Prediction of fetal growth restriction in obese women

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Introduction

In obese mothers, fetal development and placental formation occur under metabolically altered conditions. Obesity in pregnant women is characterized not only by impaired metabolism of carbohydrates and fats, but also by significant changes in the content of trace elements and vitamins (iron, copper, manganese, vitamin D, A, E and others) [1–3]. Trace substance content may decrease in excess body fat, forming deficiencies, or cumulate, exerting toxic effects [4; 5]. Based on these studies, it is assumed that metals and other chemical elements may be involved in the pathogenesis of obesity and related complications. Copper is an essential nutrient for humans, but both deficiency and excess can be detrimental to the body. Observational studies associate increased copper levels with the development of cardiovascular diseases, liver pathology, and musculoskeletal disorders [6–8]. The role of free copper in the pathogenesis of obesity, insulin resistance and type 2 diabetes mellitus is mediated by the pro-oxidant and pro-inflammatory effects of the metal, which is indirectly confirmed by the inverse correlation between increased copper levels in the serum of obese patients and decreased activity of serum antioxidant systems1. Elevated levels of free copper in the body increase oxidative stress and accelerate tissue and organ damage, thus contributing to the development of disease¹.

Obesity during pregnancy is more likely to cause obstetric complications [9]. Despite excessive maternal nutrition, disorders of uteroplacental circulation can lead to progressive placental insufficiency (PI) and low birth weight babies born at term [10]. Besides, gestation process in obese mother runs amid changes in rheological and coagulation properties of blood – increase in total coagulant potential, decrease in fibrinolytic activity, which leads to disorders of intraplacental hemodynamics and development of pregnancy complications [9]. Placental insufficiency leads to nutritional, endocrine, immune, and gas exchange function disorders resulting in the fetal growth restriction syndrome (FGR) [11]. Morphological criteria of placental insufficiency are formed during the first or second wave of trophoblast invasion (6–8 and 14–16 weeks, respectively) [12], but clinical manifestations in the form of blood flow dysfunction in the uteroplacental channel and fetal developmental retardation are formed in the second half of pregnancy. Obese mothers are twice as likely to give birth to fetuses with growth restriction, due to dysfunction of the placenta and intrauterine production of insulin-like growth factor in the fetus [13]. The main methods for predicting fetal growth restriction are based on ultrasound measurement of fetal size during pregnancy3, the presence of biochemical and genetic markers [14].

Thus, fetal growth restriction remains a difficult pathology to predict and requires further analysis, among others in obese women.

The objective of the study was to develop a method of predicting fetal growth restriction in obese women in the first trimester of pregnancy based on the study of free copper in the blood serum.

Materials and methods

The study was conducted in compliance with the ethical principles of medical research involving human subjects as outlined in the World Health Organisation's Declaration of Helsinki. 85 obese pregnant women at 6-9 weeks of gestation at the Family Planning and Prenatal Diagnostic Centre of the Polyclinic were examined FSFEI HE Perm State Medical University named after Academician E.A.Wagner of the Ministry of Healthcare of the Russian Federation. Obesity was defined by body mass index (BMI) (ratio of height squared (m) to weight (kg)) with a value > 30 kg/m2. All pregnant women were classified into two groups according to free copper percentage: group A – obese pregnant women with free copper > 25 % (n = 26); group B – obese pregnant women with free copper percentage < 25 % (n = 59). The control group consisted of 20 pregnant women with normal body weight. All patients had their serum levels of total copper (Cutot) determined using the colorimetric method [15], ceruloplasmin (CP) according to the method [16], and the percentage of free copper (Cufree) was calculated. Calculation of free copper index was carried out by the formula: CU free = (Сu total – (CP*3)) / Cutotal · 100, where Сufree – content of free copper in blood serum, %; СuTotal – is the content of total copper in serum, µmol/l; CP is the content of ceruloplasmin in serum, mg/ml; 3 is the conversion factor. Methods of descriptive statistics were used to analyse the results obtained; the reliability of intergroup differences was assessed by t-test for independent samples. The difference was deemed reliable at a significance level of p < 0.05. Relative risk was calculated at a confidence interval of 95 %. A prognostic model of the risk of a certain outcome was constructed using the binary logistic regression method.

Results and discussion

The copper content in serum of pregnant women with normal body weight was 33.7 ± 2.1 µmol/l, significantly different from women in group A (45.4 ± 8.6 µmol/l, p = 0.01) and group B (41.5 ± 7.3 µmol/l, p = 0.01), with no differences between groups A and B, p = 0.71. The serum ceruloplasmin content of obese women in group A was lower than that of women in group B (631.4 ± 94.6 vs. 734.3 ± 81.8 mg/l), and was not significantly different from that of patients with normal body weight (677.4 ± 83.4 mg/l). Free copper percenttage was calculated according to the formula, which reflects the amount of this element not bound to proteins, mainly ceruloplasmin. The calculation of free copper in women with normal body weight revealed the value of 9.8 ± 1.1 %. The rate of free copper in group A of obese pregnant women was 2.5 times higher than that of group B (34.6 ± 6.9 % vs. 14.3 ± 7.0 %, p = 0.041). Free divalent copper in excessive amounts has been proved to damage cells and induce the expression of tissue procoagulant factor [17]. Such changes in the body can lead to the development of intravascular blood clotting and thrombus formation. Expressed endothelial dysfunction develops in disorders of copper metabolism during pregnancy [18].

In group A, pregnant women with free copper > 25 % in the placental tissue were 1.5 times more likely to have changes typical of chronic placental insufficiency in the placental tissue (Table), and 6.4 times more likely to develop a syndrome of fetal growth restriction than those with less than 25 % free copper [OR = 6.38; 95 % CI 2.39–16.99 p = 0.01]. In obesity combined with high levels of Cu free (25 %), placental insufficiency was detected in 61.5 % of cases, which in 38.5 % resulted in fetal growth restriction, compared to obese women, where placental insufficiency was detected in 39 % and fetal growth restriction in only 6 % (p = 0.001) (Figure).

 

Relative risk of placenta pathology development (histologic signs) in obese woment, %

Histologic indicators	Group А ( n = 26), abs.value/%	Group В (n = 59), abs.value/%	OR	95 % CI [LL-UP]	p
Villi stromal fibrosis	15/57.7	20/33.9	1.70	1.04–2.76	0.04
Intervillous thrombosis	10/38.5	9/15.2	2.52	1.16–5.46	0.01
Umbilical vein thrombosis	7/26.9	1/1.7	15.88	1.16–122.64	< 0.001
Dissociation	21/80.8	16/27.1	2.98	1.88–4.71	< 0.001
Sclerosing	3/11.5	6/10.1	1.12	0.30–4.19	0.85
Obliterant angiopathy of stem villi	9/34.6	8/13.6	2.55	1.11–5.87	0.02
Placental insufficiency chronical (total) compensated sub-compensated decompensated	16/61.5 6/23.0 4/15.4 6/23.0	23/39.0 10/16.9 6/10.1 7/11.9	1.57 1.36 1.51 1.62	1.01–2.45 0.55–3.35 0.46–4.91 0.56–4.63	0.05 0.50 0.49 0.36

N o t e s:  OR – odds ratio, 95 % CI [LL-UP] – confidence interval, lower and upper limits.

 

Fig. Number of cases of placental insufficiency and fetal growth restriction in obese women, %. Group А – obese women with free copper index content equal/more 25 %; Group В – obese women with free copper index content less than 25 %

 

Fetal growth restriction development under placental insufficiency in women with body mass index greater than 30 kg/m²  is accompanied by a higher percentage of free copper content (34,6 ± 6,9 против 14,3 ± 7,0 %, р = 0,041).

Stepwise logistic regression for predicting the development of fetal growth restriction determined the following predictors: placental insufficiency and percentage of free copper > 25 %, where placental insufficiency gave a proportion of correct prediction of 62.0 % (p = 0.01) and free copper of > 25 % increased the proportion of correct prediction to 74 % (p = 0.02). Prediction of fetal growth restriction in case of placental insufficiency is carried out as follows: at the first screening examination at the women's health clinic, a woman is diagnosed with a lipid metabolism disorders when she is registered for a pregnancy checkup. The content of ceruloplasmin and total copper and the percentage of free copper are determined in the blood serum of the pregnant woman during compulsory screening tests the first trimester. An obese woman with a free copper content > 25 % is considered to be at risk of fetal growth restriction and is predicted to suffer from this complication. The patent was granted № 2785904 on 26.09.22 г.²

Conclusions

The free copper level of > 25 %, determined in the first trimester of pregnancy, can be considered as a predictor of fetal growth restriction in obese pregnant women.

 

¹ Copper. (2024, April 22). Linus Pauling Institute, available at: https://lpi.oregonstate. edu/mic/ minerals/ copper

² Makarova E.L., Terekhina N.A., Padrul M.M. Prediction of fetal growth restriction in obese pregnant women. patent, № 2785904 Russian Federation. Application № 2022125228 dd. 26.09.2022. Date of registration 14.12.22г, date of publication 14.12.22. Bulletin № 35; p. 6.

About the authors

E. L. Makarova

M.A. Tverye City Clinical Hospital

Author for correspondence.
Email: makarova_803@mail.ru
ORCID iD: 0000-0002-1330-8341

Degree Candidate of the Department of Obstetrics and Gynecology №1

Russian Federation, Perm

N. A. Terekhina

E.A. Vagner Perm State Medical University

Email: makarova_803@mail.ru
ORCID iD: 0000-0002-0168-3785

DSc (Medicine), Professor, Head of the Department of Biological Chemistry

Russian Federation, Perm

M. M. Padrul

E.A. Vagner Perm State Medical University

Email: makarova_803@mail.ru
ORCID iD: 0000-0002-6111-5093

DSc (Medicine), Professor, Head of the Department of Obstetrics and Gynecology № 1

Russian Federation, Perm

References

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