2012_36

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OBSTETRICS

Gestational age of previous twin preterm birth as apredictor for subsequent singleton preterm birthTimothy J. Rafael, MD; Matthew K. Hoffman, MD, MPH; Benjamin E. Leiby, PhD; Vincenzo Berghella, MD

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OBJECTIVE: We sought to determine an optimal gestational-age cutoffof preterm twin deliveries for predicting subsequent singleton pretermbirth (PTB).

STUDY DESIGN: We performed a retrospective study of women with aspontaneous twin delivery who subsequently had a singleton gestation.Univariate and multivariate analyses determined the risk of a spontane-ous singleton PTB after a PTB of a twin gestation. Different gestational-age cutoffs of the previous twin PTB were evaluated.

RESULTS: Among 255 women, previous twin PTB at �34 weeks’ ges-
tation was associated with an increased risk of singleton PTB (odds ra- K
Am J Obstet Gynecol 2012;206:156.e1-6.

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tidttgtncwahttPan increased risk of a

doi: 10.1016/j.ajog.2011.10.008

156.e1 American Journal of Obstetrics & Gynecology FEBRUARY 2012

tio, 9.67; 95% confidence interval, 3.07–30.47). Every twin gestationalage cutoff at �34 weeks’ gestation had a significantly higher riskof subsequent singleton PTB, which was no longer significant at�34 weeks’ gestation (odds ratio, 1.68; 95% confidence interval,0.23–12.19).

CONCLUSION: In women with a previous spontaneous twin PTB at �34eeks’ gestation, there is an increased risk of subsequent singletonTB. A twin birth at �34 weeks’ gestation is not associated with an in-reased risk for a subsequent singleton PTB.

ey words: gestational age, preterm birth, singleton, twins

Cite this article as: Rafael TJ, Hoffman MK, Leiby BE, et al. Gestational age of previous twin preterm birth as a predictor for subsequent singleton preterm birth.

tt
Preterm birth (PTB) remains at the
forefront of obstetric challenges to-day. The PTB rate remains �12% in the

nited States, with well over 500,000 in-ants per year being born prematurely.1

Prematurity remains the leading cause ofinfant morbidity and death.2 The chal-enge is 2-fold: (1) identification of thoseopulations at higher risk for PTB and2) provision of interventions that pre-

From the Division of Maternal-FetalMedicine, Department of Obstetrics andGynecology, Jefferson Medical College ofThomas Jefferson University Hospital (DrsRafael and Berghella), and the Division ofBiostatistics, Department of Pharmacologyand Experimental Therapeutics, ThomasJefferson University (Dr Leiby),Philadelphia, PA; and the Department ofObstetrics and Gynecology, Christiana CareHealth System, Newark, DE (Dr Hoffman).

Received May 28, 2011; revised Sept. 9, 2011;accepted Oct. 10, 2011.

The authors report no conflict of interest.

Presented as a poster at the 31st annualmeeting of the Society for Maternal-FetalMedicine, San Francisco, CA, Feb. 7-12, 2011.

Reprints will not be available from the authors.

0002-9378/$36.00© 2012 Mosby, Inc. All rights reserved.

ent PTB. It is well accepted that one ofhe greatest risk factors in the predictionf spontaneous singleton PTB (sPTB) isrevious singleton PTB.3,4 Subsequento the identification of this at-risk popu-ation, various secondary preventative

easures (eg, progesterone, ultrasound-ndicated cerclage) have been shown toeduce the risk of subsequent sPTB.5,6

The risk of delivering a singleton in-fant prematurely after a preterm deliveryof a twin gestation, however, is not clear.Although 2 studies have shown no in-creased risk of a subsequent sPTB after atwin PTB,7,8 2 other studies have shownan increased risk.9,10 An additional ques-ion exists, in that the definition of PTBn twin infants (�37 weeks’ gestation) isefined within the same parameters ashat of a singleton infant, despite the facthat 60% of twins are born before thisestational age (GA).1 What makes thesewin pregnancies deliver prematurely isot known: is a PTB the result of simplyarrying a twin gestation, or does aoman with a twin PTB at an earlier GA

lso possess an inherent increased risk ofaving a PTB, which carries on to a fu-ure pregnancy? It was therefore our in-ention to evaluate whether a previousTB of a twin gestation is associated with

subsequent single-

on PTB and, if yes, to find an optimalwin GA cutoff in predicting this risk.

MATERIALS AND METHODSWe performed an institutional reviewboard–approved retrospective cohortstudy that analyzed a group of womenwith a twin delivery who subsequentlyhad a singleton delivery from 1996-2010.These women delivered both of theirpregnancies at Christiana Care HealthSystems, Newark, DE. Data were ex-tracted from a preexisting database thatcontains various demographic and deliv-ery information. This database containsselected obstetric and neonatal out-comes for all women who deliver at thisinstitution. The data are entered bynurses who attend the deliveries; quar-terly audits are used to ensure accuracyof data entry. These audits consistentlyhave verified the accuracy of the data toexceed 95%, with additional indepen-dent validation that demonstrates the ac-curacy of key variables.11

Subjects were considered for inclusionif the following 2 criteria were met: sin-gleton gestation and previous twin gesta-tion. Subjects were excluded for indi-cated (iatrogenic) PTBs at �37 weeks’gestation in either pregnancy, previous
PTB preceding the twin delivery, intra-

Mdwcwpfirters�

www.AJOG.org Obstetrics Research

uterine death of 1 or both twins, major fe-tal anomaly, or unclear or incomplete de-livery information. The “preterm twin”group consisted of women who had a pre-vious twin PTB between 18 and 36 weeks 6days’ gestation (after spontaneous pretermlabor or preterm premature rupture ofmembranes). The “term twin” group con-sisted of women who had a twin birth at�37 weeks’ gestation.

Demographic information that we ex-tracted included maternal age, race,body mass index (kilograms per squaremeter), smoking history, insurance sta-tus, parity, and the interpregnancy inter-val from the twin delivery to the concep-tion of the singleton gestation. The initialquery specified exclusion of any womanwho had a PTB preceding the twin preg-nancy; chart-level documents were re-viewed where appropriate if there was aquestion regarding spontaneous vs iat-rogenic delivery.

Statistical analysis was performed us-

FIGURE 1Reasons for exclusion from analys

C-section, cesarean section delivery; HIV, human immunodeficien

Rafael. GA of previous twin PTB predicts subsequent sPTB. A

ing SPSS-PC software (version 16.0;

SPSS Inc, Chicago, IL). Categoric vari-ables were compared with the use of �2

tests or Fisher’s exact test, as appropriate.Continuous variables were comparedwith the use of the Student t test or the

ann-Whitney U test for nonnormallyistributed variables. Logistic regressionas used to assess the impact of potential

onfounders. A probability value � .05as considered significant. When appro-riate, odds ratios (ORs) with 95% con-dence intervals (CIs) were estimated. Aeceiver operator curve was used to iden-ify which GAs of a previous twin deliv-ry were associated with an increasedisk of spontaneous PTB in a subsequentingleton gestation, which was defined as

37 weeks’ gestation.

RESULTSThere were 308 women who were iden-tified as having had a twin delivery fol-lowed by a singleton pregnancy in the

irus; PTB, preterm birth.

Obstet Gynecol 2012.

absence of a PTB preceding the twin ges-

FEBRUARY 2012 Americ

tation. A total of 53 women were ex-cluded after chart-level review (Figure1). After exclusion for the aforementionedcriteria, there were 255 women whose datawere available for analysis. Of these, 144women (56.5%) had a history of a twinPTB, and 111 (43.5%) had a twin termbirth. Among the variables that were stud-ied, there were no demographic differ-ences between the preterm twin group andterm twin group at the time of the single-ton pregnancy (Table 1).

The median singleton GA at deliverywas 38.0 weeks (interquartile range,38.0 –39.0) and 39.0 weeks (interquartilerange, 38.0 – 40.0) for the preterm twinand term twin groups, respectively. Amongthe preterm twin group, 16 of 144women (11.1%) had a subsequent sin-gleton sPTB, compared with 2 of 111women (1.8%) in the term twin group(OR, 6.81; 95% CI, 1.53–30.29), whichindicated an association of a previoustwin PTB with a subsequent singletonPTB. Further stratification by GA showedthat every twin GA cutoff at �34 weekshad a significantly higher risk of subse-quent singleton PTB when comparedwith the term twin group (P � .009; Ta-ble 2). In the cohort that encompassed34-36 weeks 6 days’ gestation, the oddsof subsequent singleton PTB risk wereno longer significantly higher than theterm twin group, with a PTB rate of 3.0%(OR, 1.68; 95% CI, 0.23–12.19).

The receiver operator curve demon-strated an area under the curve of 0.77,with a clear inflection point that corre-sponded to a value of 33 weeks 6 days’gestation (Figure 2). With the use of twindelivery at �34 weeks’ gestation, the sen-sitivity in that prediction of a subsequentsingleton sPTB was 77.8%, with a speci-ficity of 73.4%, a positive predictivevalue of 18.2%, and a negative predictivevalue of 97.8%.

Given the limited numbers of single-ton PTBs (n � 18), a subsequent univar-iate analysis was carried out that com-pared the cohort of previous twin PTB at�34 weeks’ gestation, with twin birth at�34 weeks’ gestation (Table 3). Theoverall rate of a subsequent singletonPTB after a twin delivery at �34 weeks’gestation was 18.2%, compared with a

is

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rate of 2.2% after a twin delivery at �34

an Journal of Obstetrics & Gynecology 156.e2

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weeks’ gestation (OR, 9.67; 95% CI,3.07–30.47). Demographic comparisonbetween the 2 new groups (twin birth at�34 weeks’ gestation and twin birth at�34 weeks’ gestation) revealed signifi-cant differences in body mass index, par-ity, and interpregnancy interval; mater-nal age at the time of delivery had aprobability value of 0.08 (Table 4). Al-though multivariate analyses demon-strated maternal age, parity, and insur-ance status to be associated withsubsequent singleton birth, adjustmentfor these and all demographic variablesdid not alter the significance of twin PTBat �34 weeks’ gestation in the predictionof subsequent sPTB (adjusted OR, 8.89-12.62; 95% CI, 2.79 – 41.55).

COMMENTWe have demonstrated a significantly in-creased risk of subsequent singletonsPTB after a sPTB at �37 weeks of a twingestation. More specifically, we defined aGA of 34 weeks as an optimal cutoff inpredicting sPTB after a twin PTB.Among those women who had a twin

TABLE 1Demographics at time of singleton

Demographic

Maternal age at singleton delivery, ya

...................................................................................................................

Maternal age �20 or �35 y, %...................................................................................................................

Race, %...................................................................................................................

White...................................................................................................................

African American...................................................................................................................

Other...................................................................................................................

Body mass index, kg/m2b

...................................................................................................................

Body mass index �19 kg/m2 or weight �120...................................................................................................................

Smoking, %c

...................................................................................................................

Private insurance, %...................................................................................................................

Parity �1 at time of twin birth, %...................................................................................................................

Interpregnancy interval, mob

...................................................................................................................

Interpregnancy interval �6 or �60 mo, %...................................................................................................................a Student t test; data are given as mean � SD; b Mann-Whitn

Rafael. GA of previous twin PTB predicts subsequent sPTB

birth at �34 weeks’ gestation, there was

156.e3 American Journal of Obstetrics & Gynecolo

not a significantly increased risk of the de-livery of a subsequent singleton preterm.

The strengths of this study include thatit is one of the larger cohort studies toanalyze the risk of sPTB in a singletonpopulation preceded by a sPTB of twins.We excluded previous PTB at the start ofthe query because a previous sPTB hasbeen shown to increase the risk of a subse-quent twin PTB,12,13 which could con-

TABLE 2Risk of subsequent singleton pretepreterm birth, stratified by gestatio

Gestational ageof twin birth, wk

Subsequenpreterm

18-226/7 (20 births) 20...................................................................................................................

23-276/7 (21 births) 14...................................................................................................................

28-316/7 (14 births) 21...................................................................................................................

32-336/7 (22 births) 18...................................................................................................................

34-366/7 (67 births) 3...................................................................................................................

�37 (111 births) 1...................................................................................................................

CI, confidence interval.a Relative to the group at �37 weeks’ gestation.

th

Group

Preterm twin: previoustwin preterm birth at<37 weeks’ gestation(n � 144)

30.4 � 5.5.........................................................................................................................

26.4.........................................................................................................................

.........................................................................................................................

68.1.........................................................................................................................

26.4.........................................................................................................................

5.6.........................................................................................................................

25.4 (21.9–30.8).........................................................................................................................

, %c 11.1.........................................................................................................................

20.1.........................................................................................................................

69.4.........................................................................................................................

39.6.........................................................................................................................

16.6 (8.3–33.9).........................................................................................................................

24.3.........................................................................................................................

test; data are given as median (interquartile range); c Fisher’s ex

J Obstet Gynecol 2012.

Rafael. GA of previous twin PTB predicts subsequent sPTB. Am

gy FEBRUARY 2012

ound our results. While also excludingonspontaneous (iatrogenic) deliveries,e also examined more demographic fac-

ors than in previous studies, which in-luded race, body mass index, smokingistory, and interpregnancy interval, all ofhich have been shown to be associatedith an increased risk of PTB.14-17 The re-

ceiver operator curve allowed us to furtherdelineate a more specific GA cutoff in pre-

birth after twinl age of twin birth

ngletonth, % Odds ratio (95% CI)a

13.63 (2.31–80.52)..................................................................................................................

9.08 (1.42–58.20)..................................................................................................................

14.86 (2.24–98.74)..................................................................................................................

12.11 (2.07–71.04)..................................................................................................................

1.68 (0.23–12.19)..................................................................................................................

Reference..................................................................................................................

P value

Term twin: previoustwin term birth at>37 weeks’ gestation(n � 111)

30.8 � 6.6 .61..................................................................................................................

34.2 .17..................................................................................................................

.47..................................................................................................................

61.3..................................................................................................................

33.3..................................................................................................................

5.4..................................................................................................................

24.3 (21.5–30.4) .55..................................................................................................................

9.9 .84..................................................................................................................

18.9 .87..................................................................................................................

62.2 .22..................................................................................................................

41.4 .76..................................................................................................................

20.0 (11.0–34.3) .23..................................................................................................................

15.3 .09..................................................................................................................

est.

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.2.........

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.8.........

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dicting subsequent singleton PTB, whichyielded a fair sensitivity and specificity.

Our study is not without weaknesses,mostly those inherent to its retrospectivenature. In addition, the number of sPTBsand the numbers of PTBs in each previ-ous PTB category were small. This couldexplain the reason that the risk of subse-quent singleton PTB did not increaseproportionately with decreasing twinGA. Ideally, larger prospective studiesshould confirm these data. We did nothave available reliable information re-garding the chorionicity of the twin ges-tation, nor did we have consistent infor-mation discerning whether the twinpregnancy was the result of assisted re-productive technology. Other informa-

FIGURE 2Receiver operator curve (ROC)

Rafael. GA of previous twin PTB predicts subsequent sPTB. A

TABLE 3Risk of subsequent singleton pretetwin preterm birth at <34 weeks’

Gestational ageof twin birth, wk

Subsequepreterm

�34 (77 births) 1...................................................................................................................

�34 (178 births)...................................................................................................................

CI, confidence interval.a Relative to the group at �34 weeks’ gestation.

Rafael. GA of previous twin PTB predicts subsequent sPTB. Am

tion regarding additional risk factors forPTB, such as cone biopsy, was also notavailable. Being a regional perinatal center,there is always the potential for referral bi-as; and given that most of our patients werewhite and had private insurance, therecould be questions regarding the externalvalidity of such a study.

The association between PTB of twinsand subsequent singleton PTB risk hasvaried in the literature. Rydhstroem7

studied a large cohort of twins (n �2979) and found no association withsubsequent sPTB, but the study neitherexcluded iatrogenic deliveries nor com-pared the outcomes of singleton preg-nancies between those twin pregnanciesthat delivered preterm and at term.

Obstet Gynecol 2012.

birth aftertation

singletonirth, % Odds ratio (95% CI)a

9.67 (3.07–30.47)..................................................................................................................

Reference..................................................................................................................



Bloom et al8 drew the same conclusion asRydhstroem by comparing subsequentsingleton outcomes after twin birth at�35 weeks’ vs �35 weeks’ gestation andincluded only spontaneous labor pa-tients; however, with a sample size of 82gestations, the study was likely under-powered to detect a significant differencebetween the 2 cohorts.

The conclusions that we have drawnare similar to those of Menard et al,9 be-ause not only did they demonstrate aignificant risk of singleton PTB with arevious twin PTB at �37 weeks’ gesta-ion (as did their cohorts of twin deliveryt 30-34 and �30 weeks’ gestation) butlso their cohort of twins that deliveredetween 34 and 37 weeks’ gestation didot have a significantly increased risk ofubsequent sPTB (relative risk, 1.42;5% CI, 0.40 –5.01). That study, how-ver, did not exclude for either indicatedTBs or a previous PTB that preceded

he twin gestation. Because this study in-luded mostly publicly funded Africanmerican women and given our results

n a mostly privately funded white co-ort, the results of the study by Menardt al9 provide some evidence of the gen-ralizability of our findings. The most re-ent study by Facco et al10 had a cohort of67 women, and as in our study, they ex-luded women with both a previous PTBnd indicated PTBs. Although they dem-nstrated an increased risk of subse-uent singleton sPTB at �37 weeks’ ges-ation (OR, 5.0; 95% CI, 1.1–22.9), theyid not subdivide their cohort to furtherxamine a more discrete GA, after whichhe risk of subsequent sPTB may no lon-er have been increased. We believe thatur larger cohort (n � 255), with similar

nclusion criteria as Facco et al10 and theincorporation of a similar subset of GA co-horts as Menard et al,9 further adds to theliterature by reinforcing the twin GA cutoffof 34 weeks’ gestation in the prediction ofsubsequent singleton PTB risk.

The exact cause behind PTB is un-known, although the mechanisms thatare involved usually represent a finalcommon pathway of 4 different incitingcauses: (1) maternal and/or fetal stress,(2) inflammation, (3) abruption (decid-ual bleeding), and (4) pathologic me-

m J

rmges

ntb

8.2.........

2.2.........

chanical stretching of the uterus.18 It is


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Research Obstetrics www.AJOG.org

this stretching or overdistension of theuterus that has been implicated in thecause of twin PTB, because mechanicalstretching of the uterus can induce oxyto-cin receptors, cyclooxygenase-2, and inter-leukin-8 expression.19 How this mecha-nism would implicate future singletonPTB risk is unknown, but in theory thosewomen who have an early twin PTB (eg,�34 weeks’ gestation) are likely to havecauses that are analogous to those womenwho have an early singleton PTB (eg, cer-vical insufficiency, genetic predisposition,infection/inflammation), which explainstheir increased risk of subsequent sPTB.

The implications of this study for bothresearch and clinical care are clear. Re-garding research, interventions for pre-vention of PTB that have been shown tohave some benefit for women with pre-vious singleton sPTB (eg, 17 alpha-hy-droxyprogesterone caproate, cerclage)should be tested for efficacy in random-ized-controlled trials in this cohort ofwomen with previous twin PTB at �34weeks’ gestation. Assuming an approxi-mate 18.2% risk of singleton PTB at �37weeks’ gestation after a twin PTB at �34weeks’ gestation, approximately 554

TABLE 4Demographics at the time of the si

Demographic

Maternal age at singleton delivery, ya

...................................................................................................................

Maternal age �20 or �35 y, %b

...................................................................................................................

Race, %...................................................................................................................

White...................................................................................................................

African American...................................................................................................................

Other...................................................................................................................

Body mass index, kg/m2c

...................................................................................................................

Body mass index �19 kg/m2 or weight �120...................................................................................................................

Smoking, %...................................................................................................................

Private insurance, %...................................................................................................................

Parity �1 at time of twin birth, %b

...................................................................................................................

Interpregnancy interval, moc

...................................................................................................................

Interpregnancy interval �6 or �60 mo, %...................................................................................................................a Student t test; data are given as mean � SD; b Fisher’s exa

Rafael. GA of previous twin PTB predicts subsequent sPTB

subjects would be needed in each arm to

156.e5 American Journal of Obstetrics & Gynecolo

demonstrate a 33% reduction in single-ton PTB, assuming 80% power with analpha of .05. Regarding clinical care, awoman who delivers a twin pregnancy at�34 weeks’ gestation may be reassuredthat her subsequent sPTB risk is low:2.2% by our data.

In conclusion, we have demonstratedthat there is an increased risk of subse-quent singleton PTB in women after aprevious twin PTB. A previous twin de-livery at �34 weeks’ gestation is associ-ated with a significantly increased risk ofa subsequent sPTB. A twin delivery at�34 weeks’ gestation is not associatedwith an increased risk of PTB in a subse-quent singleton pregnancy. f

ACKNOWLEDGMENTWe thank Dr Jason Baxter for his thoughtful ad-vice and for his critical review of the manuscript.

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leton birth (twin birth at <34 and >3

Previous twin birth

At <34 weeks’gestation (n � 77)

29.6 � 5.6.........................................................................................................................

22.1.........................................................................................................................

.........................................................................................................................

63.6.........................................................................................................................

29.9.........................................................................................................................

6.5.........................................................................................................................

25.8 (22.7–32.5).........................................................................................................................

, %b 3.9.........................................................................................................................

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31.2.........................................................................................................................

14.3 (7.2–30.3).........................................................................................................................

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3. Adams MM, Elam-Evans LD, Wilson HG, Gil-bertz DA. Rates of and factors associated withrecurrence of preterm delivery. JAMA 2000;283:1591-6.4. Esplin MS, O’Brien E, Fraser A, et al. Estimat-ing recurrence of spontaneous preterm deliv-ery. Obstet Gynecol 2008;112:516-23.5. Meis PJ, Klebanoff M, Thom E, et al. Preven-tion of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med2003;348:2379-85.6. Berghella V, Rafael TJ, Szychowski JM, RustOA, Owen J. Cerclage for short cervix on ultra-sonography in women with singleton gestationsand previous preterm birth: a meta-analysis.Obstet Gynecol 2011;117:663-71.7. Rydhstroem H. Gestational duration in thepregnancy after a preterm twin delivery. Am JObstet Gynecol 1998;178:136-9.8. Bloom SL, Yost NP, McIntire DD, Leveno KJ.Recurrence of preterm birth in singleton and twinpregnancies. Obstet Gynecol 2001;98:379-85.9. Menard MK, Newman RB, Keenan A, EbelingM. Prognostic significance of prior preterm twindelivery on subsequent singleton pregnancy.Am J Obstet Gynecol 1996;174:1429-32.10. Facco FL, Nash K, Grobman WA. Arewomen who have had a preterm twin delivery atgreater risk of preterm birth in a subsequentsingleton pregnancy? Am J Obstet Gynecol2007;197:253.e1-3.11. Zhang J, Landy HJ, Ware Branch D, et al.Contemporary patterns of spontaneous laborwith normal neonatal outcomes. Obstet Gyne-

weeks’ gestation)

P valueAt >34 weeks’gestation (n � 178)

31.0 � 6.1 .08..................................................................................................................

33.1 � .99..................................................................................................................

.89..................................................................................................................

65.7..................................................................................................................

29.2..................................................................................................................

5.1..................................................................................................................

24.6 (21.5–30.0) .05..................................................................................................................

13.5 .03..................................................................................................................

18.0 .32..................................................................................................................

66.9 .77..................................................................................................................

44.4 .05..................................................................................................................

20.0 (11.8–36.0) .004..................................................................................................................

19.1 .44..................................................................................................................

e).

ng 4

......... .........

......... .........

......... .........

......... .........

......... .........

......... .........

......... .........

lb......... .........

......... .........

......... .........

......... .........

......... .........

......... .........

ct tes rang

col 2010;116:1281-7.


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