transfer was associated with an increased MZT incidence. We have to be aware of the potential risk of MZT caused by blastocyst transfer. However, further studies are required to assess the correlation among specific AH types, embryo culture conditions, and MZT incidence.

PMID 24722789


Twin Pregnancies with Single Fetal Death: Analysis of 38 Cases

Fetal Pediatr Pathol. 2013 Feb;31(1):71-5. doi: 10.3109/15513815.2012.671446. Epub 2012 Apr 16.

Deveer R, Engin-Ustun Y, Mert I, Sarikaya E, Bozkurt S, Deveer M, Danisman N, Mollamahmutoglu L. Source Zekai Tahir Burak Women Health Research and Education Hospital , Ankara , Turkey.


The objective of this study is to evaluate fetal and maternal outcomes of twin pregnancies with intrauterine single fetal death. In 13 cases, intrauterine death of one fetus was found during the first trimester; in 25 cases, it was found after the first trimester. Obstetric complications and fibrinogen levels were compared. There were no significant differences in the number of preterm delivery, preeclampsia, and intrauterine growth restriction and there were significant differences in gestational age at delivery and birth weight between groups. Coagulation disorders did not occur. The risk for adverse pregnancy outcomes with a single fetal death during and after the first trimester is similar.

PMID 22506931


Natural history of placenta previa in twins

Obstet Gynecol. 2012 Oct;120(4):753-8.

Weis MA, Harper LM, Roehl KA, Odibo AO, Cahill AG. Source Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, Missouri 63110, USA.


OBJECTIVE: To estimate the incidence of placenta previa in twin pregnancies compared with singletons and to estimate the rate and gestational age of previa resolution in twin pregnancies. METHOD: This was a retrospective cohort of singleton and twin pregnancies undergoing ultrasonography at 15-22 weeks of gestation and of twin pregnancies undergoing serial ultrasonography from 15 to 40 weeks of gestation. Groups were defined by singleton or twin gestation and by chorionicity of twin gestation. The primary outcomes were incidence of placenta previa in each group and the percentage of all previa resolving at 24-28, 28-32, 32-36, and 36 or more weeks of gestation. RESULTS: Of 67,895 pregnancies included, 2.1% (1,381 of 65,701) of singleton and 2.5% (56 of 2,194) of twin pregnancies had previa diagnosed (P=.15). Dichorionic twins had an increased risk of placenta previa compared with singletons (adjusted odds ratio 1.54, 95% confidence interval 1.15-2.06) or monochorionic twin pregnancies (relative risk 3.29, 95% confidence interval 1.32-8.21). Of the 1,738 twin pregnancies with serial ultrasound examinations, 51 (2.9%) were noted to have previa. Sixty-nine percent of the previa resolved by 32 weeks, at between 32 and 36 weeks an additional 47% of the remaining previa resolved, and no previa resolved after 36 weeks. CONCLUSION: Dichorionic twin pregnancies are at significantly increased risk for ultrasound-diagnosed previa when compared with singleton or monochorionic pregnancies. Among twin pregnancies with previa diagnosed in the second trimester, the majority of cases resolve by 32 weeks. LEVEL OF EVIDENCE: II.

PMID 22996091

Prospective risk of intrauterine fetal death in monoamniotic twin pregnancies

Twin Res Hum Genet. 2012 Aug;15(4):522-6. doi: 10.1017/thg.2012.30.

Morikawa M, Yamada T, Yamada T, Sato S, Minakami H. Source Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.


This study was conducted to review the overall short-term outcome of monoamniotic twins in Japan and to determine the prospective risk of fetal death so as to adequately counsel parents with monoamniotic twins. Study subjects were 101 women with monoamniotic twins who were registered with the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System and who had given birth at ≥22 weeks of gestation during 2002-2009. The gestational week at delivery (mean±SD) was 31.8±3.7. Fourteen women experienced intrauterine fetal death (IUFD). Short-term outcomes of co-twins born to the 14 women included 8 IUFDs, one early neonatal death within 7 days of life (END), and 5 survivors. Four other women experienced 5 ENDs. Thus, 13.9% (28/202) of infants died perinatally (22 IUFDs and 6 ENDs), 13.9% (14/101) of women experienced IUFD, and 82.2% (83/101) of women experienced neither IUFD nor END. Structural anomalies and twin-to-twin transfusion syndrome explained 17.9% (five infants) and 10.7% (three infants) of the 28 perinatal deaths, respectively. The prospective risk of IUFD was 13.9% (14/101) for women who reached gestational week 22(-0/7), gradually decreasing thereafter but remaining at between 4.5% and 8.0% between gestational week 30(-0/7) and 36(-0/7).

PMID 22853819

Epidemiology of twinning in developed countries

Semin Perinatol. 2012 Jun;36(3):156-61. doi: 10.1053/j.semperi.2012.02.001.

Ananth CV, Chauhan SP. Source Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.


Twin births contribute disproportionately to the overall burden of perinatal morbidity and mortality in developed countries. Twins constitute 2%-4% of all births, and the rate of twining has increased by 76% between 1980 and 2009. The 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, and about 10% are due to preterm premature rupture of membranes. Mortality related to preterm birth is influenced by antecedent factors and is highest when preterm delivery is the consequence of preterm premature rupture of membranes, followed by those as a result of spontaneous preterm labor and lowest among indicated preterm births. There also appears to have been a recent decline in serious neonatal morbidity (one or more of 5-minute Apgar score <4, neonatal seizures or assisted ventilation for ≥ 30 minutes) among twin gestations. Compared with twins conceived naturally, those born of assisted reproduction methods are more likely to deliver at <37 weeks. Although perinatal mortality rates have declined among twin births, the effect of preterm delivery on trends in mortality and morbidity and other long-term consequences remain issues for major concern. With the rapid increase in the liberal use of assisted reproduction methods combined with women electing to postpone their pregnancies and increased likelihood of spontaneous twins with advancing maternal age, this review underscores the need to develop priorities to understand the peripartum and long-term consequences facing twin births. Copyright © 2012 Elsevier Inc. All rights reserved.

PMID 22713495

Neurodevelopmental outcomes of twins

Semin Perinatol. 2012 Jun;36(3):201-12. doi: 10.1053/j.semperi.2012.02.005.

Lorenz JM. Source Division of Neonatology, Department of Pediatrics, Columbia University, New York, NY, USA.


In population-based studies, the prevalence of neurodevelopmental disability is consistently higher in twins than singletons. This is largely because birth weight and gestational age (GA) distributions of twin births are shifted to the left when compared with singleton births, and lower birth weight and lower GA are associated with increased risk of neurodevelopmental disability. From a pathophysiologic perspective, a question of interest is whether neurodevelopmental outcomes of twins differ from singletons after controlling for covariates. If significant differences in outcomes persist, this would suggest that the twining process itself or something intrinsic to shared life in the womb may be responsible for observed differences. From a clinical perspective, when counseling parents at risk for preterm delivery of twins, it is useful to understand how twin outcomes compare relative to singleton outcomes at the same birth weight or GA. The purpose of this review is to examine the long-term neurodevelopmental outcomes of twins compared with singletons with control for important covariates. Copyright © 2012 Elsevier Inc. All rights reserved.

PMID 22713502


Twinning across the Developing World

PLoS One. 2011;6(9):e25239. doi: 10.1371/journal.pone.0025239. Epub 2011 Sep 28.

Smits J1, Monden C.


BACKGROUND: Until now, little was known about the variation in incidence of twin births across developing countries, because national representative data was lacking. This study provides the first comprehensive overview of national twinning rates across the developing world on the basis of reliable survey data. METHODS: Data on incidence of twinning was extracted from birth histories of women aged 15-49 interviewed in 150 Demographic and Health Surveys, held between 1987 and 2010 in 75 low and middle income countries. During the interview, information on all live births experienced by the women was recorded, including whether it was a singleton or multiple birth. Information was available for 2.47 million births experienced by 1.38 million women in a period of ten years before the interview. Twinning incidence was measured as the number of twin births per thousand births. Data for China were computed on the basis of published figures from the 1990 census. Both natural and age-standardized twinning rates are presented. RESULTS/CONCLUSIONS: The very low natural twinning rates of 6-9 per thousand births previously observed in some East Asian countries turn out to be the dominant pattern in the whole South and South-East Asian region. Very high twinning rates of above 18 per thousand are not restricted to Nigeria (until now seen as the world's twinning champion) but found in most Central-African countries. Twinning rates in Latin America turn out to be as low as those in Asia. Changes over time are small and not in a specific direction. SIGNIFICANCE: We provide the most complete and comparable overview of twinning rates across the developing world currently possible.

PMID 21980404

Birth weight in a large series of triplets

BMC Pediatr. 2011 Apr 1;11(1):24. [Epub ahead of print]

Lamb DJ, Middeldorp CM, van Beijsterveldt CE, Vink JM, Haak MC, Boomsma DI.

Abstract ABSTRACT:

BACKGROUND: Triplets are often born premature and with a low birth weight. Because the incidence of triplet births is rare, there are relatively few studies describing triplet birth weight characteristics. Earlier studies are often characterized by small sample sizes and lack information on important background variables such as zygosity. The objective of this study is to examine factors associated with birth weight in a large, population-based sample of triplets registered with the Netherlands Twin Register (NTR).

METHOD: S In a sample of 1230 triplets from 410 families, the effects of assisted reproductive techniques, zygosity, birth order, gestational age, sex, maternal smoking and alcohol consumption during pregnancy on birth weight were assessed. The resemblance among triplets for birth weight was estimated as a function of zygosity. Birth weight discordance within families was studied by the pair-wise difference between triplets, expressed as a percentage of the birth weight of the heaviest child. We compare data from triplets registered with the NTR with data from population records, which include live births, stillbirths and children that have deceased within days after birth.

RESULTS: 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 NTR sample is representative for the Dutch triplet population that is still alive 28 days after birth.

CONCLUSIONS: Birth weight is an important determinant of childhood development. Triplet status, gestational age, sex, zygosity and maternal smoking affect birth weight. The combined effects amount to a difference of 364 grams between monozygotic girl triplets of smoking mothers compared to dizygotic boy triplets of non-smoking mothers of the same gestational age. Birth weight in triplets is also influenced by genetic factors, as indicated by a larger correlation in monozygotic than in di- and trizygotic triplets.

PMID: 21453554


A genome wide linkage scan for dizygotic twinning in 525 families of mothers of dizygotic twins.

Hum Reprod. 2010 Jun;25(6):1569-80. Epub 2010 Apr 8.

Painter JN, Willemsen G, Nyholt D, Hoekstra C, Duffy DL, Henders AK, Wallace L, Healey S, Cannon-Albright LA, Skolnick M, Martin NG, Boomsma DI, Montgomery GW.

Molecular Epidemiology, Genetic Epidemiology and Neurogenetics Laboratories, Queensland Institute of Medical Research, Brisbane, Australia. Abstract

BACKGROUND: The tendency to conceive dizygotic (DZ) twins is a complex trait influenced by genetic and environmental factors. To search for new candidate loci for twinning, we conducted a genome-wide linkage scan in 525 families using microsatellite and single nucleotide polymorphism marker panels.

METHODS AND RESULTS: Non-parametric linkage analyses, including 523 families containing a total of 1115 mothers of DZ twins (MODZT) from Australia and New Zealand (ANZ) and The Netherlands (NL), produced four linkage peaks above the threshold for suggestive linkage, including a highly suggestive peak at the extreme telomeric end of chromosome 6 with an exponential logarithm of odds [(exp)LOD] score of 2.813 (P = 0.0002). Since the DZ twinning rate increases steeply with maternal age independent of genetic effects, we also investigated linkage including only families where at least one MODZT gave birth to her first set of twins before the age of 30. These analyses produced a maximum expLOD score of 2.718 (P = 0.0002), largely due to linkage signal from the ANZ cohort, however, ordered subset analyses indicated this result is most likely a chance finding in the combined dataset. Linkage analyses were also performed for two large DZ twinning families from the USA, one of which produced a peak on chromosome 2 in the region of two potential candidate genes. Sequencing of FSHR and FIGLA, along with INHBB in MODZTs from two large NL families with family specific linkage peaks directly over this gene, revealed a potentially functional variant in the 5' untranslated region of FSHR that segregated with the DZ twinning phenotype in the Utah family.

CONCLUSION: Our data provide further evidence for complex inheritance of familial DZ twinning.

PMID: 20378614


Fetal volume and crown-rump length from 7 to 10 weeks of gestational age in singletons and twins

Eur J Obstet Gynecol Reprod Biol. 2009 Jul;145(1):32-5. Epub 2009 Apr 21. Martins WP, Nastri CO, Barra DA, Navarro PA, Mauad Filho F, Ferriani RA.

Escola de Ultra-sonografia de Ribeirão Preto (EURP) e Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil. Abstract OBJECTIVE(S): We intend to verify if fetal volume and crown-rump length were different between singletons and twins in pregnancies aged from 7 to 10 weeks and to evaluate if fetal volume is more accurate to determine the gestational age than crown-rump length at this gestational age.

STUDY DESIGN: From 52 days (7 weeks and 3 days) to 73 days (10 weeks and 3 days) weekly three-dimensional ultrasonography was performed in 20 twin fetuses and 20 singletons. Crown-rump length and fetal volume using VOCAL were assessed in all examinations. The 'true' gestational age was based on oocyte retrieval.

RESULTS: At the age of 52 days, the crown-rump length was 11.74+/-0.27 mm (mean+/-S.D.) and 11.48+/-0.22 mm (singletons and twins, respectively), while the fetal volume was 0.354+/-0.015 cm(3) and 0.324+/-0.012 cm(3). At the gestational age of 73 days, the crown-rump length was 36.19+/-0.90 mm and 35.87+/-0.54 mm and the fetal volume was 6.204+/-0.090 cm(3) and 6.083+/-0.081 cm(3). The total relative increase observed was much higher for fetal volume than for CRL: 1705+/-301% vs. 210+/-33% in singletons and 1827+/-305% vs. 214+/-25% in twins. The 95% limits of agreement (+/-2.3 days vs.+/-3.2 days, fetal volume vs. crown-rump length) and the intraclass correlation coefficients (0.989 vs. 0.978) between the "true" gestational age and that predicted by fetal volume were better than those predicted by crown-rump length. No significant difference was identified between singletons and twins for both fetal volume and crown-rump length.

CONCLUSION(S): Twins and singletons had similar fetal volume and crown-rump length between the 7th and 10th week of gestational age. Additionally, fetal volume assessed by VOCAL was better than crown-rump length to estimate the gestational age at the evaluated period. However, the improvement was small and probably without clinical significance. CONDENSATION: Fetal volume and crown-rump length were similar between singletons and twins. Fetal volume relative increase was higher and the predicted gestational age was better.

PMID 19386409

Early research on human genetics using the twin method: who really invented the method?

Twin Res Hum Genet. 2009 Jun;12(3):237-45.

Mayo O.

CSIRO Livestock Industries, Australia.

Abstract The twin method consists of a formal comparison between the resemblance between identical (monozygotic, MZ) twins and the resemblance between fraternal (dizygotic, DZ) twins for some trait of interest. It was developed between 1900 and about 1940, as more accurate tools for diagnosis of zygosity and for statistically analyzing the resemblance between relatives were built. Its early use was in the demonstration that a trait was inherited or that part of the causation of a trait was genetical, but it has now evolved to the point that twin registries constitute an important resource for the identification of specific genes and their interactions both with other genes and with the internal and external environment. Who really invented the method is still an unsettled question, which this article explores.

PMID 19456215

Traces of embryogenesis are the same in monozygotic and dizygotic twins: not compatible with double ovulation.

Hum Reprod. 2009 Jun;24(6):1255-66. Epub 2009 Feb 27.

Boklage CE.

Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. Abstract Common knowledge of over a century has it that monozygotic and dizygotic twinning events occur by unrelated mechanisms: monozygotic twinning 'splits' embryos, producing anomalously re-arranged embryogenic asymmetries; dizygotic twinning begins with independent ovulations yielding undisturbed parallel embryogeneses with no expectation of departures from singleton outcomes. The anomalies statistically associated with twin births are due to the re-arranged embryos of the monozygotics. Common knowledge further requires that dizygotic pairs are dichorionic; monochorionicity is exclusive to monozygotic pairs. These are fundamental certainties in the literature of twin biology. Multiple observations contradict those common knowledge understandings. The double ovulation hypothesis of dizygotic twinning is untenable. Girl-boy twins differ subtly from all other humans of either sex, absolutely not representative of all dizygotics. Embryogenesis of dizygotic twins differs from singleton development at least as much as monozygotic embryogenesis does, and in the same ways, and the differences between singletons and twins of both zygosities represent a coherent system of re-arranged embryogenic asymmetries. Dizygotic twinning and monozygotic twinning have the same list of consequences of anomalous embryogenesis. Those include an unignorable fraction of dizygotic pairs that are in fact monochorionic, plus many more sharing co-twins' cells in tissues other than a common chorion. The idea that monozygotic and dizygotic twinning events arise from the same embryogenic mechanism is the only plausible hypothesis that might explain all of the observations.

PMID 19252194

Heritability of testis size

Twin Res Hum Genet. 2009 Aug;12(4):351-5.

Estourgie-van Burk GF, Bartels M, Delemarre-van de Waal HA, Boomsma DI.

Department of Pediatrics, VU University Medical Center, Amsterdam, the Netherlands. Abstract Testis size is an important feature of male pubertal development. The genetic and environmental contributions to variation in human testis size have hardly been studied. We estimated the heritability of human testicular size in a group of mono- and dizygotic twins and their non-twin brothers (145 twins and 20 brothers from 95 families). Participants were 18 years old on average and all had reached Tanner development stage 4 or higher. Dizygotic twins and their siblings had a larger mean testis volume than monozygotic twins and their siblings. There was significant familial resemblance, with higher correlations in monozygotic twin pairs (0.59) than in dizygotic twin and sibling pairs (0.34). Heritability was estimated at 59% (95% CI = 37-75%), but a model that excluded genetic influences and attributed all familial resemblance to shared environment, fitted the data only marginally worse. The finding of larger mean testis volume in dizygotic twins may be of interest for future research into the mechanisms underlying dizygotic twinning.

PMID 19653835

Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells.

Eur J Hum Genet. 2009 Dec;17(12):1625-34. Epub 2009 Jun 10.

Bliek J, Alders M, Maas SM, Oostra RJ, Mackay DM, van der Lip K, Callaway JL, Brooks A, van 't Padje S, Westerveld A, Leschot NJ, Mannens MM.

Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. Abstract The Beckwith-Wiedemann syndrome (BWS) is a growth disorder for which an increased frequency of monozygotic (MZ) twinning has been reported. With few exceptions, these twins are discordant for BWS and for females. Here, we describe the molecular and phenotypic analysis of 12 BWS twins and a triplet; seven twins are MZ, monochorionic and diamniotic, three twins are MZ, dichorionic and diamniotic and three twins are dizygotic. Twelve twins are female. In the majority of the twin pairs (11 of 13), the defect on chromosome 11p15 was hypomethylation of the paternal allele of DMR2. In 5 of 10 twins, there was additional hypomethylation of imprinted loci; in most cases, the loci affected were maternally methylated, but in two cases, hypomethylation of the paternally methylated DLK1 and H19 DMRs was detected, a novel finding in BWS. In buccal swabs of the MZ twins who share a placenta, the defect was present only in the affected twin; comparable hypomethylation in lymphocytes was detected in both the twins. The level of hypomethylation reached levels below 25%. The exchange of blood cells through vascular connections cannot fully explain the degree of hypomethylation found in the blood cell of the non-affected twin. We propose an additional mechanism through which sharing of aberrant methylation patterns in discordant twins, limited to blood cells, might occur. In a BWS-discordant MZ triplet, an intermediate level of demethylation was found in one of the non-affected sibs; this child showed mild signs of BWS. This finding supports the theory that a methylation error proceeds and possibly triggers the twinning process.

PMID 19513094 [PubMed - indexed for MEDLINE]

Mortality risk among preterm babies: immaturity versus underlying pathology.

Epidemiology. 2010 Jul;21(4):521-7.

Basso O, Wilcox A.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Abstract BACKGROUND: Deaths among preterm births are presumably due to both immaturity and the conditions that cause preterm birth. Their relative contributions are unknown.

METHODS: Using US birth certificates (1995-2002), we estimated what portion of preterm neonatal mortality may be attributable to immaturity alone. Twins have elevated mortality, yet they usually have lower mortality than singletons at most preterm weeks. Twinning itself is a cause of early birth. Thus, at any given preterm week, singletons are more likely than twins to have pathologic causes of preterm delivery. If any such cause is associated with a mortality risk higher than that conferred by twinning, it is possible for singletons to have higher mortality than twins at some preterm weeks. Thus, mortality of twins at those weeks comes closer to describing the risk due to immaturity itself. To exclude high-risk babies, we focused on singletons and twins least likely to have suffered fetal growth disruptions (ie, those with "optimal" birth weight). At each gestational week from 24 to 36, we identified (for twins and singletons separately) the 500-gram weight category with the lowest neonatal mortality, and selected the lower of the 2 mortality rates.

RESULTS: Using the above as our best estimates of mortality due to immaturity alone, we calculated that about half the mortality of singleton preterm babies was due to the pathologies that cause early delivery.

CONCLUSIONS: Factors that cause preterm birth apparently contribute a large proportion of preterm mortality. If so, the prevention of preterm mortality requires more than the postponement of delivery.

PMID 20407380

Temporal and territorial analysis of multiple deliveries in Spain (1900-2006).

Twin Res Hum Genet. 2010 Apr;13(2):207-16.

Fuster V, Zuluaga P, Román-Busto J, Colantonio SE.

Department of Zoology and Physical Anthropology, Faculty of Biology, Complutense University of Madrid and GEPS, Spain.

Abstract Temporal variations in the frequency of multiple maternities in many Western European countries have been described. However, within a single country, regional differences are observed. Urban industrialized regions and rural agricultural areas have experienced in recent decades a distinct decline in multiple deliveries, which in cases have been related to maternal age and parity changes. Research on multiple deliveries in Spain is scarce and none of the studies go back to the beginning of the 20th century or consider regional variation over an extended period of time. The present paper is a yearly study on multiple deliveries in Spain since 1900 including a geographical analysis. Rather than dealing with recent changes in multi-parity, this paper is concerned with Spain's long-term national variation (between 1900 and 2006). The changing pattern of double and triple deliveries was analyzed using data from the Spanish National Statistics Institute (INE). Twinning rates in Spain are low in comparison to those of equivalent periods in other countries, and the minimum rates correspond to the 1980s decade. Results were interpreted by taking into account the influence of age at maternity and reproductive variation up to 1990. A good fit between observed and predicted rates was obtained after the application of models, which besides maternal age and parity, include their interaction. Regarding territorial variability, the values corresponding to southern, northern and insular Spanish provinces are consistent with an earlier reduction of the crude birth rate in the north-east regions and latter in the southern regions and the Canary Islands.

PMID 20397751

Long-term neurodevelopmental outcome of monochorionic and matched dichorionic twins.

PLoS One. 2009 Aug 28;4(8):e6815.

Hack KE, Koopman-Esseboom C, Derks JB, Elias SG, de Kleine MJ, Baerts W, Go AT, Schaap AH, van der Hoeven MA, Eggink AJ, Sollie KM, Weisglas-Kuperus N, A Visser GH.

Department of Obstetrics, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands. Abstract BACKGROUND: Monochorionic (MC) twins are at increased risk for perinatal mortality and serious morbidity due to the presence of placental vascular anastomoses. Cerebral injury can be secondary to haemodynamic and hematological disorders during pregnancy (especially twin-to-twin transfusion syndrome (TTTS) or intrauterine co-twin death) or from postnatal injury associated with prematurity and low birth weight, common complications in twin pregnancies. We investigated neurodevelopmental outcome in MC and dichorionic (DC) twins at the age of two years.

METHODS: This was a prospective cohort study. Cerebral palsy (CP) was studied in 182 MC infants and 189 DC infants matched for weight and age at delivery, gender, ethnicity of the mother and study center. After losses to follow-up, 282 of the 366 infants without CP were available to be tested with the Griffiths Mental Developmental Scales at 22 months corrected age, all born between January 2005 and January 2006 in nine perinatal centers in The Netherlands. Due to phenotypic (un)alikeness in mono-or dizygosity, the principal investigator was not blinded to chorionic status; perinatal outcome, with exception of co-twin death, was not known to the examiner.

FINDINGS: Four out of 182 MC infants had CP (2.2%) - two of the four CP-cases were due to complications specific to MC twin pregnancies (TTTS and co-twin death) and the other two cases of CP were the result of cystic PVL after preterm birth - compared to one sibling of a DC twin (0.5%; OR 4.2, 95% CI 0.5-38.2) of unknown origin. Follow-up rate of neurodevelopmental outcome by Griffith's test was 76%. The majority of 2-year-old twins had normal developmental status. There were no significant differences between MC and DC twins. One MC infant (0.7%) had a developmental delay compared to 6 DC infants (4.2%; OR 0.2, 95% 0.0-1.4). Birth weight discordancy did not influence long-term outcome, though the smaller twin had slightly lower developmental scores than its larger co-twin.

CONCLUSIONS: There were no significant differences in occurrence of cerebral palsy as well as neurodevelopmental outcome between MC and DC twins. Outcome of MC twins seems favourable in the absence of TTTS or co-twin death.

PMID 19714240

The efficacy of Quintero staging system to assess severity of twin-twin transfusion syndrome treated with laser therapy: a systematic review with meta-analysis

Am J Perinatol. 2009 Aug;26(7):537-44. Epub 2009 Mar 12.

Rossi AC, D'Addario V. Source IV Clinic of Obstetrics and Gynecology, University of Bari, Italy.


Severity of twin-twin transfusion syndrome (TTTS) is classified in five stages according to Quintero staging. However, the efficacy of such staging was recently debated. We reviewed the efficacy of Quintero staging to predict survival rate in TTTS treated with laser therapy. Articles reporting survival rate for each stage in TTTS treated with laser therapy were reviewed. Number of twins alive per pregnancy (NAP) was compared between early (I + II) and advanced (III + IV) stages and within stages. Meta-analysis was performed according to Meta-analysis Of Observational Studies in Epidemiology guidelines. Heterogeneity was tested with chi-square for heterogeneity at a significance level of P < 0.10, and random or fixed models were generated as appropriate. A P value < 0.05 was considered statistically significant. NAP was similar between early (zero survivors: 34/228, 15%; one survivor: 49/228, 21%; two survivors: 145/228, 63%) and advanced stages (zero survivors: 38/214, 18%; one survivor: 64/214, 30%; two survivors: 112/214, 52%; P > 0.05) except for one survivor ( P < 0.05). A trend for increased NAP was observed in all stages. Because clinically relevant differences were not observed, laser therapy is the optimal treatment for all stages. As Quintero staging does not provide information about prognosis, a new staging system is proposed.

PMID 19283655


GDF9 and BMP15 are both expressed in human oocytes and play important roles in folliculogenesis

  • A dominant-negative mutation in BMP15 identified in Italian sisters causes ovarian dysgenesis
  • higher frequencies of rare mutations in both GDF9 and BMP15 in patients with premature ovarian failure (POF)

Dixit H, Rao LK, Padmalatha V, Kanakavalli M, Deenadayal M, Gupta N, Chakrabarty B, Singh L. Missense mutations in the BMP15 gene are associated with ovarian failure. Hum Genet (2006) 119:408–415.

PMID 16508750

High risk of unexpected late fetal death in monochorionic twins despite intensive ultrasound surveillance: a cohort study

PLoS Med. 2005 Jun;2(6):e172. Epub 2005 Jun 28.

Barigye O, Pasquini L, Galea P, Chambers H, Chappell L, Fisk NM. Source Centre for Fetal Care, Queen Charlotte's and Chelsea Hospital, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.


BACKGROUND: The rationale for fetal surveillance in monochorionic twin pregnancies is timely intervention to prevent the increased fetal/perinatal morbidity and mortality attributed to twin-twin transfusion syndrome and intrauterine growth restriction. We investigated the residual risk of fetal death after viability in otherwise uncomplicated monochorionic diamniotic twin pregnancies. METHODS AND FINDINGS: We searched an electronic database of 480 completed monochorionic pregnancies that underwent fortnightly ultrasound surveillance in our tertiary referral fetal medicine service between 1992 and 2004. After excluding pregnancies with twin-twin transfusion syndrome, growth restriction, structural abnormalities, or twin reversed arterial perfusion sequence, and monoamniotic and high-order multiple pregnancies, we identified 151 uncomplicated monochorionic diamniotic twin pregnancies with normal growth, normal liquor volume, and normal Doppler studies on fortnightly ultrasound scans. Ten unexpected intrauterine deaths occurred in seven (4.6%) of 151 previously uncomplicated monochorionic diamniotic pregnancies, within 2 wk of a normal scan, at a median gestational age of 34(+1) wk (weeks(+days); range 28(+0) to 36(+3)). Two of the five cases that underwent autopsy had features suggestive of acute late onset twin-twin transfusion syndrome, but no antenatal indicators of transfusional imbalance or growth restriction, either empirically or in a 1:3 gestation-matched case-control comparison. The prospective risk of unexpected antepartum stillbirth after 32 wk was 1/23 monochorionic diamniotic pregnancies (95% confidence interval 1/11 to 1/63). CONCLUSION: Despite intensive fetal surveillance, structurally normal monochorionic diamniotic twin pregnancies without TTTS or IUGR are complicated by a high rate of unexpected intrauterine death. This prospective risk of fetal death in otherwise uncomplicated monochorionic diamniotic pregnancies after 32 wk of gestation might be obviated by a policy of elective preterm delivery, which now warrants evaluation. Comment in Uncomplicated monochorionic diamniotic twins and the timing of delivery. [PLoS Med. 2005]

PMID 15971947


Staging of twin-twin transfusion syndrome

J Perinatol. 1999 Dec;19(8 Pt 1):550-5.

Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Source Florida Institute for Fetal Diagnosis and Therapy, Tampa, USA.


OBJECTIVE: The purpose of this study was to evaluate the prognostic value of sonographic and clinical parameters to develop a staging classification of twin-twin transfusion syndrome (TTTS).

STUDY DESIGN: Severe TTTS was defined as the presence of polyhydramnios (maximum vertical pocket of > or = 8 cm) and oligohydramnios (maximum vertical pocket of < or = 2 cm). Nonvisualization of the bladder in the donor twin (-BDT) and absence of presence of hydrops was also noted. The middle cerebral artery, umbilical artery, ductus venosus, and umbilical vein in both fetuses were assessed with pulsed Doppler. Critically abnormal Doppler studies (CADs) were defined as absent/reverse end-diastolic velocity in the umbilical artery, reverse flow in the ductus venosus, or pulsatile flow in the umbilical vein. TTTS was staged as follows: stage I, BDT still visible; stage II, BDT no longer visible, no CADs; stage III, CADs; stage IV, hydrops; stage V, demise of one or both twins. Laser photocoagulation of communicating vessels (LPCV) or umbilical cord ligation was performed depending on the severity of the condition. The study was approved by the Institutional Review Board of St. Joseph's Hospital in Tampa and by the Fetal Therapy Board at Hutzel Hospital, Detroit, and all patients gave informed consent.

RESULTS: A total of 80 of 108 referred patients met criteria for surgery, but only 65 were treated surgically: 48 with LPCV and 17 with umbilical cord ligation. Complete Doppler data were obtainable in 41 of 48 LPCV patients. Survival rates by stage for one or two fetuses were statistically different (chi-squared analysis = 12.9, df = 6, p = 0.044). Neither percent size discordance nor gestational age at diagnosis were predictive of outcome.

CONCLUSION: Staging of TTTS using the proposed criteria has prognostic significance. This staging system may allow comparison of outcome data of TTTS with different treatment modalities.

PMID 10645517

Prevalence of premature ovarian failure in monozygotic and dizygotic twins