Estimating the individual singleton preterm birth risk: nomogram establishment and independent validation
Original Article

Estimating the individual singleton preterm birth risk: nomogram establishment and independent validation

Ting Gao1,2#, Tianwei Wang3#, Wan Tang1#, Pu Xu1, Tianyang Qian1, Han Qiu1, Laishuan Wang1

1Department of Neonatology, National Children’s Medical Center/Children’s Hospital of Fudan University, Shanghai, China; 2Department of Rehabilitation, Guangzhou Women’s and Children’s Medical Center, Guangzhou, China; 3Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China

Contributions: (I) Conception and design: T Gao, T Wang, L Wang; (II) Administrative support: L Wang; (III) Provision of study materials or patients: T Gao, T Wang; (IV) Collection and assembly of data: T Gao, T Wang, W Tang, P Xu, T Qian, H Qiu, L Wang; (V) Data analysis and interpretation: T Gao, T Wang, W Tang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work and should be considered as co-first authors.

Correspondence to: Prof. Laishuan Wang, PhD, MD. National Health Commission Key Laboratory of Neonatal Diseases, Department of Neonatology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai 201102, China. Email: laishuanwang@fudan.edu.cn.

Background: To establish and independently validate nomograms for predicting singleton preterm birth (PTB) risk based on a large sample size comprising data from two independent datasets.

Methods: This cohort study used data from 50 states and the District of Columbia in the National Vital Statistics System (NVSS) database between January 2016 and December 2020. Multivariate logistic regression analysis was used to confirm the independent risk factors for PTB. Statistically significant variables were incorporated into the logistic regression models to establish PTB prediction nomograms. The models were developed using the United States (US)-derived data and were independently validated using data from US Territories.

Results: A total of 16,294,529 mother-newborn pairs from the US were included in the training set, and 54,708 mother-newborn pairs from the US Territories were included in the validation set. In all, 4 nomograms were built: 1 to predict PTB probability, and another 3 to predict moderately and late PTB probability, very PTB probability, and extremely PTB probability, respectively. Hypertensive eclampsia and infertility treatment were found to be the top 2 contributors to PTB.

Conclusions: We developed and validated nomograms to predict the individualized probability of PTB, which could be useful to physicians for improved early identification of PTB and in making individualized clinical decisions.

Keywords: Preterm birth (PTB); nomogram; hypertensive eclampsia; assisted reproductive technology (ART)


Submitted Nov 21, 2022. Accepted for publication Apr 17, 2023. Published online Jun 29, 2023.

doi: 10.21037/tp-22-611


Highlight box

Key findings

• Factors affecting PTB are multi-dimensional, and the 3 most significant factors were identified as hypertensive eclampsia, assisted reproductive technology, and history of PTB.

What is known and what is new?

• Although nomograms for PTB had been established in previous studies, they were developed based on limited samples and variables.

• Male sex of the newborn, maternal age and BMI, marital status, mother’s race, parental level of education, prenatal care starting time, smoking, history of PTB, hypertensive eclampsia, infertility treatment, diabetes, hypertension, history of cesarean, birth circumstances, live birth order, gonorrhea, syphilis, and chlamydia were identified as independent predictors for PTB.

• A multidimensional comprehensive prediction model incorporating large data was established to predict the individualized probabilities of PTB.

What is the implication, and what should change now?

• Nomograms were developed according to multidimensional factors, which could be useful to physicians for improved early identification of PTB and making clinical decisions.


Introduction

Preterm birth (PTB) is defined as birth before 37 weeks’ gestation, which occurs in approximately 10% of births in the United States (US) (1). It is one of the leading causes of perinatal mortality and morbidity (2), accounting for approximately 18% of all pediatric deaths and 35% of deaths among newborns (3). An accurate and individualized assessment of the probability of PTB can assist early prevention and formulation of individualized treatment strategies for high-risk women, and improve neonatal outcomes. A nomogram including weighted calculation of various PTB-related factors can be used for individualized and accurate prediction of PTB, which is of great practical value for the clinical assessment of PTB. Although previous studies have established nomograms for PTB (4-8), they have been developed based on limited samples and variables. Factors affecting PTB are multi-dimensional, including the basic status of the mother, health status before pregnancy, complications of pregnancy, history of delivery and PTB, infertility and its treatment approach, sexually transmitted infections, living environment, and so on (9-14). Therefore, a more multidimensional prediction model incorporating large data is needed to improve the prediction of PTB. The National Vital Statistics System (NVSS) from the US is one of the largest and most comprehensive databases in the world, which records birth data in detail with objective authenticity and representativeness. Our study aimed to use the data from the NVSS database to develop and independently validate a more multidimensional nomogram for the estimation of individualized PTB risk based on multidimensional variables and the largest sample size to date. We present this article in accordance with the TRIPOD reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-22-611/rc).


Methods

This study used data from the NVSS in the US, a database that contains the birth and death records from 50 states and the District of Columbia. We obtained birth data from January 1, 2016, to December 31, 2020. All cases with complete information were included in this study. The related data can be obtained online: https://www.cdc.gov/nchs/data_access/vitalstatsonline.htm. All cases were divided into a PTB group and a full-term birth (FTB) group according to the gestational week at birth (37 weeks). Due to the data being publicly available and the study does not involve human participants, the institutional Review Board of Children’s Hospital of Fudan University deemed this study exempt from review and waived the informed consent requirement. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

The primary outcome was the risk of PTB. The secondary outcome was the risk of varying degrees of PTB (moderately and late PTB, very PTB, and extremely PTB). The relevant variables were as follows: maternal age (<20, 21–30, 31–40, and >40 years), sex (male and female), maternal body mass index (BMI) before pregnancy (underweight, normal, overweight, and obese), marital status (married and unmarried), mother’s race [White, Black, American Indian/Alaskan Native (AIAN), Asian, Native Hawaiian or Other Pacific Islander (NHOPI), and more than 1 race], parental education attainment (< high school, high school, associate degree, and ≥ bachelor’s degree), prenatal care starting time (1st to 3rd month, 4th to 6th month, 7th to final month, and no prenatal care), smoking (no smoking, smoking before pregnancy, and smoking during pregnancy), history of PTB and cesareans, hypertensive eclampsia, infertility and its treatment [no treatment, fertility-enhancing drugs, assisted reproductive technology (ART), and other treatments], diabetes (pre-pregnancy diabetes, gestational diabetes, and no diabetes), hypertension (pre-pregnancy hypertension, gestational hypertension, and no hypertension), live birth order, mother’s nativity (born in the US, born outside the US, and unknown), gonorrhea, syphilis, chlamydia, hepatitis B, and hepatitis C.

To better understand the different degrees of PTB, we divided the newborns into 3 subgroups: moderately and late PTB group (32 weeks ≤ gestational weeks <37 weeks), very PTB group (28 weeks ≤ gestational weeks <32 weeks), and extremely PTB group (22 weeks ≤ gestational weeks <28 weeks). We compared the differences in these abovementioned factors between the PTB and FTB groups by univariate logistic regression analyses, respectively. Multivariate logistic regression analyses were used to identify the independent predictors. We used the final data (16,294,529 samples) to establish 4 risk prediction nomograms, and then used the US Territories data from Puerto Rico, Virgin Islands, Guam, American Samoa, and Northern Marianas to perform external validation (54,708 samples). Further, we used the concordance index (C-index), calibration plots, and receiver operating characteristic (ROC) curves to validate the performance of these models.

Statistical analysis

Statistical analysis was performed using IBM 23.0 software (IBM Corp., Armonk, NY, USA) and R (version 4.1.2; R Foundation for Statistical Computing, Vienna, Austria). Univariate analyses were conducted to assess the association of PTB with factors. All statistical tests were 2-sided with 0.05 significance levels. Multivariate logistic regression analyses were used to identify the independent predictors for PTB. The prediction nomograms were developed by R based on a multivariate logistic regression model. The calibration curves were used to evaluate the consistency of the nomograms. The aptitude of each nomogram for predicting PTB risk was appraised by the C-index and the area under the receiver operating characteristic curve (AUC).


Results

A total of 16,294,529 samples were enrolled, as shown in Figure 1. The detailed information is listed in Table 1. Univariate analysis revealed that 20 variables had relationship with PTB. Table 2 displays the multivariate logistic regression analysis results, showing that male sex of the newborn [odds ratio (OR): 0.910; 95% confidence interval (CI): 0.907–0.913; P<0.001], maternal age <20 (OR: 1.155; 95% CI: 1.144–1.166; P<0.001), maternal BMI (OR: 1.224; 95% CI: 1.212–1.236; P<0.001), marital status (OR: 1.142; 95% CI: 1.137–1.146; P<0.001), mother’s race (OR: 1.425; 95% CI: 1.418–1.432; P<0.001), mother’s level of education (OR: 1.167; 95% CI: 1.158–1.176; P<0.001), father’s level of education (OR: 1.180; 95% CI: 1.172–1.189; P=0.047), prenatal care starting time (OR: 2.284; 95% CI: 2.256–2.312; P<0.001), smoking (OR: 1.208; 95% CI: 1.199–1.217; P<0.001), history of PTB (OR: 2.771; 95% CI: 2.752–2.790; P<0.001), hypertensive eclampsia (OR: 4.075; 95% CI: 3.987–4.164; P<0.001), infertility treatment (OR: 2.977; 95% CI: 2.940–3.014; P<0.001), diabetes (OR: 2.015; 95% CI: 1.988–2.042; P<0.001), hypertension (OR: 2.547; 95% CI: 2.534–2.561; P<0.001), history of cesarean (OR: 1.089; 95% CI: 1.084–1.094; P<0.001), nativity (OR: 0.978; 95% CI: 0.973–0.982; P<0.001), live birth order (OR: 1.029; 95% CI: 1.024–1.034; P<0.001), gonorrhea (OR: 1.140; 95% CI: 1.100–1.181; P<0.001), syphilis (OR: 1.095; 95% CI: 1.040–1.153; P<0.001), and chlamydia (OR: 1.028; 95% CI: 1.014–1.042; P<0.001) were independent predictors for PTB. In addition, the comparison of characteristics of different degrees of PTB and FTB are listed in Table S1. The detailed information from multivariate logistic regression analysis of these 3 models is shown in Tables S2-S4.

Figure 1 Study flow diagram. PTB, preterm birth; FTB, full-term birth.

Table 1

Population characteristics

Variables FTB group, N (%) PTB group, N (%) P value
All population 14,518,114 (100.0) 1,776,415 (100.0)
Year <0.001
   2016 3,021,461 (20.8) 356,284 (20.1)
   2017 2,954,513 (20.4) 356,739 (20.1)
   2018 2,913,994 (20.1) 354,401 (20.0)
   2019 2,873,800 (19.8) 366,091 (20.6)
   2020 2,754,346 (18.9) 342,900 (19.3)
Maternal age <0.001
   <20 528,824 (3.6) 76,366 (4.3)
   20–30 6,835,689 (47.1) 785,330 (44.2)
   31–40 6,679,838 (46.0) 824,490 (46.4)
   >40 473,763 (3.3) 90,229 (5.1)
Sex of newborn <0.001
   Male 7,124,839 (49.1) 829,014 (46.7)
   Female 7,393,275 (50.9) 947,401 (53.3)
Mother’s education <0.001
   < High school 1,525,921 (10.5) 234,230 (13.2)
   High school 3,357,889 (23.1) 462,173 (26.0)
   AD 4,086,022 (28.1) 515,623 (29.0)
   ≥ BD 5,376,325 (37.0) 541,797 (30.5)
   Unknown 171,957 (1.2) 22,592 (1.3)
Smoking <0.001
   No smoking 13,555,015 (93.4) 1,622,400 (91.3)
   Smoking cessation 270,926 (1.9) 33,000 (1.9)
   Smoking 692,173 (4.8) 121,015 (6.8)
History of PTB <0.001
   Yes 374,940 (2.6) 148,322 (8.3)
   No 14,143,174 (97.4) 1,628,093 (91.7)
Diabetes <0.001
   Pre-pregnancy 112,194 (0.8) 164,153 (9.2)
   Gestational 970,722 (6.7) 38,168 (0.2)
   No 13,435,198 (92.5) 1,574,094 (88.6)
Chlamydia <0.001
   Yes 185,898 (1.3) 28,629 (1.6)
   No 14,313,866 (98.6) 1,740,816 (98.0)
   Unknown 18,350 (0.1) 6,790 (0.4)
Gonorrhea <0.001
   Yes 23,365 (0.2) 4,516 (0.3)
   No 14,476,399 (99.7) 1,764,929 (99.4)
   Unknown 18,350 (0.1) 6,790 (0.4)
Hepatitis B <0.001
   Yes 30,763 (0.2) 4,102 (0.2)
   No 14,469,001 (99.7) 1,765,343 (99.4)
   Unknown 18,350 (0.1) 6,790 (0.4)
Prenatal care starting time <0.001
   1st to 3rd month 11,670,225 (80.4) 1,334,440 (75.1)
   4th to 6th month 2,130,762 (14.7) 328,269 (18.5)
   7th to final month 561,230 (3.9) 67,417 (3.8)
   No prenatal care 155,897 (1.1) 46,289 (2.6)
Mother’s race <0.001
   White 11,126,214 (76.6) 1,260,596 (70.9)
   Black 1,778,873 (12.3) 326,829 (18.4)
   AIAN 118,473 (0.8) 17,701 (1.0)
   Asian 1095,352 (7.5) 118,769 (6.7)
   NHOPI 41,768 (0.3) 7,147 (0.4)
   >1 race 357,434 (2.5) 45,373 (2.6)
Maternal BMI <0.001
   Normal 6,187,556 (42.6) 669,411 (37.7)
   Underweight 429,259 (2.9) 57,838 (3.3)
   Overweight 3,828,984 (26.4) 458,299 (25.8)
   Obesity 3,827,848 (26.4) 551,396 (31.0)
   Unknown 244,467 (1.7) 39,441 (2.2)
Infertility treatment <0.001
   No 14,255,558 (98.2) 1,696,659 (95.5)
   FEDT 108,543 (0.7) 30,778 (1.7)
   ART 138,200 (1.0) 44,664 (2.5)
   Other treatments 15,813 (0.1) 4,314 (0.2)
Previous cesareans <0.001
   Yes 2,213,891 (15.2) 329,463 (18.5)
   No 12,304,223 (84.8) 1,446,952 (81.5)
Father’s education <0.001
   < High school 1,776,843 (12.3) 260,640 (14.7)
   High school 4149519 (28.6) 573,027 (32.3)
   AD 3,694,278 (25.4) 443,923 (25.0)
   ≥ BD 4,539,764 (31.3) 444,003 (25.0)
   Unknown 357,710 (2.5) 54,822 (3.1)
Mother’s nativity <0.001
   In the US 11,032,782 (76.0) 1,354,549 (76.3)
   Outside the US 3,465,698 (23.9) 419,127 (23.6)
   Unknown 19,634 (0.1) 2,739 (0.2)
Hypertension eclampsia <0.001
   Yes 26,125 (0.2) 15,391 (0.9)
   No 14,491,989 (99.8) 1,761,024 (99.1)
Hypertension <0.001
   Pre-pregnancy 245,404 (1.7) 76,365 (4.3)
   Gestational 886,156 (6.1) 258,871 (14.6)
   No 13,386,554 (92.2) 1,441,179 (81.1)
Marital status <0.001
   Married 8,888,021 (61.2) 1,005,385 (56.6)
   Unmarried 4,127,076 (28.4) 618,577 (34.8)
   Unknown 1,503,017 (10.4) 152,453 (8.6)
Syphilis <0.001
   Yes 11,995 (0.1) 2,318 (0.1)
   No 14,487,769 (99.8) 1,767,127 (99.5)
   Unknown 18,350 (0.1) 6,790 (0.4)
Hepatitis C <0.001
   Yes 44,229 (0.3) 9,891 (0.6)
   No 14,455,535 (99.6) 1,759,554 (99.1)
   Unknown 18,350 (0.1) 6,790 (0.4)
Live birth order <0.001
   1 5,555,199 (38.3) 610,729 (34.4)
   2 4,813,305 (33.2) 551,339 (31.0)
   3 2,457,445 (16.9) 324,556 (18.3)
   4 1,004,828 (6.9) 160,607 (9.0)
   5 371,942 (2.6) 69,344 (3.9)
   6 151,213 (1.0) 29,738 (1.7)
   7 68,075 (0.5) 13,425 (0.8)
   ≥8 76,534 (0.5) 13,945 (0.8)
   Unknown 19,573 (0.1) 2,732 (0.2)

FTB, full-term birth; PTB, preterm birth; AD, associate degree; BD, bachelor’s degree; US, United States; AIAN, American Indian/Alaskan Native; NHOPI, Native Hawaiian or Other Pacific Islander; BMI, body mass index; FEDT, fertility-enhancing drugs therapy; ART, assisted reproductive technology.

Table 2

Multivariate logistic regression analyses results on PTB

Factor OR 95% CI P value
Sex (female vs. male) 0.910 0.907–0.913 <0.001
Maternal age (year)
   <20 vs. 20–30 1.155 1.144–1.166 <0.001
   31–40 vs. 20–30 1.108 1.104–1.113 <0.001
   >40 vs. 20–30 1.389 1.377–1.402 <0.001
Maternal BMI
   Underweight vs. normal 1.224 1.212–1.236 <0.001
   Overweight vs. normal 0.984 0.980–0.988 <0.001
   Obesity vs. normal 0.998 0.993–1.002 <0.001
Marital status (unmarried vs. married) 1.142 1.137–1.146 <0.001
Race of mother
   Black vs. White 1.425 1.418–1.432 <0.001
   AIAN vs. White 1.074 1.056–1.093 <0.001
   Asian vs. White 1.113 1.104–1.122 <0.001
   NHOPI vs. White 1.310 1.272–1.348 <0.001
   >1 race vs. White 1.067 1.055–1.079 <0.001
Mother’s education
   < High school vs. ≥ bachelor’s degree 1.167 1.158–1.176 <0.001
   High school vs. ≥ bachelor’s degree 1.115 1.108–1.122 <0.001
   Associate degree vs. ≥ bachelor’s degree 1.080 1.075–1.086 <0.001
Father’s education
   <High school vs. ≥ bachelor’s degree 1.180 1.172–1.189 0.047
   High school vs. ≥ bachelor’s degree 1.173 1.166–1.180 <0.001
   Associate degree vs. ≥ bachelor’s degree 1.099 1.093–1.105 <0.001
Prenatal care starting time
   4th to 6th month vs. 1st to 3rd month 1.249 1.243–1.255 <0.001
   7th to final month vs. 1st to 3rd month 0.994 0.985–1.003 0.217
   No vs. 1st to 3rd month 2.284 2.256–2.312 <0.001
Smoking
   Smoking cessation vs. no smoking 0.943 0.932–0.955 <0.001
   Smoking vs. no smoking 1.208 1.199–1.217 <0.001
History of preterm (yes vs. no) 2.771 2.752–2.790 <0.001
Hypertensive eclampsia (yes vs. no) 4.075 3.987–4.164 <0.001
Infertility treatment
   Other treatments vs. no 2.550 2.462–2.642 <0.001
   FEDT vs. no 2.728 2.690–2.766 <0.001
   ART vs. no 2.977 2.940–3.014 <0.001
Diabetes
   Pre-pregnancy diabetes vs. no 2.015 1.988–2.042 <0.001
   Gestational diabetes vs. no 1.234 1.226–1.241 <0.001
Hypertension
   Pre-pregnancy hypertension vs. no 2.243 2.222–2.264 <0.001
   Gestational hypertension vs. no 2.547 2.534–2.561 <0.001
History of cesareans (yes vs. no) 1.089 1.084–1.094 <0.001
Live birth order
   2 vs. 1 1.029 1.024–1.034 <0.001
   3 vs. 1 1.092 1.086–1.098 <0.001
   4 vs. 1 1.206 1.198–1.215 <0.001
   5 vs. 1 1.284 1.271–1.297 <0.001
   6 vs. 1 1.271 1.253–1.290 <0.001
   7 vs. 1 1.219 1.193–1.245 <0.001
   ≥8 vs. 1 1.081 1.059–1.104 <0.001
Nativity
   Not in the US vs. in the US 0.978 0.973–0.982 <0.001
   Unknown vs. in the US 0.987 0.943–1.034 0.585
Gonorrhea (yes vs. no) 1.140 1.100–1.181 <0.001
Syphilis (yes vs. no) 1.095 1.040–1.153 <0.001
Chlamydia (yes vs. no) 1.028 1.014–1.042 <0.001

PTB, preterm birth; OR, odds ratio; CI, confidence interval; BMI, body mass index; AIAN, American Indian/Alaskan Native; NHOPI, Native Hawaiian or Other Pacific Islander; FEDT, fertility-enhancing drugs therapy; ART, assisted reproductive technology; US, United States.

A final nomogram was established (Figure 2). The variables that were found to increase the probability of PTB included sex (male newborn), maternal age (<20 years, >40 years), maternal BMI (underweight, overweight, and obesity), marital status (unmarried), mother’s race (non-white), mother’s and father’s level of education (< high school), prenatal care starting time (not at all, 4th to 6th month, and 7th to final month), smoking, history of PTB, hypertensive eclampsia, infertility treatment, diabetes, hypertension, history of cesarean, live-birth order, nativity (not in the US), gonorrhea, syphilis, and chlamydia. The detailed score of each variable in the model and the prediction PTB probability corresponding to the total point are shown in Table S5. The score of each variable in the moderately and late PTB, very PTB, and extremely PTB risk model and the prediction probability corresponding to the total points are shown in Table S6, Table S7, and Table S8, respectively. To use the nomogram, first, locate a specific point of an individual patient on each variable axis; second, draw a vertical line upwards in the variable axis, with each variable corresponding to a specific point on the Points scale (top); third, sum all the points of each variable, and locate on the Total Points scale (bottom); forth, draw a vertical line downwards, corresponding to the PTB probability axis to determine the PTB probability. We found that the risk variables were identical in 3 models (PTB model, moderately and late PTB model, and very PTB model), whereas the weights of variables were different with different contribution degrees. We also found that hypertensive eclampsia (1st) and infertility treatment (2nd) were the top 2 contributors in all these 3 models. In addition, a slight difference between the extremely PTB model and the other 3 models was revealed, with syphilis and chlamydia not included in the extremely PTB model since they were not independent predictors. The top 2 contributors in the extremely PTB model were prenatal care starting time (1st) and infertility treatment (2nd).

Figure 2 A nomogram for predicting the risk of preterm birth. BMI, body mass index; OW, overweight; UW, underweight; AIAN, American Indian/Alaskan Native; NHOPI, Native Hawaiian or Other Pacific Islander; BD, bachelor’s degree; AD, associate degree; HS, high school; OT, other treatment; FED, infertility-enhancing drugs; ART, assisted reproductive technology; UN, unknown; US, United States; PTB, preterm birth.

The C-index and the AUC under the ROC curves in the training set and validation set were 0.652 (95% CI: 0.652–0.653, Figure 3A) and 0.642 (95% CI: 0.635–0.649, Figure 3B), respectively. For the predicted PTB risk plots in both the training set and validation set (Figure 3C,3D), both of these lines slightly strayed from the ideal reference line toward the low end of the outcome scale; however the observed and optimism-corrected lines were nearly consistent, indicating that this model’s predictions were consistent with the expectations.

Figure 3 Time-dependent ROC curves of preterm birth in training set (A) and validation set (B). Calibration curves for the risk of the PTB training set (C) and validation set (D). Time-dependent ROC curves of moderately and late PTB, very PTB, and extremely PTB in the training groups (E) and the independent validation groups (F). Calibration curves for moderately and late PTB (training set, G; validation set, H), very PTB (training set, I; validation set, J), and extremely PTB (training set, K; validation set, L). TP, true positive; AUC, area under the ROC curve; ROC, receiver operating characteristic; PTB, preterm birth.

In addition, we established 3 prediction nomograms for moderately and late PTB, very PTB, and extremely PTB, respectively (Figures S1-S3). In the training set, the C-index and the AUC were 0.647 (95% CI: 0.646–0.647, Figure 3E) in moderately and late PTB, 0.693 (95% CI: 0.692–0.695, Figure 3E) in very PTB, and 0.726 (95% CI: 0.724–0.728, Figure 3E) in extremely PTB. In the validation set, the C-index and the AUC were 0.638 (95% CI: 0.630–0.645, Figure 3F) in moderately and late PTB, 0.702 (95% CI: 0.682–0.722, Figure 3F) in very PTB, and 0.705 (95% CI: 0.676–0.734, Figure 3F) in extremely PTB. The calibration curves in both the training set and validation set showed that the predicted value approximated the observed value in these 3 models (Figure 3G-3L). Overall, our external validation results showed that these prediction nomograms had moderate consistency and discrimination, and that they had reliable predictive performance.


Discussion

The goal of this study was to develop and independently validate prediction models for PTB based on a large population and multidimensional analyses. The contribution degree of different variables to the model from high to low was hypertensive eclampsia, infertility treatment, history of PTB, hypertension, prenatal care starting time, smoking, diabetes, mother’s race, maternal age, live-birth order, smoking, maternal BMI, father’s level of education, mother’s level of education, marital status, gonorrhea, sex of the newborn, syphilis, history of cesareans, chlamydia, and nativity. In addition, 3 nomograms for moderately and late PTB, very PTB, and extremely PTB were developed for further predicting different degrees of PTB probabilities, respectively. These models could predict the probability of PTB individually and provide a reference for clinicians in individualized decision making.

Hypertensive eclampsia is one of the most common life-threatening maternal diseases worldwide and is closely associated with PTB, increasing the risk of PTB (13,15). In our study, 0.9% of women had hypertensive eclampsia in the PTB group, which was significantly higher than in the FTB group. Hypertensive eclampsia was shown to be an independent predictor for PTB. In addition, in 3 of our nomograms, hypertensive eclampsia had the greatest contribution to PTB.

As the incidence of infertility increases, more parents undergo infertility treatment, such as fertility-enhancing drugs and ART. However, infertility treatment may increase the risk of PTB (16). In our study, we found that 4.4% of children of parents who underwent infertility treatment experienced PTB, which was much higher than that in FTB group (0.8%). Of the parents who underwent infertility treatment, 56.0% received ART and 38.6% received fertility-enhancing drug treatment, and infertility treatment was confirmed as an independent predictor, which was consistent with previous studies (17,18). To summarize, infertility treatment could increase the PTB risk, and ART has the greatest impact on PTB in this regard.

An increased risk of PTB also is observed in women with a history of PTB and cesarean (1,19). Williams et al. found that compared to women without cesarean delivery history, women with cesarean delivery history in their first pregnancy were 14% more likely to have a PTB in their second pregnancy (19). Koire et al. found that a history of PTB can increase the risk of PTB (1). Our findings also supported their views that the history of PTB and cesarean had relationship with PTB.

Diabetes and hypertension have also been shown to be associated with PTB (20-22), with an increasing PTB rate in mothers with diabetes and hypertension. Their findings were similar to ours; these factors were independent predictors for PTB in our study. In addition, some common infections during pregnancy are associated with PTB. The mechanism of maternal infection/inflammation leading to PTB may be related to intrauterine inflammation (23,24). There is a significant association between chlamydia infection and chorioamnionitis, and chlamydia may lead to chorioamnionitis (25). In addition, there may be a relationship between chorioamnionitis and gonorrhea (25). Chorioamnionitis was found to be an independent predictor of PTB in a previous study (26), and chlamydia and gonorrhea might lead to chorioamnionitis to increase PTB risk. Gao et al. also concluded that maternal sexually transmitted infections could increase the risk of PTB (27). Their results were consistent with our findings that gonorrhea, syphilis, and chlamydia are independent predictors of PTB.

Smoking during pregnancy can endanger the unborn child’s health, and has long been considered a risk factor for PTB (28,29). Cessation of smoking cessation can reduce such risk (10). In our study, smoking during pregnancy was shown to increase the risk of PTB compared with smoking cessation, and smoking was an independent predictor of PTB. In the US, prenatal care is associated with a lower PTB rate, and increased prenatal care participation may reduce PTB rates (30). The majority of women in our study received prenatal care, and the PTB rate was higher among women who did not receive prenatal care; the earlier prenatal care was initiated, the lower the incidence of PTB.

In addition to the relevant factors discussed above, the sex of the newborn, maternal age, marital status, mother’s race, and nativity have long been associated with PTB (4,7,12), and were also confirmed as independent predictors for PTB in our study. In addition to these variables, maternal BMI was shown to have a relationship with PTB: compared with mothers with a normal maternal BMI, those who were underweight, overweight, or obese had a higher PTB rates.

A similar PTB nomogram was developed by Mehta-Lee et al. with 192,208 samples (6), which was established based on 9 factors. Although our results supported their conclusion that the factors mentioned in their study are of significance, their nomogram did not include some variables which we found to be closely associated with PTB, such as the sex of the newborn, maternal BMI, marital status, education levels of parents, prenatal care starting time, hypertension eclampsia, infertility treatment, hypertension, history of cesareans, live-birth order, nativity, and some sexually transmitted diseases (27).

We established a multidimensional model to provide an individualized prediction of PTB. To further predict the probability of different degrees of PTB, moderately and late PTB, very PTB, and extremely PTB nomograms were also established. In addition, we also found 20 identical risk factors in the PTB, moderately and late PTB, and very PTB models, which supported the commonality of these 3 models. Although the contribution degree of each factor was different, hypertensive eclampsia (1st) and infertility treatment (2nd) were the top 2 contributors in all 3 models. The extremely PTB model was slightly different from the other 3 models, whereby syphilis and chlamydia were not independent predictors for extremely PTB. These results may be due to only 0.1% (127 samples) and 1.8% (1,697 samples) of women in the extremely PTB group having syphilis and chlamydia. In addition, the population samples were extremely limited compared with the FTB group. In addition, the prenatal care starting time (1st) had the largest contribution to the extremely PTB model, however, infertility treatment and hypertensive eclampsia (which were the top 2 contributors in the other 3 models) still contributed significantly to the extremely PTB model.

Although the consistency of these models ranged from 64.7% to 72.8%, the calibration curves showed that these 4 models had relatively good discrimination, indicating that the predicted values approximated the observed values. The validation findings showed that our models had reliable predictive performance. Therefore, our models can help physicians estimate the individualized PTB probability, the mothers with high predicted PTB risk can be screened out, and the physicians allocate more attention to them. For example, for mothers with higher model prediction-based PTB probability, physicians can make individualized obstetric examination plans, and provide them with personalized advice, such as smoking cessation, to decrease the PTB risk.

This study had several limitations. Firstly, the nomograms were established using data from the US, reducing their applicability in other countries, particularly those with different development levels or health care systems. Therefore, we will use data from different institutions and other countries for validation in future studies. Secondly, in previous studies, some other factors were associated with PTB, such as cervical length, vaginal bleeding (7), maternal thyroid function (31), preeclampsia (13), maternal marijuana use (32), and so on. These factors were not included in our nomograms as such data was absent in the NVSS database. Thirdly, the accuracy of the models is not perfect. Despite these limitations, the models were developed and validated based on the largest sample size known to date, the variables included in the models are multidimensional, and the population data is from different regions of the US, making our models more applicable and representative. In addition, the models allow us to not only predict the probability of PTB, but also to estimate the probability of different degrees of PTB.


Conclusions

Factors affecting PTB are multi-dimensional, and in this study, the 3 most significant factors were hypertensive eclampsia, ART, and history of PTB. We established 4 nomograms to predict the individual probability of PTB based on a multidimensional large sample size dataset, which can provide an individual PTB possibility estimation rather than a group estimation.


Acknowledgments

Funding: None.


Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-22-611/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-611/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Due to the data being publicly available and the study does not involve human participants, the institutional Review Board of Children’s Hospital of Fudan University deemed this study exempt from review and waived the informed consent requirement. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

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Cite this article as: Gao T, Wang T, Tang W, Xu P, Qian T, Qiu H, Wang L. Estimating the individual singleton preterm birth risk: nomogram establishment and independent validation. Transl Pediatr 2023;12(7):1305-1318. doi: 10.21037/tp-22-611

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