Abstract
Objectives:
To investigate childhood growth patterns in twins and to determine whether they show the same signs of excess growth as singletons born small-for-gestational age (SGA), which may confer future cardiometabolic risk.
Study Design:
In the Upstate KIDS cohort of infants delivered from 2008 through 2010, we compared height, weight, and BMI z-scores at 0–3 and 7–9 years of age, as well as risk of rapid weight gain in infancy and overweight/obesity beginning at 2 years, among appropriate-for-gestational age (AGA) twins (n=1121), AGA singletons (n=2684), and two groups of SGA twins: uncertain SGA twins (<10th percentile for birthweight by a singleton reference but >10th% by a population-based twin birthweight reference; n=319) and true SGA twins (<10th% by a population-based twin reference; n=144).
Results:
Compared with AGA twins, both SGA twin groups had lower weight and BMI z-scores at both time points. By 7–9 years, both groups caught up in height with AGA twins. Compared with AGA singletons, z-score differences decreased between 0–3 and 7–9 years for uncertain SGA and true SGA twins, though true SGA twins had the lowest z-scores for all measures. During infancy, twins were more likely to display rapid weight gain compared with AGA singletons (RR=2.06 to 2.67), which may reflect normal catch-up growth, as no twin group had higher prevalence of overweight/obesity at either time point.
Conclusions:
Though twins had lower height, weight, and BMI z-scores at birth and into toddlerhood, differences were reduced by 7–9 years, with no evidence of pathological growth and no group of twins showing elevated risk of overweight/obesity.
Twins are typically smaller than singletons at birth, but whether their smaller size is a result of pathologic growth restriction or normal adaptive processes is an open question. An emerging paradigm in twin research suggests that although twins are naturally growth restricted, on average, their smaller size at birth may not be the result of the same pathological conditions that lead to growth restriction in singletons, such as nutrient deficiency or other dysfunction of the utero-placental unit.1, 2 Among the compelling evidence that twin size may be the result of early fetal growth programming are fetal reduction studies, where the growth trajectory for the remaining fetus in a twin pregnancy is more similar to the growth trajectory of twins than singletons, even when reduction occurs early in pregnancy and spontaneously.2 In clinical practice, singleton birthweight centiles are typically used to classify twins, with as many as 50% classified as small-for-gestational age (SGA), defined as a birthweight less than the 10th percentile.1, 3 This high classification and the potential for differing fetal growth patterns have led to calls for the use of twin-specific instead of singleton fetal growth references to avoid over-diagnosing fetal growth restriction (FGR) in twins.1
In singletons, being SGA at birth is associated with several adult morbidities, including higher risk of overweight/obesity and cardiometabolic dysfunction,4 which may result from alterations in hypothalamic-pituitary-adrenal and glucose-insulin axes development. Manifestations of these alterations may include rapid weight gain (RWG) in infancy and increased risk of child overweight/obesity among SGA singletons.5, 6 Whether these same increased risks are conferred to SGA twins is generally unknown, as few twin studies have adequate follow-up to track adult obesity or lack singleton comparison groups.7, 8 Few studies track twin growth through childhood to compare to singletons, most occurring prior to implementation of World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) child growth charts which makes it difficult to translate results across studies or to a contemporary cohort.9–15 Even so, both the WHO and CDC growth charts were developed using singletons, and a twin growth chart may be more appropriate to track normal twin growth.12, 14 To our knowledge, no studies have compared SGA twins to either appropriate-for-gestational age (AGA) or SGA singletons. Thus, it is unclear how SGA twin growth patterns compare to singletons. Our objective in this study was to determine whether a twin reference may be more appropriate than a singleton reference for classifying SGA in twins by comparing child growth among SGA twins using singleton and twin-specific birthweight references to growth of AGA twins and singletons and SGA singletons through middle childhood.
Methods
The Upstate KIDS cohort included infants delivered between 2008–2010 in New York State (excluding New York City). The study was designed to evaluate developmental outcomes after infertility treatment. Vital records were used to recruit all multiples, infants conceived via infertility treatment, and spontaneously-conceived singletons at a 3:1 ratio to the infertility treatment group based on region of birth. The full cohort included 6,171 children and their mothers and follow-up continued until 2019. For this secondary analysis, we included twins and singletons (n=6,037) based on the following criteria (Figure 1; online): available birthweight and at least one weight measure after 4 months (n=723 excluded) and delivery at 34 gestational weeks or greater (n=326 excluded) to match cohort selection in our previous work.16 We excluded infants considered large-for-gestational age >90th percentile of birthweight (LGA; n=460), as etiology of growth pathology may be different from SGA. The New York State Department of Health and the University of Albany Institutional Review Board (IRB) approved the study and served as the IRB designated by the National Institutes of Health under a reliance agreement. All participants provided written informed consent.
Figure 1.
Diagram of sample selection and availability of follow-up measures.
Sample numbers represent those with available height or weight data.
a Sample numbers in these boxes represent those with both height and weight available to calculate BMI to determine overweight/obesity status, which is not identified until at least 2 years of age.
Child Growth Measures
On questionnaires sent at 4, 8, 12, 18, 24, 30, and 36 months, parents were asked to report their child’s length/height and weight at any doctor’s visits, including the date of the doctor’s visit. Parents were asked to report child height and weight from doctor’s visits in follow-up questionnaires sent at approximately 7, 8, and 9 years. When multiple weight or height measures were reported for the same month of age between 4–36 months, these values were averaged. We calculated BMI as kg/m2. We calculated age- and sex-standardized weight, height, and BMI z-scores using the WHO reference for measurements from 0–23 months and the CDC reference for measurements taken at 24 months or later.17, 18 Other measures of child growth were assessed using markers typically associated with pathology: RWG and risk of overweight/obesity. RWG was defined as an increase in weight z-score >0.67 at any point between birth and 12 months.6 Overweight/obesity was defined using age and sex-specific cut-points from the International Obesity Task force for children with BMI information at age 2 years or older.19
Defining Size for Gestational Age
Birthweight and gestational age at delivery were extracted from vital records. Birthweight for gestational age was based on a population reference developed by Duryea et al. close to the study years of 2008–2010.20 Because the Duryea reference only included birthweight percentiles for singletons, we replicated their methods to calculate twin-specific birthweight percentiles.16 Using these sex- and singleton/twin- specific birthweight references, we classified three groups of twins and two groups of singletons (Figure 2). “Uncertain” SGA twins included twins who would be classified as SGA (<10th percentile for gestational age by sex) by a singleton reference, but not by a twin reference. “True” SGA twins included twins who would be classified as SGA by a twin reference. Appropriately-grown (AGA) twins would not be classified as SGA by a singleton or twin reference (i.e., 10th–90th percentile of singleton birthweight). Singletons were classified as SGA (<10th percentile according to a singleton reference) or AGA (10th–90th percentile of singleton birthweight).
Figure 2.
Schematic detailing small-for-gestational age (SGA) and appropriate-for-gestational age (AGA) definitions with number included in each group.
SGA was defined in the Upstate KIDS Study cohort, 2008–2010 using the published Duryea reference for singletons and a calculated twin reference using methods from Duryea et al.20 “Uncertain” twins are those who weigh less than the 10th percentile based on a singleton reference, but greater than or equal to the 10th percentile based on a twin reference. AGA was defined as birthweight between the 10th and 90th percentile for birthweight for singletons.
Covariates
Maternal information was obtained from self-report, vital records, and ICD-9 codes from hospital discharge. We considered as covariates maternal age, pre-pregnancy BMI, race (as a proxy for unmeasured socioeconomic or other societal factors), education, insurance type, marital status, parity, alcohol use or smoking during pregnancy, infertility treatment, gestational diabetes (GDM), gestational hypertension, and preeclampsia. These covariates were selected based on their associations with both birthweight and potential child growth. We dichotomized race into White vs. non-White due to the racial/ethnic makeup of the cohort, which was predominantly White. Further identification of race/ethnic categories did not allow for consistent model convergence, due to small sizes in some twin groups, particularly in later years. Thus, these were not incorporated into our analysis.
Analysis
We used 2011 birth data from the National Vital Statistics System to calculate win-specific birthweight percentiles similar to the singleton-specific percentiles as previously published.20 We compared baseline characteristics between SGA groups in twins and singletons, using ANOVA/t-tests and chi-squared tests for continuous and categorical variables, respectively. Longitudinal growth was assessed in separate models at 0–3 years and 7–9 years using linear mixed models with random coefficient cubic splines for age and age-gender interactions to estimate mean differences in weight, length, and BMI z-scores with 95% confidence intervals (CI). All models included a child-level random intercept to account for repeated measurements within each time period, and twin models included a maternal random intercept to account for correlation between twins with a nested child-level random intercept. Using Poisson regression with a robust error variance, we calculated adjusted risk ratio (aRR) of RWG in those 0–12 months and overweight/obesity in those 2 years or older with corresponding 95% CI. We adjusted models for all covariates except GDM and hypertensive disorders of pregnancy, as they were not strongly associated with SGA status. Analyses were conducted to compare twin groups to each other and to singletons using dummy variables for each group of SGA compared with a reference group. For example, we compared each of the three twin groups to an AGA singleton reference group and compared uncertain and true SGA twins to an AGA twin reference group. We also compared SGA singletons to AGA singletons, and all three twin groups to SGA singletons. All analyses were conducted in SAS v9.4 (SAS Institute, Inc.).
Results
The sample we studied included 1,584 twins and 2,944 singletons with birthweight and at least one other measure of weight in childhood. Availability of growth measures at each time is described in Figure 1 (online). Among twins, 1,121 (70.8%) were appropriate-for-gestational age (AGA), 319 (20.1%) were SGA according to a singleton reference, but not a twin reference (uncertain SGA), and 144 (9.1%) were SGA by a twin reference (true SGA). Among singletons, 2,684 were AGA, and 260 were SGA (8.8%). Demographic characteristics by SGA groups are presented for twins (Table 1) and singletons (Table 2; online). There were no differences by SGA group for GDM, hypertensive disorders, or use of infertility treatment for the index pregnancy. Pre-pregnancy BMI was similar across all twin and singleton groups.
Table 1.
Descriptive characteristics of analytic sample of twins by small-for-gestational age (SGA) category, Upstate KIDS study, 2008–2010 (n=1,584)
| All Twins | AGA Twins (n=1,121) | Uncertain SGA Twins a (n=319) | True SGA Twins (n=144) | |
|---|---|---|---|---|
| Maternal age, mean (SD) b | 31.9 (5.7) | 31.8 (5.7) | 32.5 (5.7) | 31.0 (6.0) |
| Prepregnancy BMI, mean (SD) b | 27.2 (6.7) | 27.5 (6.8) | 26.8 (6.3) | 26.0 (6.5) |
| Gestational weeks at delivery, mean (SD) b | 36.7 (1.4) | 36.5 (1.5) | 37.2 (1.2) | 36.4 (1.3) |
| Race, n (%) | ||||
| Non-Hispanic White | 1311 (82.8) | 930 (83.0) | 270 (84.6) | 111 (77.1) |
| Other race/ethnicity b | 273 (17.2) | 191 (17.0) | 49 (15.4) | 33 (22.9) |
| Education, n (%) | ||||
| <High School | 65 (4.1) | 45 (4.0) | 14 (4.4) | 6 (4.2) |
| High School or equivalent | 143 (9.0) | 100 (8.9) | 23 (7.2) | 20 (13.9) |
| Some college/Associates degree | 423 (26.7) | 304 (27.1) | 79 (24.8) | 40 (27.8) |
| Bachelor’s degree | 406 (25.6) | 288 (25.7) | 86 (27.0) | 32 (22.2) |
| Advanced degree | 547 (34.5) | 384 (34.3) | 117 (36.7) | 46 (31.9) |
| Insurance Type (Private), n (%) | 1288 (81.4) | 918 (82.0) | 260 (81.5) | 110 (76.4) |
| Marital Status (Married), n (%) b | 1381 (91.8) | 991 (92.5) | 275 (91.7) | 115 (85.8) |
| Parity (Parous), n (%) b | 875 (55.7) | 646 (58.0) | 167 (52.9) | 62 (43.4) |
| Alcohol use in pregnancy, n (%) | 169 (10.7) | 116 (10.4) | 41 (12.9) | 12 (8.3) |
| Smoking in pregnancy, n (%) b | ||||
| Never smoked | 1028 (64.9) | 739 (65.9) | 203 (63.6) | 86 (59.7) |
| Smoked prior to pregnancy | 394 (24.9) | 279 (24.9) | 86 (27.0) | 29 (20.1) |
| Smoked during pregnancy | 162 (10.2) | 103 (9.2) | 30 (9.4) | 29 (20.1) |
| Gestational Diabetes, n (%) | 163 (10.3) | 114 (10.2) | 36 (11.3) | 13 (9.03) |
| Gestational Hypertension, n (%) | 235 (14.8) | 176 (15.7) | 40 (12.5) | 19 (13.2) |
| Preeclampsia, n (%) | 324 (20.5) | 237 (21.1) | 55 (17.2) | 32 (22.2) |
| Any infertility treatment, n (%) | 677 (42.7) | 467 (41.7) | 152 (47.7) | 58 (40.3) |
AGA=appropriate-for-gestational age; BMI=body mass index; SGA=small-for-gestational age
Uncertain SGA twins category excludes twins who would be considered SGA using a twin-specific reference
Indicates statistically significant differences (P-value <0.05) between twin categories
Other race/ethnicity includes Black, Hispanic, Asian, and mixed race. Groups combined to facilitate model convergence.
Table 2.
Descriptive characteristics of analytic sample of singletons by small-for-gestational age (SGA) category, Upstate KIDS study, 2008–2010 (n=2,944)
| All | AGA Singletons (n=2,684) | SGA Singletons (n=260) | |
|---|---|---|---|
| Maternal age, mean (SD) a | 30.4 (6.0) | 30.5 (6.0) | 28.8 (6.1) |
| Prepregnancy BMI, mean (SD) | 26.6 (6.6) | 26.6 (6.5) | 26.6 (7.3) |
| Gestational weeks at delivery, mean (SD) | 38.9 (1.4) | 38.9 (1.4) | 38.9 (1.4) |
| Race, n (%) a | |||
| White | 2402 (81.6) | 2202 (82.0) | 200 (76.9) |
| Non-White b | 542 (18.4) | 482 (18.0) | 60 (23.1) |
| Education, n (%) a | |||
| <HS | 142 (4.8) | 121 (4.5) | 21 (8.1) |
| HS/GED | 359 (12.2) | 306 (20.4) | 53 (20.4) |
| Some college/AA | 915 (31.1) | 835 (31.1) | 80 (30.8) |
| Bachelors degree | 646 (21.9) | 595 (22.2) | 51 (19.6) |
| Advanced degree | 882 (30.0) | 827 (30.8) | 55 (21.2) |
| Insurance Type (Private), n (%) a | 2231 (75.8) | 2057 (76.7) | 174 (66.9) |
| Marital Status (Married), n (%) a | 2537 (88.8) | 2322 (89.2) | 215 (84.3) |
| Parity (Parous), n (%) a | 1496 (51.2) | 1389 (52.1) | 107 (41.8) |
| Alcohol use in pregnancy, n (%) | 386 (13.1) | 356 (13.3) | 30 (11.5) |
| Smoking in pregnancy, n (%) a | |||
| Never smoked | 1867 (63.4) | 1724 (64.2) | 143 (55.0) |
| Smoked prior to pregnancy | 671 (22.8) | 615 (22.9) | 56 (21.5) |
| Smoked during pregnancy | 406 (13.8) | 345 (12.9) | 61 (23.5) |
| GDM, n (%) | 254 (8.6) | 238 (8.9) | 16 (6.2) |
| Gestational Hypertension, n (%) | 271 (9.2) | 243 (9.1) | 28 (10.8) |
| Preeclampsia, n (%) | 195 (6.6) | 173 (6.5) | 22 (8.5) |
| Any infertility treatment, n (%) | 813 (27.6) | 745 (27.8) | 68 (26.2) |
AA=Associate’s degree; AGA=appropriate-for-gestational age; BMI=body mass index; SGA=small-for-gestational age
Indicates statistically significant differences (P-value <0.05) between singleton categories
Non-White includes Black, Hispanic, Asian, and mixed race
Comparing SGA Twins with AGA Twins
At 0–3-years, uncertain SGA twins had lower z-scores than AGA twins (Figure 3, Table 3, online) for weight (−0.63; 95% CI −0.68, −0.58), height (−0.58 95% CI −0.65, −0.51), and BMI (−0.49; 95% CI −0.56, −0.43). True SGA twins had even lower z-scores than uncertain SGA twins with almost double the mean difference for weight (−1.31; 95% CI −1.38, −1.24), height (−1.19; 95% CI −1.30, −1.08), and BMI (−0.86; 95% CI −0.96, −0.77). By 7–9-years, uncertain SGA twins had almost completely caught up with AGA twins for height z-scores (−0.15; 95% CI −0.47, 0.17), but maintained slightly lower weight (−0.29; 95% CI −0.57, −0.02) and BMI (−0.30; 95% CI −0.62, 0.01) z-scores. True SGA twins had lower z-scores for weight and BMI (Figure 3; Table 3, online) than AGA twins, and slightly lower height z-scores (−0.18; 95% CI −0.77, 0.40) that did not reach statistical significance.
Figure 3.
Differences in weight, height and BMI z-scores at 2–3 years and 7–9 years, SGA, SGA twins, true SGA twins, and SGA singletons to AGA twins and singletons.
Small-for-gestational age (SGA) was defined in the Upstate KIDS Study cohort, 2008–2010 using the published Duryea reference for singletons and a calculated twin reference using methods from Duryea et al. “Uncertain” twins are those who weigh less than the 10th percentile based on a singleton reference, but greater than or equal to the 10th percentile based on a twin reference. AGA was defined as birthweight between the 10th and 90th percentile for birthweight for singletons.
Table 3.
Mean difference in child z-scores across twin and singleton SGA categories at 0–3 years and 7–9 years using appropriate-for-gestational age twin and singleton references
| AGA twins | Uncertain SGA twins | True SGA twins | AGA singletons | AGA twins | Uncertain SGA twins | True SGA twins | SGA Singletons | |
|---|---|---|---|---|---|---|---|---|
| 0–3 years | n=1121 | n=319 | n=144 | n=2684 | n=1121 | n=319 | n=144 | n=260 |
| Weight Z | [Reference] | −0.63 (−0.68, −0.58) | −1.31 (−1.38, −1.24) | [Reference] | −0.55 (−0.58, −0.52) | −1.17 (−1.22, −1.12) | −1.88 (−1.95, −1.81) | −1.11 (−1.16, −1.06) |
| Height Z | [Reference] | −0.58 (−0.65, −0.51) | −1.19 (−1.30, −1.08) | [Reference] | −0.76 (−0.80, −0.72) | −1.32 (−1.39, −1.25) | −1.94 (−2.05, −1.84) | −1.04 (−1.11, −0.96) |
| BMI Z | [Reference] | −0.49 (−0.56, −0.43) | −0.86 (−0.96, −0.77) | [Reference] | −0.22 (−0.25, −0.18) | −0.72 (−0.78, −0.66) | −1.06 (−1.15, −0.96) | −0.75 (−0.82, −0.68) |
| 7–9 years | n=266 | n=98 | n=22 | n=870 | n=266 | n=98 | n=22 | n=81 |
| Weight Z | [Reference] | −0.29 (−0.57, −0.02) | −0.53 (−1.03, −0.04) | [Reference] | −0.11 (−0.28, 0.06) | −0.41 (−0.67, −0.15) | −0.63 (−1.13, −0.13) | −0.67 (−0.94, −0.41) |
| Height Z | [Reference] | −0.15 (−0.47, 0.17) | −0.18 (−0.77, 0.40) | [Reference] | −0.12 (−0.31, 0.07) | −0.34 (−0.64, −0.05) | −0.41 (−0.99, 0.17) | −0.56 (−0.87, −0.26) |
| BMI Z | [Reference] | −0.30 (−0.62, 0.01) | −0.57 (−1.15, 0.01) | [Reference] | −0.04 (−0.24, 0.16) | −0.32 (−0.63, −0.02) | −0.55 (−1.16, 0.05) | −0.48 (−0.80, −0.16) |
AGA=appropriate-for-gestational age; SGA=small-for-gestational age
Comparing AGA and SGA Twins with AGA Singletons
All groups of twins, including AGA twins, were lower than AGA singletons at 0–3 years, with increasingly lower weight, height, and BMI z-scores across twin size categories (Figure 3; Table 3, online). For example, when comparing to the height of AGA singletons, AGA twins were shorter by −0.76 (−0.80, −0.72) z-scores, while the difference in z-scores was −1.32 (−1.39, −1.25) for uncertain SGA twins and −1.94 (−2.05, −1.84) for true SGA twins. By 7–9 years, AGA twins had weight, height, and BMI z-scores that were no different from AGA singletons. SGA twin groups remained smaller, but the difference in z-scores was not as great as at 0–3 years. For example, when examining height, compared to AGA singletons, the difference in z-score for uncertain SGA twins reduced from −1.32 (−1.39, −1.25) at 0–3 years to −0.34 (−0.64, −0.05) at 7–9 years, which equates to a change in height deficit from −2.9 cm to −1.8 cm. This change in z-scores would also equate to a child moving from the 9th to the 37th percentile for weight.
Rapid Weight Gain and Risk of Overweight/Obesity
Compared to AGA twins, uncertain SGA twins had slightly elevated risk of rapid weight gain (Table 4) in the first 12 months (aRR=1.15; 95% CI 1.04, 1.28), as did true SGA twins (aRR=1.30; 95% CI 1.14, 1.49), which may reflect catch-up growth. Compared to AGA singletons, all twin groups had higher risk of RWG, with risk increasing from 2.07 (1.88, 2.28) for AGA twins up to 2.67 (2.32, 3.07) for true SGA twins. In either comparison, this rapid weight gain in the first year of life did not translate to increased risk of later childhood overweight/obesity. In fact, SGA twin groups had slightly lower risk of overweight/obesity than AGA twins at 2–3 and 7–9 years, though estimates were not statistically significant.
Table 4.
Adjusted risk ratio and 95% confidence intervals of rapid weight gain and overweight/obesity using appropriate-for-gestational age twin and singleton references
| AGA twins | Uncertain SGA twins | True SGA twins | AGA Singletons | AGA twins | Uncertain SGA twins | True SGA twins | SGA Singletons | |
|---|---|---|---|---|---|---|---|---|
| Excess weight gain, 0–12 months | ||||||||
| Cases/total (%) | 586/1121 (52.3) | 194/319 (60.8) | 96/144 (66.7) | 664/2684 (24.7) | 586/1121 (52.3) | 194/319 (60.8) | 96/144 (66.7) | 109/260 (41.9) |
| RR (95% CI) | [Reference] | 1.15 (1.04, 1.28) | 1.30 (1.14, 1.49) | [Reference] | 2.07 (1.88, 2.28) | 2.36 (2.1, 2.65) | 2.67 (2.32, 3.07) | 1.76 (1.5, 2.07) |
| Overweight/Obesity at 2–3 years | ||||||||
| Cases/total (%) | 99/402 (24.6) | 18/122 (14.8) | 7/40 (17.5) | 245/1042 (23.5) | 99/402 (24.6) | 18/122 (14.8) | 7/40 (17.5) | 9/81 (11.1) |
| RR (95% CI) | [Reference] | 0.75 (0.46, 1.22) | 0.72 (0.36, 1.47) | [Reference] | 1.04 (0.84, 1.3) | 0.77 (0.48, 1.24) | 0.65 (0.32, 1.32) | 0.39 (0.21, 0.73) |
| Overweight/Obesity at 7–9 years | ||||||||
| Cases/total (%) | 63/240 (26.3) | 16/88 (18.2) | 5/22 (22.7) | 212/814 (26.0) | 53/206 (25.7) | 15/76 (19.7) | 4/18 (22.2) | 22/73 (30.1) |
| RR (95% CI) | [Reference] | 0.93 (0.58, 1.47) | 0.85 (0.52, 1.38) | [Reference] | 0.92 (0.7, 1.21) | 0.90 (0.56, 1.46) | 0.78 (0.38, 1.62) | 0.71 (0.45, 1.1) |
AGA = Appropriate-for-gestational age, SGA=small-for-gestational age
Comparing SGA Singletons with Twin groups
Compared with AGA singletons, SGA singletons had lower weight, height, and BMI scores that were similar in magnitude to uncertain SGA twins at 0–3 years (Figure 3; Table 5; online). By 7–9 years, differences in z-scores for SGA singletons were more similar in magnitude to estimates for true SGA twins. When comparing twin groups directly to SGA singletons, AGA twins had higher weight, height, and BMI z-scores at both 0–3 and 7–9 years (Table 5; online). By 7–9 years, uncertain SGA twins had slightly higher z-scores than SGA singletons, though differences were not significant, while z-scores for SGA singletons and true SGA twins were similar.
Table 5.
Mean difference in child z-scores comparing twin SGA categories at 0–3 years and 7–9 years to SGA singletons
| SGA Singletons | AGA twins | Uncertain SGA twins | True SGA twins | |
|---|---|---|---|---|
| 0–3 years | ||||
| Weight Z | [Reference] | 0.57 (0.52, 0.63) | −0.05 (−0.12, 0.02) | −0.74 (−0.83, −0.66) |
| Height Z | [Reference] | 0.25 (0.17, 0.33) | −0.33 (−0.42, −0.23) | −0.93 (−1.06, −0.81) |
| BMI Z | [Reference] | 0.56 (0.49, 0.63) | 0.07 (−0.02, 0.16) | −0.30 (−0.42, −0.19) |
| 7–9 years | ||||
| Weight Z | [Reference] | 0.64 (0.35, 0.93) | 0.30 (−0.04, 0.65) | 0.08 (−0.46, 0.65) |
| Height Z | [Reference] | 0.43 (0.07, 0.78) | 0.25 (−0.17, 0.67) | 0.19 (−0.46, 0.84) |
| BMI Z | [Reference] | 0.49 (0.14, 0.84) | 0.14 (−0.27, 0.56) | −0.11 (−0.76, 0.54) |
AGA = Appropriate-for-gestational age, SGA=small-for-gestational age
Discussion
In this study of twins and singletons with longitudinal growth measures, we found that twins who were appropriately grown at birth were slightly shorter, weighed less, and had lower BMI than singletons that were appropriately grown at birth in early childhood (0–3 years). By middle childhood (7–9 years), the appropriately-grown twins all generally reached the same height, weight, and BMI as singletons. True SGA twins, who were classified as SGA according to a twin reference, remained smaller than AGA twins in weight and BMI, and smaller than AGA singletons in weight, height, and BMI by 7–9 years, with z-scores similar to SGA singletons. Uncertain SGA twins generally caught up with AGA twins by 7–9 years on height and BMI, but remained smaller on weight. They also remained smaller than AGA singletons at 7–9 years, though not as small as true SGA twins. All groups of twins had higher likelihood of rapid weight gain in the first 12 months than AGA singletons, but no increased risk of obesity at ages 2–3 or 7–9 years.
Our results are consistent with prior work among twins not separated by SGA status, finding that twins remain marginally smaller than singletons in height and weight in early childhood,11 but differences decrease as children age and most twins catch up with singletons by later childhood.9, 12, 14, 15 In contrast, one small study (n=191) that followed Japanese children into adulthood found that twins remained 2.6 cm shorter (and approximately −0.41 standard deviations [SD] at age 9) than singletons in adulthood, which the authors attributed to lower growth velocity of twins relative to singletons between birth and pre-adolescence.13 However, in a larger study that used the Norwegian National Conscript Service to compare 2,493 twins to 2,027 singletons, researchers found that male twins were only 0.6 cm shorter than male singletons in early adulthood.21 Using this same database linked to Norwegian birth data, the authors observed that although twins had BMI z-scores that were 0.49 lower than those of singletons in adulthood, this difference reduced to 0.17 after controlling for birthweight.22 These findings on the effect of birthweight on adult size are consistent with our findings that the smallest twins remained marginally smaller by 7–9 years, while AGA twins caught up with AGA singletons.
Though SGA twins by either a singleton or twin reference caught up in height with AGA twins by 7–9 years of age, they remained marginally smaller in height than AGA singletons, with slightly greater differences in weight. Our results for weight are consistent with two studies among teenagers (16–17 years) and adult women that found that twins generally reach the same height as singletons but remain leaner into adulthood.10, 23 In contrast, we observed SGA singletons remained 0.67 standard deviations lighter and 0.56 standard deviations shorter than AGA singletons by 7–9 years, which translates to an average difference of 2.8 kg and 3.1 cm. Though estimates for SGA singletons and true SGA twins were similar for weight differences relative to singletons, uncertain SGA twins appeared to be generally larger in height and weight than SGA singletons by middle childhood. These findings suggest that twins classified as SGA using a twin-specific reference may be more similar to SGA singletons than twins classified as SGA using a singleton reference.
In our previous work, SGA twins, using a singleton reference, were at higher risk of developmental delay when compared with non-SGA singletons, but not when compared with non-SGA twins.16 In total, and consistent with a recent call to use twin-specific fetal growth references for twins,1 our findings support the use of twin-specific birthweight references and potentially twin growth charts into early childhood. At least two countries have developed twin-specific child growth references,12, 14 with one finding that growth between twins and singletons became similar by age 6.12 In our sample, differences between twins and singletons were most apparent in early childhood, with evidence that size differences decrease as children get older. Typically, RWG is associated with increased risk of overweight/obesity in childhood and adiposity in later life.6, 24 However, despite all twin groups having higher risk of RWG, they did not have subsequent risk of obesity at any point in childhood after age 2, with some suggestion that obesity risk may have been lower in twins compared with singletons. Moreover, differences in height and weight between SGA twins and AGA singletons were not pathological in nature by later childhood. Though the mean z-scores for SGA twins at 0–3 years met the definition of being underweight and under height (z-scores < −1.0) according to singleton growth standards, their height and weight differences became clinically insignificant by 7–9 years, emphasizing that twins may simply display different growth patterns from singletons in early childhood. Use of singleton growth charts in this period may cause unnecessary worry as twins will generally be classified in lower height and weight percentiles relative to singletons. Future studies should investigate twin-specific growth charts in relation to risk of adult morbidity.
Among the strengths of our study was that we had a relatively large sample of twins, nearly 1600, which allowed us to explore different definitions of SGA. We also had longitudinal data collected at time points close to well-child visits when height and weight data would be collected, and all participants had at least one additional growth measure after birth, with an average of five measures reported between 0–3. Though a smaller number had follow-up in middle childhood (n=389 twins and 967 singletons), we maintained power to detect even small differences in height, weight, and BMI for our smallest group, the true SGA twin group. Additionally, because we restricted our sample to children born at 34 weeks or greater, we reduced some of the confounding associated with preterm delivery <37 weeks without excluding too many twins, as the average gestational age at twin delivery in the US is 35 weeks.25
A limitation of our study is the loss-to-follow-up by middle childhood that may have introduced selection bias as the sample aged. Only 564 twins had BMI measures at 2–3 years, and only 350 had BMI at 7–9 years. Point estimates at 7–9 were similar in effect and magnitude relative to measurements obtained between 2–3 years, but confidence intervals were wide, limiting our ability to make any strong inference about decreased risk of obesity in twins relative to singletons. Though we cannot infer lower risk of overweight/obesity in twins, the results suggest no increased risk of overweight/obesity over that of AGA singletons, even after increased RWG in twins. Furthermore, we were unable to evaluate other indicators of differential growth patterns, such as circulating biomarkers or body composition. Another limitation of our sample is that it only represents births that occurred in New York State and may not be generalizable to all US populations. There was also a high proportion of children conceived via infertility treatment. However, in prior work in this sample, only twins conceived via ovulation induction were smaller than those not conceived by treatment, and the difference of 0.12 kg over 0–3 years was minimal.26 Because of this previous finding, we adjusted for infertility treatment in our analyses, despite observing no difference between AGA twins and either SGA twin group in terms of the percentage who were conceived using infertility treatments. Though we have no information on chorionicity or zygosity of twins in our sample, prior studies have found no difference in child growth outcomes by zygosity.13
Twins had lower height, weight, and BMI z scores at birth and into toddlerhood than AGA singletons, but differences in measures were reduced by the time they reached 7–9 years, even for true SGA twins. Despite all twins displaying rapid weight gain in infancy, with risk 2–3 times that of singletons, no twin group had higher risk of overweight/obesity in early or middle childhood. Future research should prospectively follow twins to collect height and weight measures throughout childhood to construct twin-specific growth charts and confirm whether twin-specific charts more accurately characterize twin growth than singleton charts.
Supplementary Material
Funding:
This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #HHSN275201200005C, #HHSN267200700019C, #HHSN275201400013C, #HHSN275201300026I/27500004). JLG, EHY, RS, DLP, and KLG have contributed to this work as part of their official duties as employees of the United States Federal Government.
Role of Funder:
The funder/sponsor did not participate in the work, to include study design, collection, analysis, or interpretation of data, the writing of the manuscript, or the decision to submit the manuscript for publication.
Abbreviations:
- AGA
Appropriate for gestational age
- BMI
Body mass index
- CDC
Centers for Disease Control and Prevention
- LGA
Large for gestational age
- RWG
Rapid weight gain
- SGA
Small for gestational age
- WHO
World Health Organization
Footnotes
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Conflict of Interest Disclosures: The authors have no conflicts of interest to disclose.
Prior Presentation of Findings:
Findings from this work have been partially presented at the Annual Meeting of the Society for Epidemiologic Research in June, 2022 and at the Annual Meeting of the Society for Maternal Fetal Medicine in February, 2023.
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