The effect of medical and social factors on the health of children born as a result of ART in late reproductive age women

Introduction

Epidemiological studies conducted in Russia confirmed that the proportion of infertile marriages among the population of reproductive age (for women 15 to 49 years of age) ranges from 8 to 17% [1], which corresponds to the critical level sensu World Health Organization. On average, one in eighth couples faces this problem when planning their first child, and one in six couples face the challenge when planning their second child [2].

The increase in the frequency of infertile marriages and the successful correction of the reproductive health in married families using assisted reproductive technology (ART) in recent years have led to the worldwide increase in the number of children conceived through ART. In this regard, the issue of their development and health is very important [3]. At the same time, the health of children born as a result of ART is still insufficiently investigated. Existing studies were mainly aimed at examining the condition of children in infancy and early childhood. It was shown that children born after the use of ART are statistically significantly more likely to become ill and seek medical help [4, 5]. This can be explained as follows: women of late reproductive age (LRA), i.e., 35-49 years old, who make up the bulk of women seeking ART, most often constitute a risk group, and the course of their pregnancy is complicated with diabetes mellitus, hypertension, etc. Thus, rather poor health of newborn offspring of such mothers is a reflection of maternal health: it can be explained by the aftereffects of pregnancy [6].

All published studies pointed out the critical impact of maternal factors, such as age at the time of conception, obstetric history, social wellbeing, etc. Taking into account the fact that women of LRA are increasingly seeking medical treatment for infertility, it is necessary to separately investigate the characteristics of the development of children’s health in this group of women, and also to examine what medical and social factors affect the health of children born as a result of ART.

Hence, our study goal was to investigate the effect of medical and social factors on the health of children born as a result of ART by LRA women.

Material and Methods

Study subjects and sampling procedure

This study of the effect of medical and social factors on the health of children born as a result of ART by LRA women included 648 preschool-age children (4-6 years old). They constituted the main group (MG). All children resided in the city of Samara and were observed in children’s polyclinics. The control group (CG) included 648 children (4-6 years old) who were born from spontaneous conception and met the following criteria: their mother’s age at birth between 35-45 years, their age from 4 to 6 years, born from a singleton full-term (≥37 weeks of gestation) pregnancy. The main distinguishing feature between the MG and CG was birth after using ART. Donor gametes were not used. The study also included mothers of all these children; hence, the total sample of mothers included 648 mothers of children from the MG with a mean age of 39.11±0.5 years and 648 mothers of children from the CG with a mean age of 38.95±0.76 years.

Methods

We employed the following research methods: sociological (questionnaires), direct observation, analytical, and statistical. To participate in the study, voluntary informed consent was signed by all legal representatives of the children (i.e., their mothers). The health of children in the MG and CG was assessed comprehensively, based on polyclinic visits, medical examinations, and a study of the child’s development history. The analysis included the following parameters characterizing the health of the children under study: annual frequency of illnesses, duration of illnesses during the year, and a number of chronic diseases per child. Depending on the value of the above criteria, all examined children were distributed among three health assessment subgroups.

The subgroup with good health (subgroup I) included children for whom all listed criteria had positive values. The subgroup with fair health (subgroup II) included children with intermediate values of all listed criteria. The subgroup III included children with poor health. They were characterized by an annual frequency of four or more cases of illness, sickness for 40 days or more per year, and three or more chronic diseases per child. This subgroup included children for whom two of the listed signs had positive values. 

To analyze the features of the social and hygienic characteristics, as well as health and lifestyle of mothers raising the examined children, we developed a special questionnaire containing 63 questions, Questionnaire for Medical and Social Examination of the Family of a Child Born in Late Reproductive Age. The compiled questionnaire had the following sections: Medical Activity (11 questions), Social Factors (17 questions), Medical and Biological Risk Factors for Pregnancy and Childbirth (25 questions), and Medical and Biological Risk Factors for Early Childhood (10 questions). We studied the course of pregnancy and childbirth, as well as the morbidity of mothers, based on their questionnaires and outpatient medical records, followed by filling out sample medical records for studying the health of LRA women.

When analyzing the effect of medical and social factors as risk factors for the health of the examined children in the MG and CG, we used the method of assessing the odds ratios (OR). Children other than those with good health (health assessment subgroups II and III) born as a result of ART were compared with children with good health in the CG (health assessment subgroup I), using a four-field table for case-control studies.

Study design

At the first stage of our study, all children were characterized by three health assessment subgroups. At the second stage, we analyzed the features of the social and hygienic characteristics, health, the course of pregnancy and childbirth, as well as morbidity and lifestyle of mothers raising children of the MG and CG. Medical and social risk factors for the children’s health were identified. At the third stage of the study, we analyzed the effect of medical and social factors on the health of children born as a result of ART to LRA women in comparison with the CG.

Statistical data processing

Statistical data processing was carried out on a personal computer by the SPSS Statistics version 21 software using parametric and nonparametric statistics methods. For quantitative features, the normality of distribution was assessed; if the distribution was normal, parametric criteria (mean, error of the mean, Student’s t-test) were used to characterize the feature. For qualitative features, the Pearson’s chi-squared test with Yates’s continuity correction was employed. To detect the statistical relationship between the studied independent features, we used correlation analysis and the Pearson’s criterion. The critical significance level when testing statistical hypotheses was set at 0.05. To determine the strength of the relationship between the studied events, we used the OR calculation; a four-field table was used for case-control studies. OR>1 implied that there was a relationship between the events. OR≤1 suggested no relationship. For each OR value, we indicated the confidence interval (CI), along with the upper and lower limits of CI. 95% CI >1 or <1 implied statistical significance of the relationship between the examined features. 95% CI ≥1 or ≤1 (i.e.,1 was included in the CI values) indicated no relationship between the studied features. We also calculated the standard error of the relative risk (S).

Results

Characterization of the examined children by health assessment subgroups

As a result of the comprehensive assessment of children’s health, the subgroup I (good health) included 18.0% of children in the MG vs. 21.9% in the CG (p=0.055). The proportion of the subgroup including children with poor health in the MG was 56.2% vs. 36.1% in the CG (p=0.048). The remaining children in the MG (25.8%) and CG (42.0%) formed a subgroup with fair health (subgroup II, p=0.046). No age-based differences were found within the subgroups.

Analysis of health features, obstetric history, gynecological anamnesis, and social and hygienic characteristics of mothers raising the examined children

A study of the health status in mothers of the examined children showed that among women in the MG, the level of general morbidity was significantly higher: 2902.4 ‰ vs. 947.7 ‰ in the CG (p<0.001). As for the structure of morbidity in MG mothers, the top place is taken by diseases of the genitourinary system: 1082.6 ‰ vs. 146.9 ‰, i.e., 7.4 times higher (p<0.001). The second place is represented by diseases of the endocrine system: 586.3 ‰ vs. 90.0 ‰ in the CG (i.e., 6.5 times higher p<0.001). The third place belongs to respiratory diseases: 513.7‰ vs. 355.4‰ in the CG (p=0.023). In the MG, 270.1% of mothers have over three chronic diseases vs. 15.2% of mothers in the CG (p<0.001). The rate of comorbidity of chronic diseases per woman in the MG is 2.7±1.2 vs. 0.4±0.1 in the CG (p=0.009).

When studying the obstetric history and gynecological anamnesis of the examined mothers, we discovered that every second woman in the MG had undergone surgical interventions on the pelvic organs vs. every sixth mother in the CG. Sexually transmitted infections were diagnosed and treated in 69.6% of women in the MG, which is 1.7 times more often than in the CG. MG women had a history of abortions, noninflammatory and inflammatory diseases of the genitals 3 times more often. It was revealed that among mothers in the MG, compared with the CG, there was a significantly higher incidence of unfavorable course of previous pregnancies, as well as complications of pregnancy and childbirth, such as nonviable pregnancy, recurrent pregnancy loss, preterm birth, ectopic pregnancy, anemia during pregnancy, gestosis, acute diseases during pregnancy, vaginal infections during pregnancy, and complications of the first and (or) second half of pregnancy (Table 1).

Table 1. Comparative analysis of obstetric and gynecological history, and social and hygienic characteristics of women in the main (MG) and control (CG) groups (per 100 women)

Investigation of the social and hygienic characteristics in mothers revealed the following features: in the MG, women with higher education prevailed, whose professional activity was associated with various adverse workplace conditions, including the majority of mothers in the MG working on a computer, every fourth woman working in conditions of noise pollution, 7.8% of mothers working with chemicals. In the CG, more favorable workplace conditions were observed. Regular workplace conflict situations occurred in every second woman of the MG, along with an increased level of anxiety and stress. The majority of the examined children in both MG and CG were born to families where the parents were officially married. We established that mothers in the MG were smokers 3.9 times more frequently than in the CG (Table 1).

Effect of medical and social factors on the health of children born after ART by LRA women (vs. the control)

Analyzing the effect of medical and social risk factors on the health of children born after the use of ART by LRA women, we employed the odds ratio assessment method (Table 2). We classified the assumed risk factors into the following groups: indicators of parental health (complications in the first and in the second half of pregnancy, chronic diseases in the father and mother, alcohol abuse by the mother and father, hereditary burden), medical activity and lifestyle of families (failure to comply with medical recommendations, smoking during pregnancy by the mother and other family members, children’s participation in sports, commitment to body hardening, being outdoors), and early childhood factors (complicated delivery, short breastfeeding or its absence, low birth weight).

Table 2. Rank distribution of medical and social factors affecting the health of children born as a result of ART by LAR women

We identified 18 significant risk factors that negatively affected the health of children born as a result of ART. They are listed below.

 Indicators of parental health:

1. Father over 40 years old at the time of birth;

2. Mother over 38 years old at the time of birth;

3. Hereditary burden on the maternal side;

4. Complications in the second half of pregnancy;

5. Complications in the first half of pregnancy;

6. Alcohol abuse by the father;

7. Alcohol abuse by the mother;

8. Chronic diseases of the mother;

9. Chronic diseases of the father.

Medical activity and lifestyle of families:

1. Insufficient time spent outdoors with the child;

2. Failure to follow doctor’s prescriptions;

3. Lack of daytime sleep in the child in the weekends;

4. Lack of body hardening in the child;

5. Smoking during pregnancy: father.

6. Smoking during pregnancy: mother.

Early childhood factors:

1. Complicated delivery in mothers;

2. Breastfeeding less than for six months;

3. Low birth weight.

Preterm births and multiple pregnancies, as medical and social factors, were excluded from the study in compliance with the design of group recruitment.

Discussion

Studies examining the effect of ART, along with medical and social factors, on long-term health outcomes in offspring face multiple challenges. First, subfertility of the parents increases the risk of multiple health problems in the offspring, regardless of whether conception was medically assisted or not. The invasiveness of the required treatments probably increases the risk to the offspring. Besides that, it is difficult to control for factors that may also increase the risk of childhood morbidity, such as multiple embryo transfer, preterm birth, low birth weight, maternal chronic diseases, as well as maternal and paternal alcohol abuse and smoking. A challenge in collecting such data is that it takes time to detect associations between rare events and ART. The results obtained in our study are consistent with those of other authors [4, 5, 8].

However, this is the first study conducted in a special group of children born to LRA women after ART and obtaining the data on the effect of parental health indicators, their medical activity, and early childhood factors on the health of children 4-6 years of age.

The field of reproductive medicine is slowly advancing from improving the efficacy of the interventions to focusing on optimizing the health of offspring born after the use of this method. Conducting more and better studies on the relationship between the use of ART and long-term health outcomes in children is essential [7, 8]. However, any increased risk observed among children born as a result of ART should be critically assessed [9, 10].

Over the past three decades, researchers were studying the potential perinatal health risks of children born using ART (4, 9, 10). Currently, a decrease in the number of adverse outcomes associated with a reduction in the number of multiple births is reported [5]. At the same time, it is essential to examine the long-term consequences for the health of children due to the possibility of an increased risk of somatic morbidity in childhood vs. children born after spontaneous conception [3, 11, 12].

 Identification of the most important medical and social factors affecting the health of children born to LRA women is necessary for the development of an algorithm and a program for stratification of the health risk in children born as a result of ART. This is crucial for revealing a group of children with an increased risk of health deviations and for developing a differentiated approach to the formation of children groups that are in need of priority follow-up care.

Conclusion

We identified 18 significant medical and social risk factors that had an adverse effect on the health of children born to LRA women after using ART. The most important of these were insufficient time spent outdoors with the child, complications during childbirth for the mother, mother’s age over 38 years at the time of childbirth, complications in the first and second halves of pregnancy, chronic diseases of the mother, duration of breastfeeding less than six months, and low birth weight of the child.

Limitations

Our study results are limited by the failure to use multivariate analysis methods due to the difficulty of taking into account the indirect impact of interdependent components under conditions of uncertainty. They are also limited by the nonlinear nature of the mutual influence of objects and processes; their insufficient consistency; as well as heterogeneity and inconsistency of information about objects and processes, and their influence on each other.

Acknowledgments

The authors thank the staff of the Regional Center of Reproductive Medicine DYNASTY in Samara, Russia, for the opportunity to review the medical records of women who were enrolled in the ART program at the center.

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in compliance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study protocol was approved by the Ethics Committee of the participating clinical centers. Written informed consent was obtained from all participants prior to their inclusion in the study.