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Review question What are the optimal ultrasound measurements to determine in multiple ? a) Are the measurements and charts (crown–rump length, biparietal diameter and head circumference) used for dating singletons equally effective for or are there systematic errors introduced from using these charts?

Study details Participants Investigation Outcome measures and results Comments

First author, year: Population: Investigation : 1) Crown-rump length (mm) Funding: Martins 200931 N = 40 CRL in fetuses CRL at 52 days No details reported 20 twin and 20 singleton Twins = 11.48 ± 0.22 P = 0.45 Country: fetuses with gestational age Comparison: Singletons = 11.74 ± 0.27 Limitations: Brazil 52 – 73 days CRL in singleton fetuses CRL at 59 days Main bias will arise from Twins = 19.36 ± 0.31 P = 0.85 operator and equipment, and a Study design: Inclusion criteria: Methods described Singletons = 19.26 ± 0.43 small sample size Prospective and adequately? CRL at 66 days cohort transfer with a Yes Twins = 26.51 ± 0.33 P = 0.91 N=10 twin in which positive , 3-D ultrasound (US) scans Singletons = 26.44 ± 0.57 both fetuses measured (not Study dates: maternal age ≤ 35 years, performed weekly from 52 days CRL at 73 days independent) No details reported maternal BMI ≤30kg/m2, to 73 days and for each in Twins = 35.87 ± 0.54 P = 0.76 acceptance to join research a twin pregnancy Singletons = 36.19 ± 0.90 Categorical analysis in small Aim of study: CRL measured using the 2) Weekly relative increase in CRL (mm) blocks of gestational age, Primary: Exclusion criteria: longitudinal plane of the fetus in CRL at 5 –59 days rather than unified analysis of To examine whether Absence from one or more the 3-D US multiplanar view Twins = 0.69 ± 0.03 P = 0.33 repeated measurements fetal volume (FV) and of four evaluation dates Equipment details reported Singletons = 0.69 ± 0.02 crown-rump length Details of charts used not CRL at 59 – 66 days Confidence intervals for (CRL) are different in Other details: reported Twins = 0.37 ± 0.02 P = 0.90 estimated effect size not singleton and twin Gestational age determined Singletons = 0.38 ± 0.02 reported Study details Participants Investigation Outcome measures and results Comments pregnancies by adding 14 days to the Operator number/experience: CRL at 66 – 73 days Secondary : number of days between A single operator performed all Twins = 0.35 ± 0.02 P = 0.90 * Results reported by authors To evaluate the oocyte retrieval and date of scans Singletons = 0.37 ± 0.02 as mean ± SD but actually comparative accuracy the ultrasound scan All data reported as mean ± standard error mean ± SE of FV and CRL to All twins were dichorionic (SE)* Probably the same participants determine gestational Details of maternal ethnicity as in Martins 200832 but at age not reported earlier gestational age First author, year: Population: Investigation: 1) Crown-rump length (mm) Funding: Martins 200832 N = 40 fetuses CRL in twin fetuses CRL at 73 days No details reported 20 twin and 20 singleton Twins = 35.9 ± 2.4 P = 0.76 Country: fetuses with gestational age Comparison: Singletons = 36.2 ± 4.0 Limitations: Brazil 73 – 101 days CRL in singleton fetuses CRL at 80 days Main bias will arise from Twins = 50.8 ± 2.8 P = 0.62 operator and equipment, and a Study design: Inclusion criteria: Methods described Singletons = 50.4 ± 3.0 small sample size Prospective In vitro fertilisation and adequately? CRL at 87 days Confidence intervals for cohort embryo transfer with a Yes Twins = 63.4 ± 2.3 P = 0.19 estimated effect size not positive pregnancy test 3-D ultrasound (US) scans Singletons = 64.4 ± 2.3 reported Study dates: performed 2 weeks after performed weekly from 73-101 CRL at 94 days Probably the same participants No details reported transfer, maternal age ≤ 35 days; for twins, a scan was Twins = 75.4 ± 2.5 P = 0.41 as in Martins 200931 but at later years, maternal BMI performed for each fetus Singletons = 74.7 ± 2.7 gestational age Aim of study: ≤25kg/m2, first IVF cycle, CRL measured using the CRL at 101 days To compare crown- absence of uterine longitudinal plane of the fetus in Twins = 85.2 ± 5.5 P = 0.83 rump length (CRL) pathologies and acceptance the 3-D US multiplanar view Singletons = 85.6 ± 5.5 and fetal head and to join research Equipment details reported trunk (HT) volume Details of charts used not 2) Weekly relative increase in CRL (mm) between singletons Exclusion criteria: reported CRL at 73 – 80 days and twins conceived None specified Twins = 0.42 ± 0.11 P = 0.57 after in vitro Operator number/experience Singletons = 0.40 ± 0.11 fertilisation (IVF) Other details: A single operator performed all CRL at 80 – 87 days Gestational age determined scans Twins = 0.25 ± 0.06 P = 0.11 by adding 14 days to the Singletons = 0.28 ± 0.06 number of days between CRL at 87 – 94 days oocyte retrieval and date of Twins = 0.19 ± 0.05 P = 0.06 the ultrasound scan Singletons = 0.19 ± 0.04 No details of maternal CRL at 94 – 101 days Study details Participants Investigation Outcome measures and results Comments

ethnicity or chorionicity of Twins = 0.13 ± 0.05 P = 0.31 twins reported Singletons = 0.15 ± 0.05 All data reported as mean ± SD First author, year: Population: Investigation: Comparison of difference in actual and Funding: Gardosi 199730 N = 86 fetuses Common regression line estimated BPD (from regression line) in twins No details reported Fetuses were from 63 derived for 85 datapoints for and singletons Country: pregnancies resulting from biparietal diameter (BPD) (39 in Twins: N = 46 Limitations: UK ART, comprising 40 singletons, 46 in twins) Mean residual = 0.12 mm Main bias will arise because singletons and 46 twins between 111 and 173 days‟ SD = 2.07 mm this is a retrospective study Study design: , and residuals Singletons: N = 39 analysing data from a database Retrospective Inclusion criteria: calculated for singletons and Mean residual = 0.14 mm Also, as data were obtained (regression analysis) Pregnancy achieved by ART twins SD = 2.21 mm from 25 different hospitals, bias in 1994 and 1995 in the Difference between means = 0.26 mm may arise in measurements Study dates: Nottingham University Methods described Standard Error = 0.46 mm from different operators of Database of Research and Treatment adequately? P = 0.57 differing experience using consecutive singleton Unit in Reproduction, mid- Yes 95% CI -0.66 to 1.18 different equipment and twin pregnancies trimester ultrasound results Ultrasound biometry was Sample size may also be an resulting from assisted from all 25 booking hospitals, conducted as part of routine issue reproduction written maternal consent to mid-trimester scans in 25 techniques (ART) in analyse data different hospitals by 1994 and 1995 was ultrasonographers who were studied Exclusion criteria: unaware of conception dates Pregnancies with missing In pregnancies where more Aim of study: data than one second trimester scan To investigate the size had been performed, the of singleton versus Other details: measurements at the time of twin pregnancies at Gestational age calculated the detailed structural scan the time of a second by adding 14 days to the were taken for analysis trimester dating scan conceptual age at scan Details of charts used not which was the interval reported between the day of fertilisation (or frozen embryo replacement) and the day of the ultrasound scan No details of maternal Study details Participants Investigation Outcome measures and results Comments

ethnicity or chorionicity of twins reported First author, year: Population: Investigation : Differences in dating of twins and triplets Funding: Chervenak 199835 N = 238 women Stepwise multiple regression Mean difference in dating of twins versus No details reported 152 singleton, 67 twin and 19 used to derive a dating formula singletons Country: triplet in singleton pregnancies using i) using the prediction formula and applying the Limitations: USA BPD, femur length, head maximum of each biometric parameter in the Main limitation is that it is a Inclusion criteria: circumference and abdominal formula = 0.8 days cross-sectional study Study design: IVF conception, initial circumference* ii) using the prediction formula and applying Bias may also arise from Retrospective second-trimester ultrasound Formula was compared with 38 the minimum of each biometric parameter in different operators with differing (regression analysis) (US) scan performed 14-22 previously published formulae, the formula = −1.3 days experience and different weeks‟ gestation based on and then applied to twin and iii) using the prediction formula and applying equipment Study dates: menstrual age (day of egg triplet populations the average of maximum and minimum of Singletons: retrieval and fertilisation plus Methods described each biometric parameter in the formula = Study does not use January 1993 - 14 days) adequately? −0.3 days conventional ultrasound June 1996 For singletons, delivery at > Yes Mean difference in dating of triplets versus formulae to assess gestational Twins and triplets: 37 weeks, birthweight >2500 Ultrasound biometry conducted singletons age when comparing singleton July 1990 - December g with no congenital in a single ultrasound unit as i) using the prediction formula and applying the and multiple pregnancies 1994 abnormalities part of routine mid-trimester maximum of each biometric parameter in the For multiple pregnancies, examination (14-22 weeks) formula = 0.8 days Aim of study: delivery at > 24 weeks, alive Equipment details reported ii) using the prediction formula and applying To analyse accuracy at birth with no congenital Details of charts not reported the minimum of each biometric parameter in of fetal biometry abnormalities Operator number/experience: the formula = −3.4 days (biparietal diameter All scans were performed by iii) using the prediction formula and applying [BPD], head Exclusion criteria: one of five sonographers the average of maximum and minimum of circumference, Not reported (under supervision of a each biometric parameter in the formula = abdominal sonologist) −1.3 days circumference and Other details: *Best fitting model for estimated femur length) at 14-22 No details of maternal gestational age = [51.68 + weeks for prediction of ethnicity or chorionicity of 2.324* head circumference + gestational age in twins/triplets reported 2.092 * abdominal singleton, twin, and circumference + 5.18 * femur triplet pregnancies length] resulting from in vitro fertilisation (IVF) Study details Participants Investigation Outcome measures and results Comments

First author, year: Population: Investigation: Difference in dating of twins versus singletons Funding: Wennerholm 199836 N = 337 pregnancies Gestational age calculated from - gestational age (GA) calculated using Study supported by Göteborg 253 singleton pregnancies formula* based on BPD in formula based on biparietal diameter Medical Society and the Country: and 84 twin pregnancies twins measurements Swedish Medical Research Sweden (168 twins) Twins: Mean GA = 116.8 days Council Comparison: SD = 6.1 days Study design: Inclusion criteria: Gestational age calculated from Singletons: Mean GA = 118.9 days Limitations: Retrospective cohort Women with IVF singleton formula* based on BPD in SD = 9.0 days Main limitation is the study (reviewing and twin pregnancies who singletons Difference between means stated by the retrospective nature of the delivery records) received antenatal care and authors to be not statistically significant; no p- study were delivered at Methods described values or confidence intervals reported Bias may also arise from Study dates: Sahlgrenska University adequately? different operators with differing January 1990 - Hospital between 1990 and Yes Difference in dating of twins versus singletons experience and different December 1996 1996 US measurements performed - gestational age (GA) calculated using day of equipment All women had at least one using modern, commercially oocyte retrieval Aim of study: first-trimester US scan available real-time scanners Twins: Mean GA = 120.9 days To compare the For each parameter, the SD = 8.6 days gestational age Exclusion criteria: average of three Singletons: Mean GA = 118.2 days calculated from day of Women with fetuses with measurements was used SD = 5.3 days oocyte retrieval to that congenital malformations, Details of charts not reported Difference between means stated by the from ultrasound (US) unobtainable femur length, authors to be not statistically significant; no p- measurements presence of more than one Operator number/experience: values or confidence intervals reported (biparietal diameter at first US measurements performed [BPD with or without trimester scan by specially trained femur length) in the second trimester of Other details: * Gestational age (days) = [BPD pregnancies resulting Gestational age was × 2.10 + 39.1 ] from in vitro calculated from the day of fertilisation (IVF) oocyte retrieval and converted into menstrual age by adding 14 days All participants were healthy Swedish women; no details of chorionicity reported for twin pregnancies Study details Participants Investigation Outcome measures and results Comments

First author, year: Population: Investigation: Mean difference between actual gestational Funding: Dias 201033 N = 376 pregnancies Mean differences between age and estimated gestational age There was no funding for the 266 singleton pregnancies actual gestational ages and using Robinson‟s formula study Country: and 110 twin pregnancies gestational ages estimated Singleton: 1.41 (1.15 to 1.68) days UK Inclusion criteria: from CRL measurements were Bigger twin: 2.4 (2.4 to 2.6) days Limitations: Dichorionic twin and derived for singletons and Smaller twin: 0.91 (0.55 to 1.30) days Main limitation is the Study design: singleton pregnancies twins. Three different CRL- using Rossavik‟s formula retrospective nature of the Retrospective cohort resulting from IVF or based dating formulae* were Singleton: 0.14 (0.01 to 0.28) days study study intracytoplasmic sperm used to estimate gestational Bigger twin: 1.27 (1.05 to 1.5) days A further limitation may be the injection (ICSI), seen for age Smaller twin: -0.51 (-0.30 to -0.72)days fact that the ultrasonographers Study dates: routine obstetric care Methods described using Von Kaisenberg‟s formula had prior knowledge of the June 1997 - October between June 1997 and adequately? Singleton: -0.54 (-0.41 to -0.67) days dates of conception 2009 October 2009; only scans Yes Bigger twin: 0.58 (0.36 to 0.8) days done between 11 and 14 A single CRL measurement Smaller twin: -1.18 (-0.97 to -1.4) days Aim of study: weeks of pregnancy were was taken with the fetus in a Mean difference between actual CRL To assess the included neutral . For each measurement and CRL estimated from date of performance of Exclusion criteria: foetus, the gestational age conception (i.e. from IVF history) validated singleton Monochorionic twin calculated from the date of using Robinson‟s formula crown-rump length pregnancies conception was compared with Singleton: 2.72 (2.49 to 2.95) mm (CRL) formulae in Other details: the estimated gestational age Bigger twin: 4.7 (4.4 to 5.1) mm dating twin Gestational age was from foetal size (CRL) using Smaller twin: 1.77 (1.4 to 2.1) mm pregnancies at 11-14 calculated by using the three different formulae using Rossavik‟s formula weeks of pregnancy embryo transfer date as a Operator number/experience: Singleton: 0.24 (1.8 to 2.5) mm proxy for the date of Scans were only carried out by Bigger twin: 2.1 (0.01 to 0.46) mm conception. sonographers who were Smaller twin: −0.86 (−0.5 to −1.2) mm IVF/ICSI singleton certified for first-trimester using Von Kaisenberg‟s formula pregnancies were used for ultrasound assessment Singleton: −0.91 (−0.7 to −1.13) mm comparison to control for any * 1. Robinson: GA = 8.052 * Bigger twin: 0.98 (0.6 to 1.35) mm variation in dating between √(CRL * 1.037) + 23.73 Smaller twin: −2.0 (−1.6 to −2.4) mm and/or early fetal growth that 2. Rossavik: GA = 49.5 + 0.6 * might occur in pregnancies CRL achieved by ART 3. Von Kaisenberg: GA = 49.1115 + 0.5954 * CRL First author, year: Population: Investigation: Difference in mean biometry z-scores Funding: Dias 201034 N = 376 pregnancies Observed fetal biometry for Not reported Study details Participants Investigation Outcome measures and results Comments

269 singleton pregnancies different head circumference, Head circumference formulae: Country: and 119 twin pregnancies femur length and TCD were Singleton vs. bigger twin p=0.01 Limitations: UK Inclusion criteria: compared with expected fetal Singleton vs. smaller twin p< 0.005 Potential overlap with other Non-anomalous dichorionic size for gestational age Singleton vs. average twin size p=1 Dias 2010 study33 Study design: twins and singletons with a Main limitation is the Retrospective case second trimester ultrasound Mean differences between Femur length formulae: retrospective nature of the control study between 16 and 26 weeks. actual gestational ages and Singleton vs. bigger twin p=0.7 study Pregnancies conceived by gestational ages estimated Singleton vs. smaller twin p<0.005 Study dates: IVF or intracytoplasmic from measurements were Singleton vs. average twin size p=1 June 1999 – March sperm injection. Women derived for singletons and 2010 seen in routine obstetric twins. Three different setting between June 1999 measurement formulae for Aim of study: and March 2010 head circumference and femur To determine whether Exclusion criteria: length were used to estimate singleton head Monochorionic twin gestational age (Chitty et al, circumference pregnancies (n= 8) Verburg et al, Salomon et al) formulae can be used Other details: Operator number/experience: to accurately date twin Expected age was calculated Scans were only carried out by pregnancy by using the embryo transfer trained sonographers date as a proxy for the date of conception (day 14) Expected age was calculated by using the embryo transfer Mean gestational age at date as a proxy for the date of inclusion: conception (day 14) Singletons: 21.7 ±1.1 weeks Twins: 21.4 ±1.2 weeks P=0.56