Risk factors associated with fetal growth restriction in pregnancies complicated by thick placenta

Abstract

Background

To identify risk factors affecting the occurrence of fetal growth restriction (FGR) in cases of thick placenta.

Methods

The retrospective study included 128 women who gave birth with a diagnosis of thick placenta between February 2016 to September 2022. Based on FGR (defined as birth weight less than the 10th percentile for gestational age), the participants were divided into FGR group and non-FGR group. Data included maternal demographic characteristics, pregnancy and placental parameters, and neonatal outcomes were analyzed.

Results

There was no significant difference regarding maternal demographic characteristics within two groups (P > 0.05). The rate of preeclampsia and abnormal umbilical artery pulsatility index was significantly higher in FGR group compared with non-FGR group (P < 0.05); A trend of gradual growth of placental thickness and thinner thickness of initial-onset thick placenta were more frequently to see in FGR group (P < 0.05). Higher rate of worse composite neonatal outcome was noted in the FGR group as compared with non-FGR group (P < 0.05). Univariate logistic regression analysis found that the emergence of preeclampsia, abnormal umbilical artery pulsatility index, a trend of gradual growth of placental thickness and reduced thickness of initial-onset thick placenta has a positive relation with the occurrence of FGR. The highest area under curve (AUC) of thickness of initial-onset thick placenta (cutoff = 50.5 mm) for predicting FGR was 0.715. The AUC could be improved to 0,798, 0.821, 0.740 when combined with preeclampsia, abnormal umbilical artery pulsatility index, and a trend of gradual growth of placental thickness, respectively. The AUC of thickness of initial-onset thick placenta combined with preeclampsia and abnormal umbilical artery pulsatility index to predict FGR was the highest (AUC=0.869).

Conclusion

Thickness of initial-onset thick placenta combined with preeclampsia and abnormal umbilical artery pulsatility index is expected to be valid and reliable predictors for FGR prediction.

Background

Fetal growth restriction (FGR), is a complex condition involving placental dysfunction at multiple levels [1, 2]. The condition is associated with increased risks of adverse perinatal and neonatal outcome [3], and is a major cause of stillbirth [4]. By contrast, planned delivery of FGR reduces stillbirth but may be associated with increased neonatal morbidity related to iatrogenic prematurity [5]. Fetuses with FGR present with increased risk for abnormal brain structure and function [6]. Additionally, FGR has a strong influence in fetal cardiovascular health [7] and is an important risk factor for late-onset hypertension [8]. As an significant public health burden, FGR has a 20% to 30% risk of recurrence [9], and there is no available effective cure for FGR other than delivery [10], even aspirin only provides a modest risk reduction in women at risk [11].

Given the above, early diagnosis, close follow-up and timely delivery of pregnancies with FGR are important for improved perinatal outcome [12]. However, gold standards to detect growth-restricted fetuses are lacking [13]. Therefore, better methods of stratifying women at highest risk of FGR have the potential to result in improved experience and outcomes of pregnancy [14]. Along with increasing popularity and availability of the expertise of ultrasound has enabled it to be used in monitoring and evaluation of FGR [15]. Since changes in placental morphology may reflect poor placental development [16] and could be used as an indicator to assess placental function [17], thus, examination of placental morphometry can possibly disclose information for the detection of FGR [18].

Among these placental morphological parameters, placental thickness (PT) is more informative [19] and highly reproducible [20], with measurements being optimized with ultrasound technique [21]. The PT represents how dense the vascularization and branching of the chorionic villi are for nutrient exchange and is the main parameter of placental growth, can provide indirect information about the fetus and the placenta. Under normal condition, the central region of the most placenta has the thickest diameter. The association between FGR and PT has been extensively explored, and the role of thick placenta in determining the occurrence of FGR was still inconclusive [22, 23]. Therefore, the purposes of this study were to identify the relationship between increased PT and FGR through serial evaluation of thick placenta throughout the pregnancy, and determine risk factors associated with FGR in pregnancies with thick placenta.

Materials and methods

Study design

This study was performed at seven obstetrics departments affiliated to the Anhui maternal and Child Health care Hospital, Hefei, China between February 2016 to September 2022, it is the largest tertiary obstetrics and gynecology hospital in Anhui province, with 20,000 deliveries on average per year.

The inclusion criteria included women with singleton pregnancies who underwent routine prenatal care throughout gestation in our hospital, with ultrasound finding of thick placenta, and delivery at the author’s institution with detailed antepartum and postpartum information. Pregnancy age was determined by fetal crown-rump measured by the first trimester ultrasound.

The exclusion criteria were multiple pregnancies, known fetal chromosomal or structural anomaly, immune and non-immune hydrops fetalis, intrauterine or maternal infection, placental abnormalities (placenta previa, placental lakes, placental chorioangioma, chorioangiomatosis, and cord angiomyxoma), pre-gestational diseases, gestational diabetes, unsure of gestational age, and missing records.

All pregnant women underwent PT measurement trans-abdominally at each routine screening ultrasound (GE VOLUSON E10 using a curvilinear transducer-3.5 MHz). The PT was measured in millimeters (mm) at the level of cord insertion site if it is centric or <2 cm eccentric, if the cord insertion was marginal or velamentous, the thickest portion of the placenta was observed [24]. Three measurements were carried out for each evaluation, and the mean value of the measurements was recorded. Meanwhile, fetal biometry including biparietal diameter, head circumference, femur length, and abdominal circumference was assessed as did routinely. The evaluation of the umbilical artery was also conducted [25]. Placentas were determined to be thick if the thickness value was above the 95th percentile for gestational age [26].

Due to an increased rate of perinatal morbidity and mortality, the need for strengthened antenatal surveillance should be performed for pregnant women with thickened placenta. However, until currently there were no recommendations per leading obstetric organizations and experts regarding types of surveillance and frequency of antenatal surveillance in pregnancies complicated by a thickened placenta. According to existing literature, when a thickened placenta is identified, a more thorough investigation to determine the etiology of thickened placenta should be carried out. If no established etiology can be determined, repeat sonographic measurement should be performed [27]. In our hospital, monitoring included umbilical artery at an interval of 2 weeks. For thickened placenta in the third trimester, ultrasonic monitoring 1 time per week should be considered.

Information on maternal and pregnancy characteristics was recorded, regarding maternal age; body mass index (BMI); gravidity; parity; mode of delivery; occurrence of placental abruption and placental adhesion; maternal ethnicity; health conditions (tobacco and alcohol use); the presence of preeclampsia, eccentric umbilical cord insertion, oligohydramnios and abnormal umbilical artery pulsatility index; gestational week of initial-onset thick placenta; thickness of initial-onset thick placenta; the maximum PT; growth trend of PT.

Neonatal outcome parameters included gestational age at delivery, birth weight, Apgar score < 7 at 5 min, and neonatal intensive care unit (NICU) admission.

All the above-mentioned data were collected from the electronic medical records.

Definition

Preeclampsia is defined as a blood pressure reading of 140/90mmHg or greater, measured on two separate times four hours apart after 20 weeks of gestation, co-existing with proteinuria, or without proteinuria but accompanied by at least one of the following end-organ dysfunctions: renal involvement, impaired liver function, pulmonary edema and prodromal signs like visual and cerebral symptoms [28].

FGR refers to fetal birth weight less than the 10th percentile for gestational age according to the local population growth charts [29].

Abnormal umbilical artery pulsatility index is described as pulsatility index > 95th centile for umbilical artery.

Oligohydramnios refers to amniotic fluid index less than 5 cm [30].

Thickness of initial-onset thick placenta refers to the thickness of the placenta when thick placenta is first discovered.

Gestational week of initial-onset thick placenta refers to the gestational week when thick placenta is first discovered.

Growth trend of PT refers to changes in placental thickness as gestational age increases.

Statistical analysis

The statistical analyses were performed by SPSS 13.0 statistical packages (SPSS Inc., Chicago, USA.). Counting variables were expressed by percentage. Continuous variables were expressed by mean and standard deviation (SD). Compared between two groups were analyzed with the t-test for continuous variables and the Chi-square test for categorical variables as appropriate. A univariate analysis was performed using a logistic regression model to identify the association between FGR and pregnancy parameters. The odds ratio (OR) and its 95% confidence interval (CI) were utilized to quantify this association. Receiver operating characteristic (ROC) curve was constructed to evaluate the predictive ability of various variables for the occurrence of FGR. A P < 0.05 was used only for statistical significance.

Results

During the study period, a total of 30,000 pregnant women underwent ultrasound examinations at our institution, among which, 128 cases met the inclusion criteria and with a diagnosis of thicken placenta. Of these, women who delivered FGR infants were selected as cases (FGR group, 55), women who delivered normally growth fetuses were controls (non-FGR group, 73).

The patient characteristics and pregnancy outcomes of the study population were presented in Table 1. No clinically significant differences were found between two groups regarding maternal age, BMI, gravidity and parity (P > 0.05). Percentage of placental abruption and placental adhesion was not different in FGR group compared to non-FGR group (P > 0.05). However, study participants in FGR group were more frequently to undergo cesarean section (P < 0.05). All the participants were Han Chinese and denied a history of tobacco and alcohol use.

Table 1.

Comparison of baseline characteristics and pregnancy outcomes of the study population between two groups

Variables	FGR group (n = 55)	non-FGR group (n = 73)	t/χ2	P
Maternal age (years)	29.5 ± 5	30.7 ± 5.3	1.27	0.206
BMI (kg/m2)	21.6 ± 3.4	22.1 ± 3.3	0.72	0.474
Gravidity (n, %)			0.11	0.948
1	29(52.7)	39(53.4)
2	15(27.3)	21(28.8)
≥ 3	11(20.0)	13(17.8)
Multiparity (n, %)	18(32.7)	22(30.1)	0.10	0.754
Cesarean delivery (n, %)	39(70.9)	35(47.9)	6.78	0.009
Placental abruption (n, %)	6(14.0)	4(8.7)	0.37	0.544
Adherent placenta (n, %)	8(14.5)	11(15.1)	0.01	0.934

FGR fetal growth restriction, BMI body mass index

Data are expressed by mean ± SD or n (%); P < 0.05 is considered statistically significant

Pregnancy characteristics of the study population were shown in Table 2. Compared with non-FGR group, incidence of preeclampsia and abnormal umbilical artery pulsatility index was significantly higher in FGR group (P < 0.05). Additionally, the trend towards gradual increase in PT with advancing gestational age in placentas from FGR group was more common compared to placentas in non-FGR (P < 0.05). Furthermore, thickness of initial-onset thick placenta was statistically thinner in FGR group compared to non-FGR group (P < 0.05). On the other hand, rate of eccentric umbilical cord insertion and oligohydramnios, gestational week of initial-onset thick placenta, and the maximum PT did not differ between-groups (P > 0.05).

Table 2.

Comparison of pregnancy characteristics of the study population between two groups

Variables	FGR group (n = 55)	non-FGR group (n = 73)	t/χ2	P
Eccentric umbilical cord insertion (n, %)	10(18.2)	12(16.4)	0.07	0.796
Oligohydramnios (n, %)	6(10.9)	13(17.8)	1.18	0.277
Gestational week of initial thicken placenta (weeks)	26.2 ± 4.9	28.1 ± 6.8	1.77	0.079
The maximum PT (millimeters)	60.7 ± 10	59.9 ± 9	-0.45	0.657
Preeclampsia (n, %)	29(52.7)	13(17.8)	17.35	< 0.0001
Abnormal umbilical artery pulsatility index (n, %)	23(41.8)	3(4.1)	27.56	< 0.0001
Gradual increase in PT (n, %)	51(92.7)	43(58.9)	18.40	< 0.0001
Thickness of initial thicken placenta (millimeters)	43.7 ± 9.6	51.4 ± 10.5	4.22	< 0.0001

FGR fetal growth restriction, PT placental thickness

Data are expressed by mean ± SD or n (%); P < 0.05 is considered statistically significant

Table 3 depicted the results of the univariate logistic analysis of the correlation among the FGR and various parameters based on Table 2. Women with thick placenta complicated by preeclampsia, abnormal umbilical artery pulsatility index or a trend of gradual growth of PT had a positive relation with the occurrence of FGR (OR = 5.148, 95% CI 2.313–11.455, P < 0.05; OR = 16.771, 95% CI 4.692–59.943, P < 0.05; OR = 8.895, 95% CI 2.904–27.247, P < 0.05; respectively). In addition, the reduced thickness of initial-onset thick placenta also had a positive relation with the occurrence of FGR (OR = 0.926, 95% CI 0.890–0.964, P < 0.05).

Table 3.

Univariate logistic analysis for the correlation between the various parameters and fetal growth restriction

Variables	Wald χ2	p	OR (95%CI)
Preeclampsia (n, %)	16.123	< 0.001	5.148(2.313–11.455)
Abnormal umbilical artery pulsatility index (n, %)	18.824	< 0.001	16.771(4.692–59.943)
Gradual increase in PT (n, %)	14.643	< 0.001	8.895(2.904–27.247)
Thickness of initial thicken placenta (millimeters)	14.207	< 0.001	0.926(0.890–0.964)

PT placental thickness, OR odds ratio, CI confidence interval

P < 0.05 is considered statistically significant

Table 4 described comparison of neonatal outcomes between two groups. There were 10 cases of fetal death, all of which occurred in FGR group. 8 out of 10 fetal deaths were medical termination of pregnancy (cases 1–8 due to severe fetal distress and intrauterine growth restriction, parents chose to terminate the pregnancy concerned that complications of extremely preterm or very preterm). The remaining 2 cases were as a result of intrauterine fetal death. In follow-up visits, gestational age at delivery was earlier and birth weight was smaller in FGR group than non-FGR group (P < 0.05). As expected, a higher proportion of lower Apgar scores and NICU admission was observed in FGR group on comparing with non-FGR group (P < 0.05).

Table 4.

Comparison of neonatal outcomes between two groups

Variables	FGR group (n = 55)	non-FGR group (n = 73)	t/χ2	P
Gestational age at delivery (weeks)	35.3 ± 4.1	38.6 ± 2.4	5.59	< 0.0001
Asphyxia (n, %)	3(5.5)	0(0.0)	4.08	0.044
Birth weight (kilogram)	1.9 ± 0.7	3.2 ± 0.6	11.51	< 0.0001
Grognosis			59.89	< 0.0001
Fetal demise (n, %)	10(18.2)	0(0.0)
NICU admission (n, %)	30(54.5)	5(6.8)

FGR fetal growth restriction, NICU neonatal intensive care unit

Data are expressed by mean ± SD or n (%); P < 0.05 is considered statistically significant

ROC analyse with the area under curve (AUC) of four variables was shown in Fig. 1. The thickness of initial-onset thick placenta had a highest AUC (0.715) when the optimal cut-off value was 50.5 mm, the sensitivity was 54.8%, the specificity was 81.8%. To derive optimal predictability, the thickness of initial-onset thick placenta was combined with preeclampsia, abnormal umbilical artery pulsatility index or a trend of gradual growth of PT, and the AUC was 0,798, 0.821, 0.740, respectively, with a sensitivity of 87.7%, 93.2%, 61.6%, a specificity of 58.2%, 56.4%, 80%, respectively. In addition, the AUC of thickness of initial-onset thick placenta combined with preeclampsia and abnormal umbilical artery pulsatility index was 0.869, with 90.4% sensitivity and 74.5% specificity.

Fig. 1.

The receiver operating characteristic curve of four variables in pregnant women with thick placenta to identify the optimal accuracy for the prediction of FGR. A represents ROC curve of thickness of initial-onset thick placenta combined with preeclampsia and abnormal umbilical artery pulsatility index; B represents ROC curve of thickness of initial-onset thick placenta combined with abnormal umbilical artery pulsatility index; C represents ROC curve of thickness of initial-onset thick placenta combined with preeclampsia; D represents ROC curve of thickness of initial-onset thick placenta combined with a trend of gradual growth of PT; D represents ROC curve of thickness of initial-onset thick placenta. FGR, fetal growth restriction; ROC, receiver operating characteristic; PT, placental thickness

Discussion

A thicken placenta, is usually identified by sonography measurement in most studies. The incidence of thicken placenta is thought to be rare, occurring in approximately 0.6% to 7.8% of obstetric sonography [31]. A thick placenta has been found to be consistent with insufficient placentas [32] and correlated with many maternal and fetal abnormalities [31]. Previous studies have demonstrated the involvement of thickened placenta in the increased incidence of FGR. In a retrospective observational study, PT was measured in single gravidas during 16 to 40 weeks of gestation, the authors showed that thick placenta was associated with FGR [23]. A review reinforced this association, finding PT was higher in placenta syndrome (including FGR) compared to uncomplicated pregnancies [33]. Similar results were demonstrated in a prospective observational longitudinal study, in which PT at 32 and 36 weeks was measured by ultrasound in 130 uncomplicated singleton pregnant mothers, authors concluded that the increased incidence of low-birth-weight babies in women with thick placenta [22]. In study of comparing the data of women who delivered small-for-gestational-age (SGA) infants with those of women who delivered non-SGA infants, authors opined that a relatively thick placenta was a better predictor of SGA during the second trimester of pregnancy [34].

In contrary to above-mentioned researches, our study mainly focused on serial measurements of abnormal PT through the complete pregnancy period, and detailed information was available, enabling the in-depth understanding of the relationship between FGR and thickened placenta. To our understanding, this is the first report on the topic. As it was shown in our study, not all pregnant women with thickened placenta will be complicated with FGR. In the current study, we observed that women who delivered FGR infants had a significantly higher incidence of preeclampsia and abnormal umbilical artery pulsatility index, and both variables were positively associated with the occurrence of FGR. It has been well-established that the most common placental pathology underlying preeclampsia is maternal vascular malperfusion [35]. Meanwhile, maternal vascular malperfusion is also associated with abnormal in umbilical artery Doppler [25]. Therefore, it is likely that the underlying mechanism for the development of FGR in pregnancies complicated with thicken placenta is the vascular compromise that is a result from abnormal placental development and is expressed by maternal vascular malperfusion, and the emergence of preeclampsia and abnormal umbilical artery Doppler is the best proof of that.

Another noteworthy results of the current study were that the changes in placental thickness profile were positively associated with the occurrence of FGR in pregnancies with thicken placenta, including a trend of gradual growth of PT. Additionally, compared with pregnant women in the non-FGR group, patients.

who developed FGR had significantly thinner thickness of initial-onset thick placenta. During normal pregnancy, PT has a positive correlation with neonatal birth weight [36]. In contrast, reduced PT is indicative of impaired development and function of the placenta [37]. Previous reports have described an association of decreased PT with elevated risk of low birth weight [38–40]. This might be explained by inadequate arborization of the villous tree results in decreased vascular nutrient exchange. To meet the fetal demands, the placenta will compensatory proliferation thereby result in thickened placenta. However, increase in PT does not mean increased placental function. In support of this, we demonstrated in the current study that no significant difference in the maximum PT between those with FGR compared to those without FGR. Our findings were in agreement with a previous study, who stated that increased PT was due to over-inflation of the inter-villous space by maternal blood rather than by the adaptive formation of functional placental tissue [41].

In the study, the optimum cut-off value of thickness of initial-onset thick placenta for FGR prediction was found to be 50.5 mm with 54.8% sensitivity and 81.8% specificity (area under the ROC curve 0.715, P < 0.0001). However, accuracy of thickness of initial-onset thick placenta is still not optimal and a combination of more variables will be helpful for the prediction of FGR. Hence, ROC curve analysis was performed to further evaluate the utility of thickness of initial-onset thick placenta combined with preeclampsia, abnormal umbilical artery pulsatility index and a trend of gradual growth of PT. It is noteworthy that the AUC of thickness of initial-onset thick placenta combined with preeclampsia and abnormal umbilical artery pulsatility index was the highest (AUC=0.869), which means that the combination of thickness of initial-onset thick placenta, preeclampsia and abnormal umbilical artery pulsatility index has the best predictive ability for FGR.

Regarding the neonatal outcomes, the results from our data found an increased incidence of poor Apgar scores and NICU admissions, and reduced gestational age at delivery and birth weight among cases complicated with thickened placenta and FGR. The increase in adverse perinatal outcome in the FGR group compared to the control non-FGR group indicated that the thickened placenta complicated by FGR may represent a latent phase in serious placental dysfunction.

Strengths and limitations

Our study had several limitations. First, this was a retrospective study with a small sample size, the generalizability of our findings may be limited; Second, in our study, we did not differentiate pathologic FGR from constitutionally small infants, and given the lower incidence of abnormal PT, we didn’t have enough cases for subtype analysis i.e. early onset and late onset FGR; Third, routine pathological examination was not performed for all placentas in our study, thus limiting our deeper level of assessment of underlying pathologies driving the risk of FGR in pregnancy with thick placenta; However, this study also has a number of strengths. A main strength was that the study was conducted at a single tertiary referral center, all the patients were follow up till childbirth and delivered at the same center, enabling us to collect detailed information on maternal and pregnancy characteristics, and detailed information about growth trend of abnormal PT from the serial measurements; Furthermore, the study was done with consideration of fetal outcomes, strengthen this study to achieve more conclusive results; Finally, all the sonographers in this study have received professional training, and PT were measured precisely and recorded by well-trained data collectors under the close supervision of the senior sonographer, which was good for elimination of inter- and intra-observer variabilities.

Conclusions

In conclusion, the current study suggests that in prenatal follow-up, combined evaluation of thickness of initial-onset thick placenta and the emergence of preeclampsia and abnormal umbilical artery pulsatility index has important clinical value for the early prediction of FGR in women with thick placenta. Future prospective studies with larger numbers of patients are warranted to confirm these findings. Through which, we could identify at risk pregnancies for growth restriction or even increased risk of adverse neonatal outcomes.

Abbreviations

FGR

Fetal growth restriction

PT

placental thickness

BMI

body mass index

NICU

neonatal intensive care unit

SD

standard deviation

OR

odds ratio

CI

confidence interval

SGA

small-for-gestational-age

ROC

receiver operating characteristic

AUC

area under curve

Authors’ contributions

J Yi produced the initial full write up of the manuscript; J Yi, XL Li, XY Liu and GP Ma contributed to data collection and analysis; J Yi, L Chen and XL Meng revised the final manuscript carefully.

Funding

Not applicable.

Data availability

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This retrospective research was approved by Anhui Maternal and Child health care Hospital. All methods were performed in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.