Ultrasound Obstet Gynecol 2013; 42: 329334Published online 4 August 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12486
Does 17--hydroxyprogesterone caproate affect fetalbiometry and birth weight in twin pregnancy?E. J. H. MULDER*, E. M. J. VERSTEEGH, K. W. M. BLOEMENKAMP, A. C. LIM,B. W. J. MOL, D. J. BEKEDAM, A. KWEE*, H. W. BRUINSE* and G. C. M. L. CHRISTIAENS**Department of Obstetrics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands; Department of Obstetrics, LeidenUniversity Medical Center (LUMC), Leiden, The Netherlands; Department of Obstetrics, Academic Medical Center (AMC), Amsterdam,The Netherlands; Department of Obstetrics, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
KEYWORDS: 17--hydroxyprogesterone caproate; fetal growth; preterm birth; twins
Objective Increasingly, maternal administration of 17--hydroxyprogesterone caproate (17-OHPC) is utilized toprevent preterm birth, but the fetal safety of 17-OHPCis still a matter of concern. This study aimed to assesswhether exposure to 17-OHPC during the second andthird trimesters of pregnancy affects fetal biometry intwin gestations.
Methods This study included a subset of women witha twin pregnancy who had been previously included ina randomized clinical trial comparing the effectivenessof 17-OHPC and placebo on neonatal outcomes andpreterm birth rates in multiple pregnancy. In the presentstudy, the individual growth patterns of femur length,head circumference and abdominal circumference werecompared between fetuses of women who had beenrandomized to receive weekly injections of either 17-OHPC (n= 52) or placebo (n= 58) at between 1620and 36 weeks gestation.
Results The three biometric variables assessed developedsimilarly in fetuses in both the group exposed to 17-OHPC and the placebo group during the second half ofpregnancy. Birth weight adjusted for parity and fetal sexwas also comparable between groups.
Conclusion The use of 17-OHPC has no adverse effectson fetal biometry and birth weight in twins. Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
Preterm birth, defined by the World Health Organizationas birth before 37 weeks gestation1, is the leadingcause of neonatal mortality and morbidity. Prophylacticadministration of 17--hydroxyprogesterone caproate(17-OHPC) to women with a singleton pregnancy anda history of spontaneous preterm delivery can reduce the
Correspondence to: Dr E. J. H. Mulder, Department of Obstetrics, Wilhelmina Childrens Hospital, University Medical Center, KE.04.123.1,Lundlaan 6, 3584 EA Utrecht, The Netherlands (e-mail: email@example.com)
Accepted: 18 March 2013
recurrence of preterm birth24. Progesterone is believed toexert an inhibitory effect on prostaglandins and oxytocinand to decrease the number of oxytocin receptors and gapjunctions in the myometrium, which are crucial elementsin the activation of (preterm) delivery5. However, the fetalsafety of 17-OHPC is still a matter for concern69.
Our study was prompted by the case of a pregnantwoman at increased risk of recurrent preterm birth. At20 weeks gestation, after 4 weeks of 17-OHPC treatment,ultrasonography showed extremely shortened fetal longbones (far below the third percentile). At this time,treatment was discontinued on the mothers initiativeand fetal catch-up growth was observed, such that allbones had a length at or above the third percentile by32 weeks, except for femur length, which remained belowthe third percentile until delivery at term. Birth weightwas below the fifth percentile and was much lower thanthat of a previous unexposed sibling.
In light of this case, we decided to assess whetherantenatal exposure to 17-OHPC affects the growthtrajectory of individual fetuses. For this purpose, we useddata from a large Dutch randomized controlled trial onthe prevention of preterm birth in multiple pregnancies(AMPHIA trial)10. This trial compared neonatal out-comes of pregnancies randomized for maternal use of17-OHPC vs placebo, and showed no beneficial effect of17-OHPC administration on the rates of preterm birthand neonatal morbidity in multiple pregnancies.
The present study was a secondary analysis of data fromthe AMPHIA trial (ISRCTN Register, www.isrctn.org,ISRCTN40512715). This trial was a multicenter, double-blind, placebo-controlled, randomized trial comparing theeffect on neonatal outcome of weekly intramuscular injec-tions of either 17-OHPC or placebo10. The original trialincluded a total of 671 pregnant women with multiple
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. ORIGINAL PAPER
330 Mulder et al.
pregnancies treated at 55 obstetric clinics in The Nether-lands randomized between August 2006 and August2009. The study was approved by the research ethicscommittee of the Academic Medical Center in Amsterdam(Ref MEC 05/102), and written informed consent wasobtained from each participant. Patients received their firstinjection of 17-OHPC (250 mg in 1 mL of castor oil) orplacebo (1 mL of castor oil) at between 16 and 20 weeksgestation, and their last injection at 36 weeks except incases in which delivery occurred before 36 weeks.
The present sample used for modeling fetal growthtrajectories consisted of all 126 AMPHIA participantsfrom four clinics, distributed as follows: UniversityMedical Center Utrecht, Utrecht (n= 43); AcademicMedical Center, Amsterdam (n= 35); Onze Lieve VrouweGasthuis, Amsterdam (n= 27); and Leiden UniversityMedical Center, Leiden (n= 21). Data on maternal andpregnancy characteristics, including dates of injection,chorionicity, gestational age (GA) at delivery and birthweight, were collected from the AMPHIA Trial database.Serial ultrasonographic measurements of femur length,head circumference and abdominal circumference, maderegularly on individual fetuses between 15 and 40 weeksgestation, were retrospectively collected from electronicpatient records kept by each of the four clinics.
The fetal ultrasound examinations were carried outby trained and accredited ultrasonographers under thesupervision of an obstetrician in each center. Fetalbiometry on twins was performed biweekly as part ofroutine care using standard methods11 and accordingto nationally accepted guidelines for fetal ultrasoundbiometry of the Dutch Society of Obstetrics andGynecology (Fetal Biometry protocol, NVOG, version1.0, released 2008). We distinguished between the twofetuses to allow for assessment of the individual twinsduring repeat scans. We referred to the one that is lowerin the pelvis (and therefore the one due to be born first)as Fetus 1 or Twin A. Additional intrauterine mappingincluded assessment of fetal sex, location in the placenta,intrapair growth discordance (if present) and fetal positionon the right side vs the left side of the uterus. Fetalposition is generally stable from 24 weeks onwards, butswapping of positions can sometimes occur. To check forthis, the longitudinal biometric measurements of each pairwere scrutinized for unexpected, illogical, or unrealisticdiscrepancies in biometry during data preparation. Suchdeviations occurred infrequently and were correctedbefore statistical analysis was carried out.
For inclusion in our analysis, participants were requiredto have a twin pregnancy with delivery at or after27 weeks gestation, and to have had at least three serialultrasound measurements, the final measurement beingmade after 26 weeks. These inclusion criteria were met by110 out of the 126 women (Figure 1).
To demonstrate a difference of 2 mm in femur lengthbetween the two randomization groups at 23 weeks
gestation, the study required 200 fetuses (100 pertreatment arm) to have 80% power and a 5% type-1error probability. The randomization code was notdisclosed to the investigators until all biometric data hadbeen collected.
Data management and statistical analysis were per-formed with SPSS for Windows (version 18, IBM/SPSSInc., Chicago, IL, USA). Results were summarized withthe use of standard descriptive statistics: n (%) for cate-gorical variables and mean (SD) for continuous variables.Groups were evaluated for equivalence using the chi-square or Fishers exact test for categorical measures,as appropriate, and t-tests for continuous variables. Vari-ables that were not normally distributed were transformed(log or square root). Fetal biometry and birth weight wereanalyzed at the individual twin level.
The serial measurements available for each fetus wereanalyzed with multilevel (mixed-effects) modeling toproduce individual growth trajectories. The first levelcomprises the repeated measurements on an individualfetus, the second level the twin number (1 or 2) and thethird level the individual mother. Mixed-effects modelsallow for intrafetal correlation of repeated measurements,make use of the exact age at measurement and accountfor a dissimilar number of measurements on each fetus.Such models also allow for individual variation ingrowth trajectories, as random effects permit variabilityin intercept, slope and curvature between subjects. Weexplored quadratic and cubic functions of GA for eachfetal biometric variable. The GA terms (linear, quadraticand cubic) were included as both fixed and random effects.Treatment (17-OHPC vs placebo) was included as a maineffect and also as an interaction with the GA terms.
The potential effect of 17-OHPC treatment on birthweight was studied in a multivariable regression analysis(SPSS option: General Linear Models, GLM).
Maternal characteristics and outcome of pregnancy arepresented in Table 1. Most variables were similar betweenthe 17-OHPC and placebo groups. However, there was anunbalanced distribution regarding chorionicity and modeof conception, with larger proportions of monochorionicand spontaneously conceived pregnancies in the placebogroup than in the 17-OHPC group. All 220 fetuses wereborn alive and none died in the neonatal period.
In total, there were 1325, 1211 and 1367 measurementsof fetal femur length, head circumference and abdominalcircumference, respectively, with an average of 6 (range,311) per fetus for each biometric variable; these numbersdid not differ statistically between groups (P=0.74, 0.63and 0.33, respectively). The time interval between thefinal biometric measurement and birth was 1.9 (range,0.17.3) weeks in the 17-OHPC group and 1.7 (range,05.7) weeks in the placebo group (P=0.60).
Mixed-effects models were applied to the serial datafor femur length, head circumference and abdominalcircumference. A quadratic function of GA (centered at
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 329334.
Fetal growth and 17-OHPC 331
Excluded:Triplet pregnancy (n = 7) Delivery < 27 weeks or last fetal measurement < 26 weeks (n = 7)
Fewer than three fetal measurements (n = 2)
Women who met inclusion criteria(n = 110)
Women who participated inAMPHIA trial at four centers
(n = 126)
Women randomized to17-OHPC(n = 52)
Women randomized toplacebo(n = 58)
Neonatal outcomeavailable(n = 104)
Neonatal outcomeavailable(n = 116)
Figure 1 Flow-chart of study population. 17-OHPC, 17--hydroxyprogesterone caproate.
15 weeks) with random effects for the intercept (constant)and the linear (GA) and quadratic (GA2) terms fit thedata best. The models also included the main effectof treatment (17-OHPC vs placebo) and treatment-by-GA and treatment-by-GA2 interactions as fixed effects.Chorionicity and mode of conception, considered ascovariables, were handled similarly. The results forthe final models are shown in Table 2. The threebiometric variables showed a non-linear increase in sizebetween 15 and 40 weeks gestation, demonstrated bythe highly significant growth curve parameters (intercept,GA and GA2). There was a significant main effectof chorionicity on all biometric variables. The threeparameters measured were smaller in monochorionicthan in dichorionic twins at 15 weeks gestation, andthe differences remained throughout pregnancy forfemur length and abdominal circumference. For headcircumference, the initial difference in size decreasedwith increasing gestation (significant chorionicity-by-GAinteraction). Twin number (1 or 2), mode of conception,and treatment with 17-OHPC did not influence the shapeof the three growth curves. Treatment-by-chorionicityinteractions were not significant. Figure 2 shows thegrowth curves of femur length for the placebo and 17-OHPC groups separately, illustrating the absence of effectof intrauterine exposure to 17-OHPC on fetal growth.
In the total sample of 220 fetuses, mean GA at birthwas 36.0 (range, 27.440.3) weeks and mean birthweight was 2408 (range, 6504450) g (Figure 3). GA atbirth and birth weight were similar between the placeboand 17-OHPC groups in univariate analysis (Table 1).To ascertain whether exposure to 17-OHPC has an inde-pendent effect on birth weight, we analyzed with GLM
the birth-weight data for all infants using age at birth(centered at 36 weeks) and treatment as predictors. Parity,chorionicity, ethnicity and fetal gender were included ascovariables. A linear model fitted the data best. The meanpredicted birth weight at 36 weeks gestation was 2412 g(SE 52 g) and was 170 g (SE 8 g) lower or higher foreach week that birth occurred before or after 36 weeks,respectively (P
332 Mulder et al.
Table 1 Baseline characteristics and outcome data of twin pregnancies included in this study according to exposure to17--hydroxyprogesterone caproate (17-OHPC) or placebo
group (n= 58) PMaternal characteristics
Age (years) 34.2 4.3 33.45.2 0.40Body mass index (kg/m2) 24.4 5.1 23.84.3 0.48Race 0.44
Caucasian 39 (75.0) 48 (82.8)Other 13 (25.0) 10 (17.2)
Higher education 22 (42.3) 30 (51.7) 0.43Smoker 8 (15.4) 12 (20.7) 0.62Alcohol consumption 1 (1.9) 2 (3.4) 1.00
Pregnancy characteristicsNulliparous 27 (51.9) 37 (63.8) 0.21Mode of conception 0.009
Spontaneous 26 (50.0) 44 (75.9)Assisted reproduction treatment* 26 (50.0) 14 (24.1)
Chorionicity 0.022Monochorionic 4 (7.7) 14 (24.1)Dichorionic 48 (92.3) 44 (75.9)
Outcome of pregnancyGestational age at birth (weeks) 36.5 2.5 35.73.0 0.11Delivery before 32 weeks gestation 3 (5.8) 7 (12.1) 0.33Gender 0.27
Male 46/104 (44.2) 60/116 (51.7)Female 58/104 (55.8) 56/116 (48.3)
Birth weight (g) 2461 519 2359627 0.19Birth weight20% 8 (15.4) 5 (8.6) 0.38
Data shown as mean SD or n (%). *Ovarian hyperstimulation, in-vitro fertilization or intracytoplasmic sperm injection. ((Larger birthweight smaller birth weight)/larger birth weight)100%.
Table 2 Statistical results of linear mixed modeling for fetal biometric measurements
Variable Femur length Head circumference Abdominal circumference
Intercept 16.7 (0.3)*** 10.7 (0.04)*** 92.1 (1.5)***Time effects
GA 3.3 (0.05)*** 0.557 (0.006)*** 12.6 (0.2)***GA2 0.041 (0.002)*** 0.011 (0.0002)*** 0.108 (0.008)***
Group effectsFetus 2 vs Fetus 1 0.08 (0.22) 0.04 (0.03) 0.6 (0.9)Monochor...