Abstract
Objective:
To assess the association between delayed fusion of the amniotic and chorion diagnosed at 16 weeks of gestation and maternal-fetal outcomes.
Methods:
This prospective cohort study was conducted at Tianjin Central Hospital of Gynaecology Obsterics, China, from February 2022 to March 2024. A total of 331 singleton pregnant women with low risk of fetal chromosomal abnormalities were enrolled. Ultrasound examinations at 16 weeks’ gestation identified cases of delayed fusion of amnion and chorion. Maternal and fetal outcomes were compared between the delayed fusion group and the timely fusion group.
Results:
Delayed fusion occurred in 28.00% (91/325) of cases. Post-delivery fetal membrane histopathology revealed no structural abnormalities attributable to delayed fusion. No significant differences were observed in maternal complications (gestational diabetes mellitus, hypertensive disorders, obesity, anemia) and 5-minute Apgar scores between groups. In addition, miscarriage rates were unaffected by delayed fusion. Notably, the delayed fusion group had a significantly higher incidence of preterm births (8.79% (8/91) vs. 2.56% (6/234), P = 0.028). After adjustment for confounders, infants in the delayed fusion group had a significantly lower mean birth weight (172.05 g less) than those in the timely fusion group.
Conclusion:
Delayed fusion at 16 weeks did not alter fetal membrane structure after delivery and was not associated with most maternal or neonatal complications in this cohort. However, it may be an independent risk factor for preterm birth and reduced birth weight, warranting further investigation.
Keywords: Maternal-fetal medicine, Ultrasound screening, Delayed fusion of amnion and chorion, Preterm birth, Birth weight
Introduction
During early pregnancy, the fetus is surrounded by amniotic fluid and the chorion, separated by the coelomic cavity. As gestation advances, particularly around 14–16 weeks, the amniotic cavity enlarges and eventually fuses with the chorion, obliterating the coelomic cavity and forming the fetal membranes.1,2 Persistent chorionic–amniotic separation, whether spontaneous or secondary to invasive intrauterine procedures such as amniocentesis or fetal surgery, is considered abnormal and remains a subject of ongoing investigation.
Chorionic–amniotic separation observed at different gestational ages may reflect delayed fusion, or alternatively, a secondary separation after initial fusion. The latter, usually detected between 20 and 30 weeks of gestation, has been associated with increased risks of preterm delivery, premature rupture of membranes, and fetal demise.3,4,5,6,7 In contrast, the impact of delayed fusion diagnosed at 16 weeks on adverse outcomes has been insufficiently studied, with available reports largely confined to cases involving fetal chromosomal abnormalities8,9,10 or structural anomalies such as ileal atresia and umbilical cord ulceration.11
The physiological fusion of the amniotic and chorionic membranes during the first and second trimesters contributes to the structural stability of the gestational sac, enabling it to withstand the mechanical stresses of pregnancy, while also participating in nutrient and gas exchange and hormone production. Moreover, fusion establishes the fetal membrane barrier, which protects the fetus against infection and other external insults.12,13 The clinical implications of incomplete fusion by 16 weeks, particularly in pregnancies considered at low risk for fetal chromosomal abnormalities, remain unclear. Clarifying the significance of delayed fusion at this stage may help refine antenatal risk stratification and optimize surveillance strategies.
The present study aimed to investigate the impact of delayed amniotic–chorionic fusion, defined as persistent separation of the chorionic and amniotic membranes beyond 16 weeks of gestation, as detected by ultrasonography,14 on maternal and fetal outcomes in pregnancies with a low risk of fetal chromosomal abnormalities.
Materials and methods
Study design and participants
This prospective cohort study was conducted at the Prenatal Diagnosis and Fetal Medicine Center of Tianjin Central Hospital of Gynaecology Obsterics between February 2022 and March 2024. Singleton pregnant women undergoing routine prenatal examinations were consecutively enrolled.
The inclusion criteria were: gestational age between 11 and 13+6 weeks confirmed by ultrasound, singleton pregnancy, nuchal translucency < 3 mm, and low-risk results for fetal chromosomal abnormalities on noninvasive prenatal testing. Exclusion criteria were conception via assisted reproductive technology, maternal smoking during pregnancy,15 preexisting diabetes mellitus or chronic hypertension, and sonographic diagnosis of subchorionic hematoma or amniotic band syndrome.
Gestational age assessment and histopathological examination
Gestational age was determined according to the last menstrual period and subsequently adjusted by crown–rump length measured by ultrasonography at 11-13+6 weeks of gestation.16 After delivery, the fetal membrane tissue was immediately immersed in formalin. Following 24 hours of fixation, the tissue was dehydrated, embedded in paraffin, and sectioned at a thickness of 4 μm. Sections were then stained with hematoxylin and eosin (H&E).
Ultrasound evaluation of amnion and chorion
All participants underwent standardized ultrasound examination at 16 weeks of gestation using a Voluson E10 system (GE Healthcare). Ultrasound images were digitally archived in the hospital information system. Eligibility required the demonstration of freely separated amniotic membranes on first-trimester ultrasound performed at 11–13+6 weeks of gestation (Fig. 1A). At 16 weeks, the status of amniotic-chorionic fusion was independently assessed by two certified sonographers (L.Z. and L.L.). Fusion was classified as timely or delayed. Timely fusion was defined as the presence of a single, continuous hyperechoic line representing the fused membranes, whereas delayed fusion was defined as the persistence of a distinct hypoechoic space between the amnion and chorion (Fig. 1B, C).
Figure 1.
Representative images illustrating the developmental status of the amnion and chorion across gestation. A Ultrasound image of the amniotic sac at 11–13+6 weeks of gestation. During this period, the amnion and chorion are not yet fused, and the yolk sac is clearly visible. B Timely fusion of the amnion and chorion, visible as a single, continuous hyperechoic line. C Delayed fusion of the amnion and chorion. Arrows indicate distinct amniotic membranes not yet fused with the chorion. Scale bar = 1 cm.
Outcome measures
Data on gestational age at birth (days), neonatal birth weight, and Apgar scores were retrieved from medical records. Neonates were classified as preterm (< 37 weeks of gestation) or full-term (≥ 37 to 42 weeks) according to gestational age at birth.
Sample size estimation
As the exact incidence of delayed amniotic–chorionic fusion has not been previously reported, an a priori sample size calculation was not feasible. Consequently, all eligible participants during the designated study period were included. No missing data were present for the analyzed clinical variables.
Interobserver agreement assessment
Interobserver agreement for the assessment of delayed amniotic–chorionic fusion was evaluated using Cohen’s kappa statistic in a randomly selected subset of 33 cases (10% of the cohort). The inter-rater agreement between the two blinded sonographers was excellent (κ = 0.930).
Covariates and confounders
Potential confounding factors known to influence neonatal birth weight were extracted from medical records and structured questionnaires administered at enrollment. These included neonatal sex, pregnancy-related complications (e.g., gestational diabetes mellitus, hypertensive disorders), maternal age, parity (nulliparous vs. multiparous), and maternal education level (≤ junior college vs. ≥ bachelor’s degree). Sociodemographic data were collected via structured questionnaires at enrollment.
Statistical analysis
Continuous variables with non-normal distribution were presented as medians and interquartile ranges, and categorical variables as frequencies and percentages. Between-group comparisons were performed using the Mann–Whitney U test for continuous variables and Pearson’s chi-square or continuity correction tests for categorical variables. Simple linear regression was initially used to examine unadjusted associations between potential predictors and neonatal birth weight. Variables with P values < 0.20 in bivariate analyses were subsequently included in a multivariable linear regression model using the enter method to identify independent predictors.17 A two-sided P value < 0.05 was considered statistically significant. All analyses were conducted using SPSS software (version 26.0; IBM Corp., Armonk, NY, USA).
Ethical approval
The study protocol was approved by the Ethics Committee of Tianjin Central Hospital of Gynaecology and Obstetrics (No. 2021KY105, December 23, 2021) and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrollment.
Results
The original dataset included 331 pregnant women. After excluding 6 participants lost to follow-up, the final study cohort comprised 234 pregnancies with timely amniotic–chorionic fusion and 91 pregnancies with delayed fusion (Fig. 2).
Figure 2.
Flowchart of the study. ART: Assisted reproduction technology; HP: Hypertention; NT: Nuchal translucency; NIPT: Noninvasive prenatal testing.
Delayed fusion of the amnion and chorion at 16 weeks was observed in 28.00% (91/325) of the cohort. Ultrasound examination conducted before delivery (37-42 weeks of gestation) demonstrated fusion of the amnion and chorion, appearing as a single linear structure (Fig. 3A, B). Postpartum histopathological evaluation of the fetal membranes (chorion-amnion) using H&E staining revealed similar morphological features in both the delayed fusion and timely fusion groups (Fig. 3C, D).
Figure 3.
Delayed fusion did not affect fetal membrane structure. A&B Representative ultrasound images of fetal membranes in the group of delayed fusion of amnion and chorion (A) and in the group of fused amnion and chorion (B) at 37-42 weeks of gestation. Scale bar = 1 cm. C&D Representative HE images of fetal membranes in the group of delayed fusion of amnion and chorion (C) and in the group of fused amnion and chorion (D) after delivery (200X). HE: Hematoxylin-eosin staining.
No significant differences were observed between the two groups regarding the incidence of gestational diabetes mellitus, hypertensive disorders of pregnancy, obesity, or anemia, suggesting that delayed amnion-chorion fusion does not affect the occurrence of these pregnancy complications. Likewise, the rates of miscarriage (0.43% (1/234) vs. 1.10% (1/91)) and live birth (99.57% (233/234) vs. 98.90% (90/91)) were comparable between groups (Table 1).
Table 1.
The association of maternal and neonatal characteristics with timely and delayed fusion of amnion and chorion.
| Characteristic | Timely fusion (n = 234) | Delayed fusion (n = 91) | Statistical analysis | P |
|---|---|---|---|---|
| Maternal characteristics | ||||
| Maternal age (years) | 31.00 (28.75, 34.00) | 30.00 (28.00, 34.00) | –0.492 | 0.623* |
| Mode of delivery | 2.776 | 0.096† | ||
| Vaginal delivery | 120 (51.28) | 56 (61.54) | ||
| Cesarean section | 114 (48.72) | 35 (38.46) | ||
| Parity | 1.179 | 0.277† | ||
| Primipara | 166 (70.94) | 70 (76.92) | ||
| Multipara | 68 (29.06) | 21 (23.08) | ||
| Pregnancy-related complications | ||||
| Gestational diabetes mellitus | 46 (19.66) | 16 (17.58) | 0.183 | 0.669† |
| Hypertensive disorders | 15 (6.41) | 8 (8.79) | 0.565 | 0.452† |
| Obesity | 44 (18.80) | 23 (25.27) | 1.677 | 0.195† |
| Anemia | 11 (4.70) | 3 (3.30) | 0.065 | 0.798‡ |
| Educational level | 4.367 | 0.037† | ||
| Junior college or below | 49 (20.94) | 10 (10.99) | ||
| Bachelor’s degree or above | 185 (79.06) | 81 (89.01) | ||
| Pregnancy outcomes | < 0.001 | > 0.999‡ | ||
| Live birth | 233 (99.57) | 90 (98.90) | ||
| Gestational age at delivery | 4.812 | 0.028‡ | ||
| ≥ 37 weeks | 227 (97.01) | 82 (90.11) | ||
| < 37 weeks | 6 (2.56) | 8 (8.79) | ||
| Spontaneous abortion | 1 (0.43) | 1 (1.10) | – | – |
| Neonatal outcomes (live births only) | ||||
| Gestational age at birth (days) | 276.00 (271.00, 281.00) | 276.00 (270.00, 281.00) | –0.185 | 0.927* |
| Apgar score (5 min) | 10.00 (10.00, 10.00) | 10.00 (10.00, 10.00) | –0.398 | 0.691* |
| Birth weight by sex (g) | 3330.00 (3070.00, 3590.00) | 3175.00 (2960.00, 3405.00) | –3.158 | 0.002* |
| Male | 3410.00 (3130.00, 3600.00) | 3200.00 (3025.00, 3450.00) | –2.089 | 0.037* |
| Female | 3300.00 (3027.50, 3565.00) | 3140.00 (2765.00, 3385.00) | –2.593 | 0.010* |
| Noeonatal sex | 0.672 | 0.412† | ||
| Male | 115 (49.36) | 49 (54.44) | ||
| Female | 118 (50.64) | 41 (45.56) |
Data were presented as median (IQR) or n (%). P < 0.05 considered statistically significant different. IQR: Interquartile range; –: Spontaneous abortion occurred in one patient per group, both non-live births; therefore, no statistical test was applied.
*Mann-Whitney U test.
†Chi-squared values.
‡Continuity correction Chi-squared test.
Among women with live births, the rate of preterm delivery was significantly higher in the delayed fusion group than in the timely fusion group (8.79% (8/91) vs. 2.56% (6/234), P = 0.028), indicating that delayed fusion may increase the risk of preterm birth. Although the gestational age at delivery did not differ significantly, neonates in the delayed fusion group had lower mean birth weights, with an overall reduction of 155 g compared to those in the timely fusion group. Stratified by sex, male neonates (n = 164) in the delayed fusion group weighed 210 g less on average, whereas female neonates (n = 159) had a 160 g lower mean birth weight.
Potential confounders of birth weight are summarized in Table 2. Variables including gestational diabetes mellitus (P = 0.136), hypertensive disorders of pregnancy (P < 0.001), obesity (P = 0.019), gestational age at birth (P < 0.001), and infant sex (P = 0.088) were identified as possible confounders (P < 0.20). After adjustment in multivariable regression models, delayed amniotic-chorionic fusion was independently associated with a significantly lower neonatal birth weight, with infants in the delayed fusion group weighing 172.05 g less than those in the timely fusion group.
Table 2.
Predictive factors of newborn birth weight based on bivariate linear regression.
| Variable | Bivariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| B (95% CI) | β | P | B (95% CI) | β | P | |
| Maternal age (years) | –5.914 (–20.511, 8.683) | –0.044 | 0.426 | – | – | – |
| GDM | 102.449 (–32.251, 237.149) | 0.083 | 0.136 | 121.044 (20.169, 221.918) | 0.098 | 0.019 |
| Hypertensive disorders | –490.492 (–694.812, –286.173) | –0.255 | < 0.001 | –240.743 (–405.107, –76.379) | –0.125 | 0.004 |
| Maternal obesity | 155.547 (25.372, 285.723) | 0.130 | 0.019 | 175.891 (76.467, 275.315) | 0.147 | 0.001 |
| Maternal anemia | 123.530 (–137.544, 384.604) | 0.052 | 0.353 | – | – | – |
| Educational level | ||||||
| Junior college or below | Reference | – | – | Reference | – | – |
| Bachelor’s degree or above | –56.140 (–195.646, 83.365) | –0.044 | 0.429 | – | – | – |
| Gestational age at birth (weeks) | 27.512 (23.705, 31.319) | 0.622 | < 0.001 | 25.989 (22.254, 29.723) | 0.587 | < 0.001 |
| Infant sex | ||||||
| Female | Reference | – | – | Reference | – | – |
| Male | 92.204 (–13.795, 198.202) | 0.095 | 0.088 | 119.655 (40.929, 198.380) | 0.123 | 0.003 |
| Fusion of amnion and chorion | ||||||
| Timely fusion | – | – | – | Reference | – | – |
| Delayed fusion | – | – | – | –172.050 (–260.098, –84.003) | –0.159 | < 0.001 |
CI: Confidence interval; B: Unstandardized regression coefficient; β: Standardized coefficient; GDM: Gestational diabetes mellitus; –: Not applicable or indicating the variable was not included in the multivariate model due to lack of statistical significance in bivariate analysis (P > 0.2) or clinical relevance.
Discussion
In our prospective cohort, approximately one in three pregnancies exhibited separation of the amnion and chorion on ultrasound at 16 weeks. Delayed amniotic-chorionic fusion was not associated with hypertensive disorders of pregnancy, gestational diabetes mellitus, obesity, or spontaneous abortion; however, it was linked to higher rates of preterm birth and lower neonatal birth weight. To our knowledge, this is the first study to demonstrate that delayed amniotic-chorionic fusion at 16 weeks may represent a sonographically detectable risk factor for adverse maternal-fetal outcomes.
The precise timing of physiological fusion between the amnion and chorion remains a topic of debate. Only one previous study involving 200 structurally normal singleton fetuses reported complete fusion by 14 weeks.10 In our prior clinical observations, we noted that some women carrying otherwise healthy fetuses still exhibited unfused amnion and chorion beyond 14 weeks. In the present study, we systematically assessed amniotic-chorionic fusion at 16 weeks in a cohort of Chinese pregnant women and found that approximately one-third (91/325) of pregnancies displayed delayed fusion on ultrasound. Importantly, delayed fusion in these cases represented a temporary delay in union, as all instances ultimately showed fusion on follow-up scans without evidence of amniotic band syndrome (second-trimester data not shown), and postpartum histopathological analysis revealed no significant differences in the fetal membranes between groups.
Persistent separation of the chorioamniotic membrane is generally considered abnormal.2 The gestational timing of its diagnosis significantly influences pregnancy outcomes. For example, chorioamniotic membrane separation diagnosed at 28 weeks is strongly associated with an increased risk of preterm delivery,14 and detection before 30 weeks carries a higher risk than diagnoses made after 30 weeks.18 Delayed amniotic-chorionic fusion at 14–18 weeks has also been linked to fetal structural and/or chromosomal abnormalities.8,10,19 However, in pregnancies with a low risk of fetal chromosomal anomalies, the clinical significance of delayed fusion identified during the first and second trimesters has remained unclear. Our findings indicate that delayed fusion at 16 weeks does not significantly affect miscarriage rates or other pregnancy-related complications, including gestational diabetes mellitus, hypertensive disorders, obesity, or anemia, but it is associated with a significantly higher incidence of preterm birth.
Fetal birth weight serves as a direct indicator of intrauterine growth.20,21 In this study, neonates born to pregnancies with delayed fusion at 16 weeks weighed on average 172.05 g less than those in the timely fusion group. Future investigations should consider additional parameters to determine whether reduced birth weight associated with delayed fusion affects postnatal growth and developmental outcomes.
The fusion of the amnion and chorion is critical in early pregnancy for the proper development of the amniotic sac and placenta. The precise cellular and molecular mechanisms underlying this process remain incompletely understood. It is thought to involve a combination of cellular interactions, signaling pathways, and tissue remodeling. Formation of specialized junctions between amniotic and chorionic cells may facilitate fusion,22 and these biological processes likely contribute to the disappearance of the extraembryonic coelom.23 Notably, prior studies have suggested that separation of the amnion and chorion at 15–16 weeks of gestation may be associated with oligohydramnios,8,24 implying that adequate amniotic fluid volume may play a role in the fusion process. Future studies are warranted to further elucidate the cellular and molecular mechanisms of amniotic-chorionic fusion and to investigate potential effects on fetal growth.
This study has several novel contributions. First, contrary to previous research proposing 14 weeks of gestation as the fusion milestone, we found that approximately one-third of pregnancies still exhibited delayed amniotic-chorionic fusion at 16 weeks, highlighting that the timing of fusion warrants further investigation. Second, while prior studies have largely focused on the association between amnion–chorion separation and preterm birth or fetal chromosomal abnormalities, our prospective cohort study is the first to evaluate delayed fusion in pregnancies at low risk for chromosomal anomalies. The findings clearly indicate that delayed fusion of the amnion and chorion is an ultrasound-detectable marker associated with preterm birth, even in otherwise low-risk pregnancies. These results have important implications for clinical practice, potentially informing prenatal counseling, monitoring strategies, and early interventions.
This study has several limitations. First, the exact gestational age at which fusion occurred could not be precisely determined, as longitudinal tracking was not performed. Second, delayed fusion was treated as a dichotomous variable due to the limited number of cases. Future research should consider a multilevel classification based on the distance between the amnion and chorion to more accurately assess the impact of chorioamniotic membrane separation on maternal and fetal outcomes.
Conclusion
Delayed fusion of the amnion and chorion at 16 weeks may significantly increase the incidence of preterm birth and affects the neonatal birth weight. Future multicenter studies with larger sample sizes are needed to validate these findings, establish standardized diagnostic criteria, and clarify the clinical threshold associated with low neonatal birth weight and preterm birth by quantitatively measuring the chorionic-amniotic separation distance.
Acknowledgements
We thank epidemiologist Xinyan Wang (Tianjin Central Hospital of Gynaecology Obsterics, Tianjin 300100, China) for reviewing the statistical methods section of the manuscript.
Funding
This study was sponsored by Tianjin Health Research Project (Grant No. 2023007 to JSC and Grant No. TJWJ2023MS030 to LZ) and Natural Science Foundation of Tianjin (Grant No. 21JCYBJC00100 to JSC).
Author Contributions
Qimei Lin, Jiasong Cao, Lei Zhang, and Ying Chang made substantial contributions to the conception and design of the work. Qimei Lin and Jiasong Cao participated in data acquisition, processing, statistical analysis, drafting and revising the manuscript; Lei Zhang and Ying Chang revised the manuscript; Lei Zhang, and Li Liu screened for delayed fusion of amnion and chorion; Shuqi Wang and Jing Yu collected data on pregnancy outcomes; Jing Yu checked the final version. Liying Yao, Xiaomin Zhao, and Yongmei Shen were involved in recruitment. Zongjin Li participated in the design of the research. All authors approved the final version for publication.
Conflicts of Interest
None.
Data Availability
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
Editor Note
Ying Chang is one of the editorial board members of Maternal-Fetal Medicine. The article was subject to the journal’s standard procedures, with peer review handled independently of this editor and the associated research groups.
Footnotes
Qimei Lin, Jiasong Cao, and Lei Zhang contributed equally to this study.
How to cite this article: Lin Q, Cao J, Zhang L, Yu J, Wang S, Yao L, Zhao X, Liu L, Shen Y, Li Z, Chang Y. The Impact of Delayed Fusion of Amnion and Chorion on Maternal and Fetal Outcomes: A Prospective Cohort Study. Maternal Fetal Med 2026;8(1):19–25. doi: 10.1097/FM9.0000000000000312.
References
- [1].Bromley B, Shipp TD, Benacerraf BR. Amnion-chorion separation after 17 weeks’ gestation. Obstet Gynecol 1999;94(6):1024–1026. doi: 10.1016/s0029-7844(99)00457-3. [DOI] [PubMed] [Google Scholar]
- [2].Kim YN Jeong DH Jeong SJ, et al. Complete chorioamniotic membrane separation with fetal restrictive dermopathy in two consecutive pregnancies. Prenat Diagn 2007;27(4):352–355. doi: 10.1002/pd.1673. [DOI] [PubMed] [Google Scholar]
- [3].Soni S Moldenhauer JS Spinner SS, et al. Chorioamniotic membrane separation and preterm premature rupture of membranes complicating in utero myelomeningocele repair. Am J Obstet Gynecol 2016;214(5):647.e1–647.e6477. doi: 10.1016/j.ajog.2015.12.003. [Google Scholar]
- [4].Lewi L Hanssens M Spitz B, et al. Complete chorioamniotic membrane separation. Case report and review of the literature. Fetal Diagn Ther 2004;19(1):78–82. doi: 10.1159/000074266. [DOI] [PubMed] [Google Scholar]
- [5].Graf JL Bealer JF Gibbs DL, et al. Chorioamniotic membrane separation: a potentially lethal finding. Fetal Diagn Ther 1997;12(2):81–84. doi: 10.1159/000264436. [DOI] [PubMed] [Google Scholar]
- [6].Severi FM Bocchi C Voltolini C, et al. Thickness of fetal membranes: a possible ultrasound marker for preterm delivery. Ultrasound Obstet Gynecol 2008;32(2):205–209. doi: 10.1002/uog.5406. [DOI] [PubMed] [Google Scholar]
- [7].Qi W Zhao P Wang W, et al. Magnetic resonance imaging of the supra-cervical fetal membrane detects an increased risk of prelabor rupture of membranes. Front Endocrinol (Lausanne) 2022;13:1001538. doi: 10.3389/fendo.2022.1001538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Bronshtein M, Zimmer EZ. Oligohydramnios with amnio-chorionic separation at 15-16 weeks’ gestation. Prenat Diagn 1995;15(2):161–164. doi: 10.1002/pd.1970150209. [DOI] [PubMed] [Google Scholar]
- [9].Abboud P Mansour G Zejli A, et al. Chorioamniotic separation after 14 weeks’ gestation associated with trisomy 21. Ultrasound Obstet Gynecol 2003;22(1):94–5. doi: 10.1002/uog.140. [DOI] [PubMed] [Google Scholar]
- [10].Ulm B, Ulm MR, Bernaschek G. Unfused amnion and chorion after 14 weeks of gestation: associated fetal structural and chromosomal abnormalities. Ultrasound Obstet Gynecol 1999;13(6):392–395. doi: 10.1046/j.1469-0705.1999.13060392.x. [DOI] [PubMed] [Google Scholar]
- [11].Goto H Isohata H Yamazaki Y, et al. Spontaneous complete chorioamniotic membrane separation in a fetus with ileal atresia and umbilical cord ulcer: a case report. J Clin Ultrasound 2025;53(2):369–372. doi: 10.1002/jcu.23865. [DOI] [PubMed] [Google Scholar]
- [12].Menon R, Richardson LS, Lappas M. Fetal membrane architecture, aging and inflammation in pregnancy and parturition. Placenta 2019;79:40–45. doi: 10.1016/j.placenta.2018.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Kamphof HD Posthuma S Gordijn SJ, et al. Fetal growth restriction: mechanisms, epidemiology, and management. Maternal Fetal Med 2022;4(3):186–196. doi: 10.1097/fm9.0000000000000161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].Zhu KH Young BC Shamshirsaz AA, et al. Outcomes of prenatally diagnosed spontaneous chorioamniotic membrane separation in singleton pregnancies: a systematic review of case series and case reports. Prenat Diagn 2020;40(11):1366–1374. doi: 10.1002/pd.5767. [DOI] [PubMed] [Google Scholar]
- [15].Nakamura A Pryor L Ballon M, et al. Maternal education and offspring birth weight for gestational age: the mediating effect of smoking during pregnancy. Eur J Public Health 2020;30(5):1001–1006. doi: 10.1093/eurpub/ckaa076. [DOI] [PubMed] [Google Scholar]
- [16].Carey JC Klebanoff MA Hauth JC, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 2000;342(8):534–540. doi: 10.1056/NEJM200002243420802. [DOI] [PubMed] [Google Scholar]
- [17].Silva S Saunders C Zajdenverg L, et al. Predictive factors for birth weight of newborns of mothers with gestational diabetes mellitus. Diabetes Res Clin Pract 2018;138:262–270. doi: 10.1016/j.diabres.2018.01.032. [DOI] [PubMed] [Google Scholar]
- [18].Corroenne R Yepez M Barth J, et al. Chorioamniotic membrane separation following fetal myelomeningocele repair: incidence, risk factors and impact on perinatal outcome. Ultrasound Obstet Gynecol 2020;56(5):684–693. doi: 10.1002/uog.21947. [DOI] [PubMed] [Google Scholar]
- [19].Modi BP Washington S Walsh SW, et al. Expression patterns of the chromosome 21 MicroRNA cluster (miR-99a, miR-125b and let-7c) in chorioamniotic membranes. Placenta 2017;49:1–9. doi: 10.1016/j.placenta.2016.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Mao Y Zhang C Wang Y, et al. Association between paternal age and birth weight in preterm and full-term birth: a retrospective study. Front Endocrinol (Lausanne) 2021;12:706369. doi: 10.3389/fendo.2021.706369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Li C Peng Y Zhang B, et al. Birth weight prediction models for the different gestational age stages in a Chinese population. Sci Rep 2019;9(1):10834. doi: 10.1038/s41598-019-47056-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Amberg BJ Hodges RJ Rodgers KA, et al. Why do the fetal membranes rupture early after fetoscopy? A review. Fetal Diagn Ther 2021;48(7):493–503. doi: 10.1159/000517151. [DOI] [PubMed] [Google Scholar]
- [23].Fitzsimmons ED, Bajaj T. Embryology, Amniotic Fluid. In: StatPearls (Internet). Treasure Island (FL): StatPearls Publishing; 2025 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541089/. Accessed August, 18, 2025. [Google Scholar]
- [24].ten Broek CM Bots J Varela-Lasheras I, et al. Amniotic fluid deficiency and congenital abnormalities both influence fluctuating asymmetry in developing limbs of human deceased fetuses. PLoS One 2013;8(11):e81824. doi: 10.1371/journal.pone.0081824. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.