Hypertensive disorders of pregnancy and gestational diabetes mellitus affect fetal growth and perinatal outcomes in women undergoing in vitro fertilization.

Yaxin Su: Writing – original draft, Formal analysis. Yue Niu: Formal analysis. Binbin Zhao: Writing – review & editing. Shizhen Su: Writing – review & editing. Cameron Klein: Writing – review & editing. Xiaoyang Hou: Validation, Supervision. Xiao Li: Writing – review & editing, Visualization. Hong Lv: Writing – review & editing, Visualization, Project administration.

The Institutional Ethics Committee of the Center for Reproductive Medicine of Shandong University approved the study (Ethical Review No.115, 2024). Consent was obtained from patients to participate in the study. All methods were performed in accordance with the relevant guidelines and regulations, and were performed in accordance with Declaration of Helsinki.

Not applicable.

We included 20,907 women who achieved singleton delivery following IVF treatment at the Center for Reproductive Medicine of Shandong University from January 2015 to May 2021. Data were acquired from the electronic medical records which were prospectively entered by clinicians (Ethical Review No.115, 2024). The inclusion criteria were as follows: singleton pregnancies were included in the analysis if delivery occurred at the Center for Reproductive Medicine of Shandong University after 28 weeks of gestation; age 20−40 years; and women underwent their first cycles of IVF with or without intracytoplasmic sperm injection (ICSI).The exclusion criteria were as follows: women with preimplantation genetic test cycles, donor oocyte cycles, or frozen-thawed oocyte cycles; pregestational chronic hypertension; a history of prior hypertensive disorders during pregnancy; pregestational diabetes; polycystic ovary syndrome (PCOS); or other etiologies of anovulation,such as hypothalamic or hypophysial dysfunction. In addition, if a woman had more than one singleton delivery during the first IVF cycle, only the first singleton delivery was included for analysis. Each patient was included for analysis only once. The exposures were HDP, GDM, and HDP/GDM versus unaffected (reference group). “HDP/GDM” described pregnancies complicated by both HDP and GDM. HDP diagnosis was defined as follows 18 : (1) Systolic blood pressure 140 mm Hg or more or a diastolic blood pressure of 90 mm Hg or more, or both, on 2 occasions at least 4 hours apart after 20 weeks of gestation; (2) Systolic blood pressure of 140 mm Hg and/or diastolic blood pressure of 90 mm Hg, on 1 occasion after 20 weeks of gestation with laboratory evidence of preeclampsia; (3) Gestational hypertension documented in a patient's delivery record as a laboratory complication, an indication for induction, or a rationale for cesarean delivery. GDM was defined as 2 abnormal OGTTs according to Carpentere Coustan thresholds. 19 The primary outcome, appropriate for gestational age birthweight (AGA) was defined as birth weight between the 10th and 90th percentile of the mean birth weight for gestational age. 20 Secondary outcomes included small for gestational age (SGA) and large for gestational age (LGA), defined as those infants below the 10th or above the 90th percentile at each gestational age. 21 Macrosomia and low birthweight were defined as birthweight greater than 4000 g and less than 2500 g, respectively. Additional secondary outcomes included preterm delivery, post-term delivery and cesarean section. Preterm delivery was defined as delivery before 37 weeks of gestation, and post-term was defined as deliveries occurring at or after 42 weeks of gestation. 22 The statistical analysis was performed with Statistical Package for Social Sciences (SPSS, version 27.0). The Kolmogorov-Smirnov test, histograms and Q-Q plot, was used to test the normal distribution of continuous variables. Normally distributed data are described as the mean ± standard deviation (SD) and were analysed using 1-way ANOVA or the Kruskal-Wallis test; The median (interquartile range) was used for nonnormal continuous variables. Furthermore, Categorical variables were expressed as the number of cases (n) and the percentage of occurrence (%), and were measured by χ2 analysis. Multivariate logistic regression analysis was performed to evaluate the relationships between exposures and outcomes, adjusting for confounding factors including age, body mass index (BMI), systolic blood pressure, diastolic blood pressure, infertility causes, glucose levels, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transfer, year of treatment, and number of embryos transferred. Binary logistic regression analysis was also used to investigate the interactions between different groups and the subtypes of embryo transplantation (fresh embryos and frozen embryos). Values of P<. 05 were considered statistically significant.

We screened 27,269 patients for eligibility and included 20,907 patients for analysis ( Figure 1 ). The baseline characteristics of the patients included in this study are listed in Table 1 . Of these pregnancies, 18,428 (88.1%) pregnancies were unaffected by either HDP or GDM, 872 (4.1%) were complicated by HDP, and 1715 (8.2%) pregnancies were complicated by GDM. Both HDP and GDM were present in 108 pregnancies (0.5%). Patients in the unaffected group were younger than those in the HDP group and the GDM group. Patients in the unaffected group also had a lower BMI than patients in the HDP, GDM and HDP/GDM groups. Both systolic and diastolic blood pressures were higher in the HDP and HDP/GDM groups than in the unaffected group. Blood glucose levels were higher in the HDP, GDM, and HDP/GDM groups compared to the unaffected group. The GDM and HDP/GDM groups had greater numbers of retrieved oocytes than the unaffected group, while the unaffected and GDM groups had lower proportions of single embryo transfer compared to the HDP group. The majority of women in all groups underwent blastocyst embryo transfer: unaffected (71.4%), HDP (76.8%), GDM (72.0%), and HDP/GDM (75.9%). Figure 1 Flow diagram of participant screening and enrollment. IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; PCOS, polycystic ovary syndrome. Figure 1 Su. Hypertensive disorders of pregnancy and gestational diabetes mellitus affect fetal growth. Am J Obstet Gynecol 2025 Table 1 Basic characteristics of the participants across different groups Table 1 Unaffected HDP alone GDM alone HDP/GDM P value N (%) N=18428 (88.1%) N=872 (4.1%) N=1715 (8.2%) N=108 (0.5%) Age (years) a , b , e 30 (28-33) 31 (28-34) 31 (29-34) 31.5 (28-34.75) <.001 BMI (kg/m²) a , b , c , d , f 22.58 (20.61-25.08) 24.50 (22.10-27.34) 24.03 (21.57-26.64) 26.53 (23.44-28.64) <.001 Gravidity ≥ 1, n (%) * 8743 (47.5%) 400 (45.9%) 829 (48.3%) 52 (48.1%) .698 Parity ≥ 1, n (%) * 4385 (23.8%) 176 (20.2%) 381 (22.2%) 26 (24.1%) .049 Systolic pressure (mmHg) a , c , e , f 114 (106-123) 123 (114-130) 116 (107-124) 120 (112-129) <.001 Diastolic pressure (mmHg) a , b , c , e , f 68 (62-74) 74 (67-80) 69 (63-76) 74 (66-79.75) <.001 Glucose (mmol/L) a , b , c , d , e 5.2 (4.93-5.48) 5.29 (5-5.58) 5.39 (5.08-5.68) 5.425 (5.13-5.69) <.001 Infertility causes, n (%) * <.001  Tubal factors 10403 (56.5%) 471 (54.1%) 965 (56.3%) 68 (63.0%)  Endometriosis 588 (3.2%) 18 (2.1%) 49 (2.9%) 2 (1.9%)  Uterine factors 93 (0.5%) 8 (0.9%) 11 (0.6%) 0  Male factor b 2812 (15.3%) 110 (12.6%) 218 (12.7%) 7 (6.5%)  Other factors 208 (1.1%) 13 (1.5%) 21 (1.2%) 2 (1.9%)  Mixed factors a 4311 (23.4%) 250 (28.7%) 449 (26.2%) 29 (26.9%) Number of oocytes retrieved b , c , e 3 (2-4) 3 (2-4) 3 (3-4) 3 (3-4) <.001 Donor sperm, n (%) 1217 (6.6%) 56 (6.4%) 108 (6.3%) 10 (9.3%) .674 Fertilization methods, n (%) .052  IVF 13604 (73.8%) 631 (72.4%) 1288 (75.1) 83 (76.9%)  ICSI 4123 (22.4%) 201 (23.1%) 357 (20.8%) 16 (14.8%)  Half IVF and half ICSI 701 (3.8%) 40 (4.6%) 70 (4.1%) 9 (8.3%) Endometrial thickness before embryo transfer (mm) a , * 10 (9.0-12.0) 10 (8.5-11.0) 10 (8.5-11.0) 10 (9.0-11.0) <.001 Stage of embryo transferred, n (%) .005  Cleavage-stage embryo a 5265 (28.6%) 202 (23.2%) 480 (28%) 26 (24.1%)  Blastocyst embryo a 13163 (71.4%) 670 (76.8%) 1235 (72.0%) 82 (75.9%) Number of embryos transferred, n (%) a , e .005  1 13254 (71.9%) 674 (77.3%) 1231 (71.8%) 82 (75.9%)  2 5174 (28.1%) 198 (22.7%) 484 (28.2%) 26 (24.1%) Year of treatment, n (%) <.001 2015-2016 b , e 6863 (37.2%) 331 (38.0%) 457 (26.6%) 29 (26.9%) 2017-2018 6485 (35.2%) 298 (34.2%) 606 (35.3%) 37 (34.3%) 2019-2021 b , e 5080 (27.6%) 243 (27.9%) 652 (38.0%) 42 (38.9%) GDM, gestational diabetes mellitus; HDP, hypertensive disorders of pregnancy; BMI , body mass index; IVF, in vitro fertilization; ICSI , intracytoplasmic sperm injection. a P<. 001 for the comparison between the unaffected group and the HDP group b P<. 001 for the comparison between the unaffected group and the GDM group c P <.001 for the comparison between the unaffected group and the HDP/GDMgroup d P <.001 for the comparison between the HDP group and the HDP/GDM group e P<. 001 for the comparison between the HDP and GDM groups f P<. 001 for the comparison between the HDP/GDM and GDM groups ⁎ Gravidity of 4 patients and parity of 4 patients in the unaffected group were missing. *Endometrial thickness of 43 patients in the unaffected group, 7 patients in the GDM group and 1 patient in the HDP group was missing. *Infertility causes of 13 patients in the unaffected group, 2 patients in the GDM group and 2 patients in the HDP group were missing. Su. Hypertensive disorders of pregnancy and gestational diabetes mellitus affect fetal growth. Am J Obstet Gynecol 2025 Flow diagram of participant screening and enrollment. IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; PCOS, polycystic ovary syndrome. Basic characteristics of the participants across different groups GDM, gestational diabetes mellitus; HDP, hypertensive disorders of pregnancy; BMI , body mass index; IVF, in vitro fertilization; ICSI , intracytoplasmic sperm injection. P<. 001 for the comparison between the unaffected group and the HDP group P<. 001 for the comparison between the unaffected group and the GDM group P <.001 for the comparison between the unaffected group and the HDP/GDMgroup P <.001 for the comparison between the HDP group and the HDP/GDM group P<. 001 for the comparison between the HDP and GDM groups P<. 001 for the comparison between the HDP/GDM and GDM groups Gravidity of 4 patients and parity of 4 patients in the unaffected group were missing. *Endometrial thickness of 43 patients in the unaffected group, 7 patients in the GDM group and 1 patient in the HDP group was missing. *Infertility causes of 13 patients in the unaffected group, 2 patients in the GDM group and 2 patients in the HDP group were missing. Table 2 shows a greater birthweight in the unaffected group than in the HDP group (3430 [3150–3723] g vs . 3200 [2690–3600] g, P<. 001) and the HDP/GDM group (3430 [3150–3723] g vs . 3200 [2650–3615] g, P<. 001). The GDM group had a greater birthweight than both the HDP group (3450 [3120–3800] g vs . 3200 [2690–3600] g, P<. 001) and the HDP/GDM group (3450 [3120–3800] g vs . 3200 [2650–3615] g, P<. 001). We observed increased risks of LGA (28.0 vs . 21.1% and P<. 001), macrosomia (12.9% vs . 9.1% and P<. 001), and low birthweight (4.4% vs . 2.8% and P<. 001) in the GDM group compared to the unaffected group. The HDP and HDP/GDM groups had greater risks of SGA (14.4% vs . 3.6% and P<. 001, and 13.9% vs . 3.6%, P<. 001, respectively) and low birthweight (17.6% vs . 2.8% and P<. 001, and 18.5% vs . 2.8% and P<. 001, respectively) than the unaffected group. Table 2 Pregnancy outcome frequencies by exposure group Table 2 Unaffected N  = 18428 HDP alone N  = 872 GDM alone N  = 1715 HDP/GDM N  = 108 P value Neonatal outcomes  Neonatal gender * .904   Male 9673/18351 (52.7%) 452/864 (52.3%) 911/1712 (53.2%) 60/108 (55.6%)   Female 8678/18351 (47.3%) 412/864 (47.7%) 801/1712 (46.8%) 48/108 (44.4%)  Birthweight (g) a,c,e,f,# 3430 (3150-3723) 3200 (2690-3600) 3450 (3120-3800) 3200 (2650-3615) <.001  Size for gestational age #   Macrosomia b , e 1662/18268 (9.1%) 66/863 (7.6%) 221/1710 (12.9%) 11/108 (10.2%) <.001   Low birthweight a , b , c , e , f 513/18268 (2.8%) 152/863 (17.6%) 76/1710 (4.4%) 20/108 (18.5%) <.001   AGA a , b , c 13748/18268 (75.3%) 586/863 (67.9%) 1159/1710 (67.8%) 67/108 (62.0%) <.001   LGA b , e 3859/18268 (21.1%) 153/863 (17.7%) 479/1710 (28.0%) 26/108 (24.1%) <.001   SGA a , c , e , f 661/18268 (3.6%) 124/863 (14.4%) 72/1710 (4.2%) 15/108 (13.9%) <.001 Obstetric outcomes  Preterm delivery a , b , c , e , f 946/18428 (5.1%) 200/872 (22.9%) 163/1715 (9.5%) 25/108 (23.1%) <.001  Post-term delivery 37/18428 (0.2%) 1/872 (0.1%) 1/1715 (0.1%) 0 (0.0%) .536 LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). a P <.001 for the comparison between the unaffected group and the HDP group. b P<. 001 for the comparison between the unaffected group and the GDM group. c P<. 001 for the comparison between the unaffected group and the HDP/GDM group. d P <.001 for the comparison between the HDP group and the HDP/GDM group. e P<. 001 for the comparison between the HDP and GDM groups. f P<. 001 for the comparison between the HDP/GDM and GDM groups. ⁎ Seventy-six patients in the unaffected group, 3 patients in the GDM group, and 8 patients in the HDP group delivered death babies or whose information was missing, and the gender of these babies was not analyzed. # There were 160 patients in the unaffected group, 5 patients in the GDM group, and 9 patients in the HDP group delivered death babies or whose information was missing, and the birthweight of these babies was not analyzed. Su. Hypertensive disorders of pregnancy and gestational diabetes mellitus affect fetal growth. Am J Obstet Gynecol 2025 Pregnancy outcome frequencies by exposure group LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). P <.001 for the comparison between the unaffected group and the HDP group. P<. 001 for the comparison between the unaffected group and the GDM group. P<. 001 for the comparison between the unaffected group and the HDP/GDM group. d P <.001 for the comparison between the HDP group and the HDP/GDM group. P<. 001 for the comparison between the HDP and GDM groups. P<. 001 for the comparison between the HDP/GDM and GDM groups. Seventy-six patients in the unaffected group, 3 patients in the GDM group, and 8 patients in the HDP group delivered death babies or whose information was missing, and the gender of these babies was not analyzed. There were 160 patients in the unaffected group, 5 patients in the GDM group, and 9 patients in the HDP group delivered death babies or whose information was missing, and the birthweight of these babies was not analyzed. The rates of AGA in each exposure group are presented in Table 3 . According to the unadjusted analyses, each of the 3 exposure groups had a lower rate of AGA birthweight than the unaffected groups (HDP: OR: 0.70; 95% CI: [0.60–0.81]; P<. 001; GDM: OR: 0.69; 95% CI: [0.62–0.77]; P<. 001; HDP/GDM: OR: 0.54; 95% CI: [0.36–0.79]; P=. 002). Table 3 Logistic regression analyses of neonatal outcomes. Table 3 Outcome Exposure Unadjusted Adjusted OR (95% CI) P- value aOR (95% CI) P value AGA Unaffected Reference Reference HDP alone 0.70 (0.60,0.81) <.001 0.79 (0.68,0.92) .002 GDM alone 0.69 (0.62,0.77) <.001 0.77 (0.69,0.86) <.001 HDP/GDM 0.54 (0.36,0.79) .002 0.68 (0.46,1.01) .058 SGA Unaffected Reference Reference HDP alone 4.47 (3.64,5.49) <.001 5.67 (4.56,7.04) <.001 GDM alone 1.17 (0.91,1.50) .213 1.34 (1.04,1.72) .023 HDP/GDM 4.29 (2.47,7.45) <.001 6.37 (3.63,11.18) <.001 LGA Unaffected Reference Reference HDP alone 0.80 (0.67,0.96) .017 0.65 (0.54,0.78) <.001 GDM alone 1.45 (1.30,1.62) <.001 1.24 (1.11,1.39) <.001 HDP/GDM 1.18 (0.76,1.84) .455 0.83 (0.53,1.31) .433 Macrosomia Unaffected Reference Reference HDP alone 0.82 (0.64,1.06) .147 0.65 (0.50,0.85) .002 GDM alone 1.48 (1.27,1.72) <.001 1.24 (1.06,1.45) .005 HDP/GDM 1.13 (0.60,2.11) .696 0.76 (0.40,1.44) .416 Low birthweight Unaffected Reference Reference HDP alone 7.39 (6.08,9.00) <.001 7.37 (6.00,9.06) <.001 GDM alone 1.61 (1.25,2.05) <.001 1.55 (1.20,1.99) <.001 HDP/GDM 7.86 (4.80,12.88) <.001 7.77 (4.70,12.84) <.001 LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). aOR, adjusted odds ratio; CI, confidence interval. The aOR and 95% CI were obtained via binary logistic regression analyses. Analyses were adjusted for age, BMI, systolic pressure, diastolic pressure, infertility cause, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transferred, number of embryos transferred, glucose level, and year of treatment. Su. Hypertensive disorders of pregnancy and gestational diabetes mellitus affect fetal growth. Am J Obstet Gynecol 2025 Logistic regression analyses of neonatal outcomes. LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). aOR, adjusted odds ratio; CI, confidence interval. The aOR and 95% CI were obtained via binary logistic regression analyses. Analyses were adjusted for age, BMI, systolic pressure, diastolic pressure, infertility cause, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transferred, number of embryos transferred, glucose level, and year of treatment. In the adjusted analyses, compared with unaffected pregnancies, we observed lower adjusted odds of giving birth to an AGA infant in pregnancies complicated by HDP (aOR: 0.79; 95% CI: [0.68–0.92]; P=. 002) and GDM (aOR: 0.77; 95% CI: [0.69–0.86]; P<. 001) ( Table 3 ). Similarly, the adjusted odds of delivering an AGA infant were reduced for HDP/GDM pregnancies (aOR: 0.68; 95% CI: [0.46–1.01]; P=. 058). The incidence rates of LGA and SGA in each exposure group are given in Table 2 and Figure 2 . The results examining these birthweight outcomes in the adjusted models are given in Table 3 . Figure 2 SGA and LGA incidence by different exposure group. GDM, gestational diabetes mellitus alone; HDP, hypertensive disorders of pregnancy alone; LGA, large for gestational age; SGA, small for gestational age. Figure 2 Su. Hypertensive disorders of pregnancy and gestational diabetes mellitus affect fetal growth. Am J Obstet Gynecol 2025 SGA and LGA incidence by different exposure group. GDM, gestational diabetes mellitus alone; HDP, hypertensive disorders of pregnancy alone; LGA, large for gestational age; SGA, small for gestational age. According to the unadjusted analyses, HDP pregnancies had a greater risk of SGA than unaffected pregnancies (OR: 4.47; 95% CI: [3.64–5.49]; P<. 001), and this difference was significant in the adjusted analyses (aOR: 5.67; 95% CI: [4.56–7.04]; P<. 001). Both unadjusted and adjusted analyses showed that the risk of low birth weight was greater in the HDP group than in the unaffected group (OR: 7.39; 95% CI: [6.08–9.00]; P<. 001; aOR: 7.37; 95% CI: [6.00–9.06]; P<. 001). HDP was associated with a lower risk of delivering an LGA infant according to the unadjusted (OR: 0.80; 95% CI: [0.67–0.96]; P=. 017) and adjusted (aOR: 0.65; 95% CI: [0.54–0.78]; P<. 001) models ( Table 3 ). Compared with unaffected pregnancies, GDM-affected pregnancies had greater risks of SGA (aOR: 1.34; 95% CI: [1.04–1.72]; P=. 023) and low birthweight (OR: 1.61; 95% CI: [1.25–2.05]; P<. 001; aOR: 1.55; 95% CI: [1.20–1.99]; P<. 001). GDM-affected pregnancies had a greater risk of LGA in both the unadjusted (OR: 1.45; 95% CI: [1.30–1.62]; P<. 001) and adjusted (aOR: 1.24; 95% CI: [1.11–1.39]; P<. 001) analyses. In addition, women with GDM had a greater risk of macrosomia than the unaffected group in both the unadjusted (OR: 1.48; 95% CI: [1.27–1.72]; P<. 001) and adjusted (aOR: 1.24; 95% CI: [1.06–1.45]; P=. 005) analyses. Compared with unaffected pregnancies, HDP/GDM-affected pregnancies had a greater risk of SGA (OR: 4.29; 95% CI: [2.47–7.45]; P<. 001) but not LGA (OR: 1.18; 95% CI: [0.76–1.84]; P=. 455) according to unadjusted analyses. After adjustment, the HDP/GDM group had a greater risk of SGA than the unaffected group (aOR: 6.37; 95% CI: [3.63–11.18]; P<. 001), whereas the HDP/GDM group had a similar risk of LGA compared to the unaffected group (aOR: 0.83; 95% CI: [0.53–1.31]; P=. 433). We also observed a greater risk of low birthweight in the HDP/GDM group than in the unaffected group (aOR: 7.77; 95% CI: [4.70–12.84]; P<. 001). As illustrated in Table 4 , pregnancies affected by HDP (aOR: 4.85; 95% CI: [4.06–5.79]; P<. 001), GDM (aOR: 1.76; 95% CI: [1.47–2.11]; P<. 001), and HDP/GDM (aOR: 4.61; 95% CI: [2.91–7.29]; P<. 001) were associated with greater odds of preterm delivery than unaffected pregnancies. In contrast, HDP-,GDM-, and HDP/GDM-affected pregnancies were not associated with increased odds of post-term delivery (HDP: aOR: 0.52; 95% CI: [0.07–3.88]; P=. 528; GDM: aOR: 0.28; 95% CI: [0.03–2.11]; P=. 221; HDP/GDM: aOR: 0.00; 95% CI: [0.00]; P=. 997). In addition, pregnancies affected by HDP (aOR: 4.75; 95% CI: [3.74–6.01]; P<. 001),GDM (aOR: 1.22; 95% CI: [1.09–1.37]; P<. 001), and HDP/GDM (aOR: 3.64; 95% CI: [1.93–6.85]; P<. 001) were associated with greater odds of cesarean section than were unaffected pregnancies. When analyses were restricted to AGA infants ( Table 4 ), the results were similar to those in the whole population. Table 4 Logistic regression analyses of perinatal outcomes Table 4 All infants Outcome Exposure Unadjusted Adjusted OR (95% CI) P- value aOR (95% CI) P value Preterm delivery Unaffected Reference Reference HDP alone 5.50 (4.63,6.52) <.001 4.85 (4.06,5.79) <.001 GDM alone 1.94 (1.63,2.31) <.001 1.76 (1.47,2.11) <.001 HDP/GDM 5.56 (3.54,8.74) <.001 4.61 (2.91,7.29) <.001 Post-term delivery Unaffected Reference Reference HDP alone 0.57 (0.07,4.16) .58 0.52 (0.07,3.88) .528 GDM alone 0.29 (0.04,2.11) .22 0.28 (0.03,2.11) .221 HDP/GDM 0.00 (0.00) .99 0.00 (0.00) .997 Cesarean section Unaffected Reference Reference HDP alone 5.66 (4.48,7.15) <.001 4.75 (3.74,6.01) <.001 GDM alone 1.43 (1.28,1.59) <.001 1.22 (1.09,1.37) <.001 HDP/GDM 4.97 (2.66,9.29) <.001 3.64 (1.93,6.85) <.001 AGA infants alone Outcome Exposure Unadjusted Adjusted OR (95% CI) P- value aOR (95% CI) P value Preterm delivery Unaffected Reference Reference HDP alone 4.26 (3.42,5.31) <.001 3.47 (2.76,4.36) <.001 GDM alone 1.81 (1.46,2.25) <.001 1.64 (1.32,2.05) <.001 HDP/GDM 3.98 (2.12,7.47) <.001 2.89 (1.53,5.49) .001 Postterm delivery Unaffected Reference Reference HDP alone 0.97 (0.13,7.23) .982 0.88 (0.11,6.72) .907 GDM alone 0.49 (0.06,3.65) .490 0.53 (0.07,4.01) .543 HDP/GDM 0.00 (0.00) .998 0.00 (0.00) .997 Cesarean section Unaffected Reference Reference HDP alone 5.47 (4.19,7.15) <.001 4.59 (3.50,6.03) <.001 GDM alone 1.25 (1.10,1.42) <.001 1.12 (0.98,1.28) .086 HDP/GDM 3.62 (1.85,7.11) <.001 2.65 (1.33,5.26) .005 LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). aOR, adjusted odds ratio; CI, confidence interval. The aOR and 95% CI were obtained via binary logistic regression analyses. Analyses were adjusted for age, BMI, systolic pressure, diastolic pressure, infertility cause, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transferred, number of embryos transferred,glucose level and year of treatment. Su. Hypertensive disorders of pregnancy and gestational diabetes mellitus affect fetal growth. Am J Obstet Gynecol 2025 Logistic regression analyses of perinatal outcomes LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). aOR, adjusted odds ratio; CI, confidence interval. The aOR and 95% CI were obtained via binary logistic regression analyses. Analyses were adjusted for age, BMI, systolic pressure, diastolic pressure, infertility cause, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transferred, number of embryos transferred,glucose level and year of treatment. To compare potential risks of fresh versus frozen embro transfer, we conducted subanalyses among the 4 groups, as shown in Table 5 , Table 6 . Women with HDP who underwent fresh embryo transfer had significantly greater risks of SGA (aOR: 6.32; 95% CI: [4.45–8.97]; P<. 001) and low birthweight (aOR: 7.65; 95% CI: [5.35–10.93]; P<. 001). Similarly, those who underwent frozen embryo transfer also had increased risk of SGA (aOR: 5.60; 95% CI: [4.23–7.41]; P<. 001) and low birthweight (aOR: 7.57; 95% CI: [5.86–9.78]; P<. 001) than those unaffected pregnancies. Table 5 Neonatal and perinatal outcomes by different exposures for fresh embryo transfer Table 5 Outcome Exposure Fresh embryo Unadjusted Adjusted OR (95% CI) P- value aOR (95% CI) P value AGA Unaffected Reference Reference HDP alone 0.50 (0.39,0.65) <.001 0.59 (0.45,0.76) <.001 GDM alone 0.73 (0.61,0.87) <.001 0.82 (0.68,0.98) .031 HDP/GDM 0.28 (0.14,0.57) <.001 0.36 (0.18,0.74) .006 SGA Unaffected Reference Reference HDP alone 4.46 (3.21,6.19) <.001 6.32 (4.45,8.97) <.001 GDM alone 0.74 (0.48,1.14) .184 0.83 (0.53,1.29) .419 HDP/GDM 3.77 (1.44,9.86) .007 6.07 (2.25,16.38) <.001 LGA Unaffected Reference Reference HDP alone 1.07 (0.79,1.44) .636 0.81 (0.60,1.11) .198 GDM alone 1.50 (1.25,1.81) <.001 1.29 (1.07,1.56) .008 HDP/GDM 2.44 (1.19,5.01) .015 1.63 (0.78,3.41) .187 Macrosomia Unaffected Reference Reference HDP alone 1.15 (0.76,1.72) .497 0.88 (0.58,1.34) .566 GDM alone 1.44 (1.12,1.85) .004 1.27 (0.98,1.64) .066 HDP/GDM 2.42 (0.99,5.90) .052 1.73 (0.69,4.29) .235 Low birthweight Unaffected Reference Reference HDP alone 6.53 (4.67,9.14) <.001 7.65 (5.35,10.93) <.001 GDM alone 1.14 (0.74,1.75) .537 1.17 (0.75,1.81) .471 HDP/GDM 9.96 (4.42,22.41) <.001 11.46 (4.91,26.71) <.001 Preterm delivery Unaffected Reference Reference HDP alone 5.28 (3.90,7.15) <.001 4.76 (3.47,6.53) <.001 GDM alone 1.76 (1.31,2.37) <.001 1.67 (1.23,2.25) <.001 HDP/GDM 5.26 (2.26,12.25) <.001 4.51 (1.91,10.63) <.001 Post-term delivery Unaffected Reference Reference HDP alone 0.00 (0.00,0.00) .995 0.00 (0.00,0.00) .995 GDM alone 1.23 (0.15,9.74) .843 1.36 (0.16,11.23) .773 HDP/GDM 0.00 (0.00,0.00) .998 0.00 (0.00,0.00) .998 Cesarean section Unaffected Reference Reference HDP alone 5.07 (3.49,7.35) <.001 4.12 (2.82,6.02) <.001 GDM alone 1.42 (1.20,1.69) <.001 1.26 (1.05,1.50) .012 HDP/GDM 9.89 (2.36,41.42) .002 7.38 (1.74,31.23) .007 LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). aOR, adjusted odds ratio; CI, confidence interval. The aOR and 95% CI were obtained via binary logistic regression analyses. Analyses were adjusted for age, BMI, systolic pressure, diastolic pressure, infertility cause, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transferred, number of embryos transferred,glucose level and year of treatment. Su. Hypertensive disorders of pregnancy and gestational diabetes mellitus affect fetal growth. Am J Obstet Gynecol 2025 Table 6 Neonatal and perinatal outcomes by different exposures for frozen embryo transfer Table 6 Outcome Exposure Frozen embryo Unadjusted Adjusted OR (95% CI) P- value aOR (95% CI) P value AGA Unaffected Reference Reference HDP alone 0.81 (0.67,0.97) .029 0.92 (0.76,1.11) .417 GDM alone 0.66 (0.58,0.76) <.001 0.74 (0.64,0.85) <.001 HDP/GDM 0.72 (0.44,1.17) .187 0.90 (0.55,1.47) .682 SGA Unaffected Reference Reference HDP alone 4.81 (3.68,6.28) <.001 5.60 (4.23,7.41) <.001 GDM alone 1.60 (1.17,2.18) .003 1.87 (1.37,2.57) <.001 HDP/GDM 5.00 (2.55,9.82) <.001 6.95 (3.49,13.83) <.001 LGA Unaffected Reference Reference HDP alone 0.68 (0.55,0.86) .001 0.57 (0.45,0.72) <.001 GDM alone 1.41 (1.23,1.63) <.001 1.22 (1.05,1.41) .007 HDP/GDM 0.79 (0.44,1.42) .450 0.58 (0.32,1.05) .073 Macrosomia Unaffected Reference Reference HDP alone 0.68 (0.49,0.95) .026 0.54 (0.39,0.77) <.001 GDM alone 1.50 (1.24,1.81) <.001 1.24 (1.02,1.51) .026 HDP/GDM 0.68 (0.27,1.69) .411 0.46 (0.18,1.15) .097 Low birthweight Unaffected Reference Reference HDP alone 8.14 (6.38,10.38) <.001 7.57 (5.86,9.78) <.001 GDM alone 1.98 (1.46,2.69) <.001 1.83 (1.34,2.50) <.001 HDP/GDM 7.22 (3.85,13.52) <.001 6.53 (3.44,12.39) <.001 Preterm delivery Unaffected Reference Reference HDP alone 5.58 (4.53,6.86) <.001 4.93 (3.97,6.12) <.001 GDM alone 2.04 (1.64,2.54) <.001 1.81 (1.45,2.27) <.001 HDP/GDM 5.67 (3.32,9.68) <.001 4.68 (2.71,8.09) <.001 Post-term delivery Unaffected Reference Reference HDP alone 0.67 (0.09,4.95) .697 0.60 (0.08,4.54) .627 GDM alone 0.00 (0.00,0.00) .990 0.00 (0.00,0.00) .990 HDP/GDM 0.00 (0.00,0.00) .997 0.00 (0.00,0.00) .997 Cesarean section Unaffected Reference Reference HDP alone 5.91 (4.38,7.99) <.001 5.22 (3.85,7.07) <.001 GDM alone 1.42 (1.23,1.64) <.001 1.20 (1.04,1.40) .011 HDP/GDM 3.78 (1.88,7.59) <.001 2.84 (1.40,5.77) .004 LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). aOR, adjusted odds ratio; CI, confidence interval. The aOR and 95% CI were obtained via binary logistic regression analyses. Analyses were adjusted for age, BMI, systolic pressure, diastolic pressure, infertility cause, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transferred, number of embryos transferred, glucose level and year of treatment. Su. Hypertensive disorders of pregnancy and gestational diabetes mellitus affect fetal growth\. Am J Obstet Gynecol 2025 Neonatal and perinatal outcomes by different exposures for fresh embryo transfer LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). aOR, adjusted odds ratio; CI, confidence interval. The aOR and 95% CI were obtained via binary logistic regression analyses. Analyses were adjusted for age, BMI, systolic pressure, diastolic pressure, infertility cause, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transferred, number of embryos transferred,glucose level and year of treatment. Neonatal and perinatal outcomes by different exposures for frozen embryo transfer LGA, large for gestational age and defined as the birthweight percentile over 90% for gestational age; SGA, small for gestational age and defined as the birthweight percentile under 10% for gestational age; AGA, appropriate for gestational age and defined as the birthweight percentile between 90% and 10% for gestational age (inclusive). aOR, adjusted odds ratio; CI, confidence interval. The aOR and 95% CI were obtained via binary logistic regression analyses. Analyses were adjusted for age, BMI, systolic pressure, diastolic pressure, infertility cause, number of oocytes retrieved, endometrial thickness before embryo transfer, stage of embryo transferred, number of embryos transferred, glucose level and year of treatment. Compared to unaffected pregnancies, those with GDM who underwent fresh embryo transfer (aOR: 1.29; 95% CI: [1.07–1.56]; P=. 008) or frozen embryo transfer (aOR: 1.22; 95% CI: [1.05–1.41]; P=. 007) had a greater risk of LGA. Women with GDM who underwent frozen embryo transfer had increased risks of macrosomia (aOR: 1.24; 95% CI: [1.02–1.51]; P=. 026), low birth weight (aOR: 1.83; 95% CI: [1.34–2.50]; P<. 001), and SGA (aOR: 1.87; 95% CI: [1.37–2.57]; P<. 001) compared to unaffected pregnancies. In contrast, women with GDM who underwent fresh embryo transfer did not have an increased risk of macrosomia (aOR: 1.27; 95% CI: [0.98–1.64]; P=. 066), low birth weight (aOR: 1.17; 95% CI: [0.75–1.81]; P=. 471), or SGA (aOR: 0.83; 95% CI: [0.53–1.29]; P=. 419). We also found that women who underwent either fresh or frozen embryo transfers and had pregnancies affected by HDP/GDM had greater risks of SGA, low birthweight, preterm delivery, and cesarean section compared to unaffected pregnancies. Additionally, pregnancies affected by either HDP alone or GDM alone had greater risks of preterm delivery and cesarean section compared to unaffected pregnancies.

Our findings underscores the significantly heightened risk of SGA, low birthweight, preterm delivery, and cesarean section in pregnancies complicated by both HDP and combined presence of HDP and GDM (HDP/GDM) in women undergoing IVF. Moreover, pregnancies solely affected by GDM demonstrated an increased risk of LGA, SGA, low birthweight, macrosomia, preterm delivery, and cesarean section compared to unaffected IVF pregnancies. Notably, adverse perinatal outcomes, such as preterm delivery and cesarean sections, were also more frequent in HDP/GDM-complicated pregnancies, even when the infants were average for gestational age. Additionally, our findings indicate that the detrimental impacts on fetal growth and perinatal outcomes were consistent across different embryo transfer methods in pregnancies affected by HDP/GDM. This finding highlights the importance of early identification and clinical management of HDP and GDM in women underwent IVF treatment, facilitating timely interventions that could mitigate risks during the early stages of pregnancy.

In this study we found several key associations between HDP, GDM, and risk of adverse pregnancy outcomes among women who successfully underwent conventional IVF. Pregnancies affected by HDP alone have greater risks of SGA, low birthweight, preterm delivery, and cesarean section than unaffected pregnancies. Pregnant women affected by GDM alone have greater risk of SGA, low birthweight, LGA, macrosomia, preterm delivery, and cesarean section compared to unaffected pregnant women. The comorbidity of HDP and GDM causes greater risk of SGA, low birthweight, preterm delivery, and cesarean section compared to unaffected pregnancies. A sub-analysis of fresh embryo and frozen embryo transfer among the four exposure groups found that, regardless of whether women underwent frozen or fresh embryo transfer, compared with the unaffected pregnancies, the risks associated with HDP and HDP/GDM co-morbidity remained similar. Several studies have shown that GDM is associated with a greater risk of preeclampsia, cesarean delivery, preterm birth, macrosomia, LGA, shoulder dystocia, hypoglycemia, and jaundice in newborns. 23 , 24 , 25 , 26 Our results align with these studies, supporting the relationship between GDM and LGA, macrosomia, cesarean delivery, and preterm delivery. Interestingly, we found that GDM was also a risk factor for SGA and low birthweight infants, which has not been reported previously and may be a risk specific to IVF pregnancies. Some studies have reported that HDP increases the risk of low birthweight, SGA, preterm birth, cesarean section and NICU admission. 10 , 27 , 28 Our results align with these studies, supporting an association between HDP alone and SGA, low birthweight, cesarean delivery, and preterm delivery in IVF pregnancies. Previous data on the impact of HDP/GDM comorbidity on birthweight outcomes of pregnancies is limited and inconsistent. A study conducted in 2017 that compared birthweight outcomes between pregnancies affected by GDM and those with both HDP and GDM in China indicated that pregnancies complicated by HDP/GDM were associated with a higher risk of LGA infants compared to those solely affected by GDM. 29 Onuoha et al. reported that pregnancies concurrently affected by HDP/GDM have a greater risk of neonatal morbidity, 30 whereas the relative risks of LGA and SGA were not significantly different between HDP/GDM pregnancies and unaffected pregnancies. In contrast, our findings highlight that the rates of SGA, low birthweight, cesarean delivery, and preterm delivery are greater in HDP/GDM pregnancies than in unaffected pregnancies. Our findings imply that, in HDP/GDM comorbidity, the LGA risk usually associated with GDM is not present due to HDP’s SGA influence taking precedence. The specific underlying mechanisms driving this relationship warrant further exploration. Most existing studies of the effects of GDM or HDP on fetal growth have focused on the general pregnant population, confirming associations between GDM and LGA, HDP and SGA, and the co-occurrence of HDP and GDM affecting fetal growth and neonatal outcomes. 10 , 11 , 30 While our study largely supports previous findings, contradictions between our results and others may be due to differences between IVF and normal pregnancy cohorts. Notably, although HDP, GDM, and HDP/GDM have similar effects on perinatal and neonatal outcomes in naturally conceived and IVF women, previous studies have shown that IVF itself can impact perinatal and neonatal outcomes. 31 While this study focused specifically on the effects of HDP, GDM, and HDP/GDM on perinatal and neonatal outcomes within the IVF population, it cannot be concluded that IVF alone 32 does not independently affect perinatal outcomes due to our limited sample size. Further large-scale cohort studies and mechanistic investigations are needed to clarify the specific contributions of HDP, GDM, and IVF to fetal growth and perinatal outcomes in both IVF and naturally conceived populations. Currently, it remains unclear whether the differences in pregnancy outcomes among women undergoing IVF, including those associated with HDP and GDM, are due to infertility-related maternal factors, ART practices, or both. Many studies have investigated the effects of ART on neonatal and perinatal outcomes. A meta-analysis by Rogue et al. revealed that, compared with fresh embryo transfer, frozen embryo transfer is associated with a greater rate of low birth weight and preeclampsia. 31 However, some studies have reported no differences in birth weight between fresh and cryopreserved embryo transfers, 33 making the effects of fresh embryo transfer versus frozen embryo transfer on birth weight controversial. We found that regardless of whether women underwent frozen or fresh embryo transfers, pregnancies affected by HDP/GDM had greater risks of SGA, low birthweight, preterm delivery, and cesarean section, suggesting slowed or delayed growth when compared to unaffected pregnancies. HDP pregnancies that involved either fresh or frozen embryo transfer had a greater risk of SGA and low birthweight compared to unaffected pregnancies. GDM pregnancies with either fresh or frozen embryo transfer occurred had a greater risk of LGA, and GDM pregnancies with frozen embryo transfer had increased risk of macrosomia, low birthweight, and SGA compared to unaffected pregnancies. The exact contribution of HDP and GDM, as well as the type of embryo transfer (frozen or fresh), to the observed effects on neonatal weight and perinatal outcomes need to be further investigated. A strength of our study is its large sample size and data integrity, which enabled us to thoroughly investigate the risks of neonatal weight and perinatal outcomes. Additionally, we excluded patients with pregestational diabetes, chronic hypertension, and maternal age>40 years, which are potential confounders for fetal growth and perinatal outcomes, 34 , 35 thus minimizing their impact of these confounders on our results. Furthermore, this is the first study to examine the effects of HDP/GDM on neonatal weight and perinatal outcomes in the IVF population. However, this study also has several limitations. First, it was conducted at a single academic medical center and affiliated community sites, potentially limiting its generalizability. Second, the dataset used for analyses was derived from clinical rather than research data; which may have introduced unmeasured confounding. For instance, information on several factors known to influence fetal growth—such as fetal anomalies, smoking status 36 and glucose control status 37 —was unavailable, partly due to the reliance on telephone follow-up. Moreover, given the limitations of retrospective clinical data and the need to enhance the robustness of the findings, further prospective studies are warranted. Further investigations should be performed to identify the mechanisms and pathways contributing to birth weight and perinatal outcomes in IVF pregnancies affected by HDP and GDM.

Infertility affects around 8%–12% of couples worldwide, posing a significant reproductive health challenge. 1 To address this, in vitro fertilization (IVF) has become increasingly prevalent. 2 Despite its success, concerns persist regarding the safety of IVF, particularly due to the elevated risks of hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) observed in IVF pregnancies compared with those conceived naturally. 3 , 4 , 5 HDP and GDM are among the most common complications during pregnancy, significantly contributing to maternal and perinatal morbidity and mortality worldwide. 6 , 7 , 8 These conditions are linked to an increased incidence of premature and cesarean deliveries, along with other serious neonatal morbidities. 9 Notably, HDP often leads to small-for-gestational-age (SGA) infants, whereas GDM is predominantly associated with large-for-gestational-age (LGA) infants. 10 , 11 HDP, which includes chronic hypertension, gestational hypertension, and preeclampsia, 12 can cause systemic arteriolar spasms, diminished uterine and placental blood flow, compromised placental function, and placental abruption. These pathophysiological changes significantly heighten the risk of preterm birth and fetal growth restrictions. Conversely, in GDM, excessive glucose transfer to the fetus stimulates increased fetal insulin production, promoting excessive fetal growth and potentially leading to macrosomia and LGA infants. 13 Clinical evidence suggests a causal link between HDP and GDM, where glucose-lowering interventions in GDM have demonstrated efficacy in reducing HDP risk. 14 This association is further corroborated by metabolic profiles in HDP pregnancies that resemble those seen in insulin resistance syndrome, characterized by elevated plasma levels of triglycerides and non-esterified fatty acids. 15 While numerous studies have explored the impact of GDM or HDP on fetal and perinatal outcomes in natural conceptions, 10 , 16 , 17 the impact of combined presence of HDP and GDM (HDP/GDM) on neonatal and perinatal outcomes are still limited, especially in IVF pregnancies. Given the mechanistic interplay between GDM and HDP and their contradictory effects on infant birth weight, this study aims to delineate the individual and combined impacts of HDP and GDM on fetal growth and perinatal outcomes in women undergoing IVF.

The datasets used and/or analyzed during the current study are available from the corresponding author Hong Lv upon reasonable request.