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PERINATAL COMPLICATIONS IN CHILDREN, WHICH WERE BORN
AFTER ASSISTED REPRODUCTIVE TECHNOLOGIES WITH IN
VITRO FERTIZILATION
Abdujapparova Naziraxon Erikli qizi
Obstetrician-gynaecologist at
Republican Specialized Scientific and Practical Medical
Center for Mother and Child Health of Fergana Branch
https://doi.org/10.5281/zenodo.13879640
Introduction.
In fertility problems affect 8-12% of couples of
reproductive age. Singletons born after IVF have a higher risk of adverse
perinatal outcomes such as gestational age and low birth weight, as well as
multiple meta-indicators of preterm birth (PTB), low birth weight and small for
gestational age (SGA). - confirmed by analyses. The relative risk (RR) after IVF
for PTB is 1.54 and 1.84 compared with natural singletons and the odds ratio
(OR) was 1.55. The development of IVF techniques over time and antagonist or
low-dose gonadotropin protocols and the assessment of perinatal outcomes of
recent cohorts remain important. Many factors associated with IVF may be
associated with negative perinatal outcomes. Gonadotropin stimulation
increases the risk of LBV or SGA at birth, particularly when supraphysiological
estradiol concentrations are reached on the trigger day or when many oocytes
are collected. Gonadotropin stimulation is also associated with a higher risk of
ovarian hyperstimulation syndrome, pregnancy-associated hypertension, and
gestational diabetes for the mother, and appears to be independently associated
with preterm birth. Otherwise, singletons resulting from moulting cycles pose
significantly lower risks for PTB and LBV, but higher risks for gestational age
and higher birth weight. By delaying embryo transfer in moulting cycles,
gonadotropins have no direct effect on pregnancy. Epigenetic changes are
triggered and DNA methylation is influenced by embryo cultures,
cryopreservation and laboratory methods . In addition, parental age, health and
subfertility are associated with higher perinatal risk. PTB is supported by a
meta-analysis. In studies with indifferent pregnant siblings, differences in
consanguinity were less pronounced or non-existent, leading to the conclusion
that primary infertility also plays a role. The Bern IVF cohort was established to
evaluate obstetric, perinatal and long-term outcomes in children born after
different IVF procedures stimulated and unstimulated performed in a single
center with standardized laboratory and embryo culture conditions. Natural
cycle IVF (NC-IVF) is based on the concept of natural follicle recruitment and
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single oocyte selection, while the growth of multifollicular oocytes is common in
gonadotropin-stimulated IVF. NC-IVF can serve as a model for the development
of natural ovulation, and comparison with SIVF allows assessing the impact of
gonadotropin stimulation on perinatal outcome. The aim of this study was to
first compare the perinatal outcomes of the Bern IVF cohort with those of a
fertility cohort at a third centre and the All Live Birth Registry; and second, the
registry to determine the effect of Gonadotrophin stimulation by comparing and
NC-IVF for children born in Switzerland.
Materials and methods.
The Bern IVF cohort includes couples treated at
the Department of Gynecological Endocrinology and Reproductive Medicine.
Data were collected at the Clinical Trials Unit of the University of Bern using the
electronic study data capture tools. Redcap is a secure web-based platform
designed to support data collection for research. All women born between
November 2010 and August 2018 were included, regardless of any health status.
Women with missing information on gestational age and birth weight were
excluded in case of multiple births and perinatal death.
A cohort of women from the ODS Department of Obstetrics and
Gynecology at the University Hospital of Bern were followed up during regular
ultrasound visits during the first trimester and until delivery. In this study, data
on conception, pregnancy and delivery were collected and singleton women
with a live birth were included in the analysis. All women without pre-existing
chronic diseases or disorders were included. Only women treated with IVF,
ovarian stimulation or fertilization, low perinatal mortality, women refusing
further use of their medical data for the study and excluded cases with missing
information on gestational age or birth “n” analysis.
The Swiss Live Birth Registry
of the Federal Statistical Office collects
systematic data on all live births in Switzerland. Only basic data on mothers age,
ethnicity, occupation, gender and infants gestational age, birth weight, length,
sex, siblings were collected; no medical data on the health of the mother, the
newborn, or information on the conception, pregnancy and birth process were
included. All live births registered between November 2010 and August 2018
were included (n = 669,390). Births with missing valid identifiers (N = 6,942),
multiple pregnancies (N =24,472), gestational age below 22 weeks or 500 g (N =
541) below birthgility, maternal age above 45 years at birth ( N = 960) and
gestational age and birthgilith (N = 2,479) were excluded from the analysis. A
gestational age of 22 weeks is the difference between abortion and stillbirth
according to Swiss law. They were monitored by ultrasound and measurement
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of estradiol and luteinizing hormone (LH). When the follicle diameter reached at
least 16 mm and estradiol was 700 pmol/L, women received a trigger shot of
5000 IU human chorionic gonadotropin (hCG) to induce ovulation. Oocyte
loading took place over 36 h without subsequent anesthesia. Clomiphene citrate
25 mg to reduce the risk of premature ovulation starting on day 7 of the cycle or
ibuprofen 400 mg three times daily taken by the woman 48 hour before oocyte
retrieval. For research, 75 to 350 IU of gonadotropin per day were administered
, and an antagonist or agonist protocol was performed. In SIVF treatment,
stimulation was monitored by ultrasound and measurement of serum estradiol
concentration. When more than two leading follicles reached a diameter of at
least 18 mm with appropriate estradiol concentration, ovulation was induced by
injection of CG by females. Oocytes were retrieved 36 h later under sedation.
Oocytes were fertilized by standard intracytoplasmic sperm injection
(ICSI) or in vitro. Standard embryo culture conditions were consistent across
both groups. New embryos were ultrasound-guided in the cleavage phase for 2
or 3 days in culture. Women maintained the luteal phase by administering 200
mg micronized progesterone twice daily as needed. Switzerland did not allow
longer embryo cultures until 2017 and excess zygotes were vitrified.
All
three datasets provided information on the primary outcomes, birth weight and
gestational age. The percentage of birth weight was calculated for each singleton
live birth according to the formula provided. Data on the duration of labour were
available in the Bern IVF cohort and SLBR. The mode of delivery was compared
between the Bern IVF cohort and ODS. A caesarean section was defined as
secondary if labour had already started contractions, bleeding or rupture of
membranes. The reasons for caesarean section were divided into maternal, fetal
or emergency.
Women
with regular menstrual cycles 26-32 days can choose the treatment at their own
discretion, since NC-IVF requires a regular cycle. Information on maternal age,
parity and fetal sex at delivery was available in all datasets. Additional
information on smoking and maternal div mass index from the Bern IVF and
ODS cohort during pregnancy was used.
Results
.
First,
primary perinatal outcomes were compared, and second, delivery procedures
and reasons for caesarean section were described. To compare the three data
sets, adjustments were made for maternal age, parity and sex of the child. To
compare the Berne IVF cohort and ODS, maternal BMI and smoking during
pregnancy were additionally adjusted.
Continuous
outcomes such as fertility, gestational age, survival and live birth rate were
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assessed using univariate and multivariate linear regression. To report RR and
2500% CI, modified Poisson regression was used for associations with binary
endings such as LBT (<10 y), PTB (<2004 weeks of gestation), SGA (<10th
percentile), and cesarean section. Maternal identifiers were used as cluster
variance estimates to account for singletons born to the same mother. To assess
the effect of gonadotropin stimulation, singletons born after were compared
with those born after NC-IVF, but both subgroups were compared with SLBR.
The proportion of missing data was very low: two participants in the Bern IVF
cohort were lost to follow-up (<0.01%); 18 (<0.1%) in the ODS and 2479
(<0.005%) in the SLBR were excluded because of missing birth or pregnancy
data. The interpretation of birth weight as an outcome has been controversial
because it is closely related to gestational age. Perinatal epidemiologists
recommend not adjusting birth weight for gestational age but estimating birth
weight of singletons, which is done for sensitivity analyses 37 weeks of
gestation. A p value of <0.05 is considered statistically significant.
The analysis included 636,639 deliveries. It shows the exclusions and final
study populations: the Bern IVF cohort (N =311), third-center ODS (N =2332),
and SLBR (N =633,996). Mothers in the Bern IVF cohort were on average 3.6
years older and more often primiparous than non-IVF mothers (95% CI 3.2 to
4.1 years); and compared with ODS, they smoked less and had a lower BMI.
Mean gestational age was comparable in the Berne IVF cohort and SLBR
singletons but lower in ODS singletons P < 0.001) . Singletons and SLBRs in the
Berne IVF cohort had comparable risks for PTB, which were higher for ODS
singletons (P = 0.03). Adjusted mean birth weight was lower in the Berne IVF
cohort than in SLBRs, but this difference disappeared when the comparison was
restricted to children born after the period or adjustment. All model covariates
were strong.
Birth weight percentage: the mean live birth rates did not differ but were
below 50th percentile for the three cohorts. The Berne IVF cohort and singleton
ODS had an increased risk of SGA birth compared with SLBR. Whereas for
children born at term, the risk of SGA was not statistically different for singleton
ODS (RR 1.07, 95% CI 0.95 to 1.20; P = 0.24) and singleton IVF (RR 1.27, 95% CI
0.96 to 1.70; P = 0.10), compared with both SLBR.
Discussion.
Compared with singletons in the Berne IVF cohort showed no
difference in gestational age and fertility rates, and no increased risk for LB or
PTB. On the other hand, they showed lower mean birth weight and higher risk of
SGA. There were no differences in the Berne IVF cohort compared with ODS. IVF
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mothers were older and often primiparous. Singletons born after SIVF were
lower than average birthletons and had a risk of becoming SGA compared with
it, while singletons born after SIVF were similar to SLBR singletons due to
increased pressure.
The strengths of this study are the detailed and
comprehensive information collected in the Bern IVF cohort on conception,
infertility treatment, pregnancy course and perinatal outcomes. The study
included the use of the population-based SLBR as a comparison group and it
contributes to the limited literature on perinatal outcomes in children born after
NC-IVF.The sample size of the Bern IVF cohort is limited, so for all comparisons
the focus is on reporting the 95% CI. The characteristics of women choosing NC-
IVF and those choosing SIVF may be different. In Switzerland, IVF treatment is
not subsidized; this hinders randomized controlled trials. The ODS data are
collected at a third center, which is a neonatology department where patients
are referred for treatment of pregnancy complications or for a second opinion.
The ODS mainly consists of high-risk groups; selection bias is an issue. SLBR
includes all children born alive, regardless of how long they survive after birth,
and thus perinatal deaths occurring within the first week of life. The SLBR data
include births in the Bern IVF cohort and a portion of births in the ODS.
Detection of duplicate deliveries was not dependent on the anonymized SLBR
data in the cohorts. SLBR also includes pregnant women who became pregnant
after fertility treatment in Switzerland or abroad. However, compared to SLBR,
the proportion of both cohorts is too small to influence the average outcome
figures.Different demographic characteristics of parents undergoing IVF higher
age, lower parity have been demonstrated in other countries; these
characteristics may reflect a transition to higher childbearing age and a delay in
diagnosis of parental infertility. On the other hand, IVF mothers in this study had
fewer pregnancy complications and a healthier lifestyle compared to ODS
mothers; this may positively impact perinatal outcomes. Regarding perinatal
outcomes, the results of the current study are encouraging; the results of the
previous meta-analysis were not confirmed. In this study, gestational age and
fertility rate were not lower and the risk of PTB and LBV was not increased after
IVF. And the low crude mean live birth rate and the risk of SGA in IVF infants
could only be confirmed in a flawed analysis. Both PTB and intrauterine growth
restriction reduce birth weight, and SGA is a result of intrauterine growth
restriction, which sometimes requires induction of labor or cesarean section.
Also in this study, cesarean section was associated with LBV and PTB. Maternal
age and parity are other independent risk factors associated with perinatal
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outcome. The current results are partly explained by the high age and low parity
of IVF mothers. IVF may affect intrauterine growth, but maternal factors seemed
more important in this study. Endometrial receptivity or there are other
possible explanations for vanishing twins that cannot be controlled.
A separate study in
Switzerland found that regional differences mainly influenced birth weight;
maternal age influenced gestational age, but surprisingly, regional differences in
caesarean section rates were not associated with differences in fertility or
gestational age. Fertility rates below 50 were observed for all three populations.
The current fertility rates are based on children born in England and are not sex-
specific. They were not fully converted to Swiss singletons. The low birth weight
percentage of Swiss cohorts may reflect different distributions of parental traits.
Fertility rates specifically designed for US singletons showed very little
difference population standards. Similar average fertility rates are encouraging
for this IVF population. Three cohort studies have assessed the effects of
gonadotrophin stimulation compared with NC-IVF. In the Japanese IVF registry
study, data from 8,224 singletons after NSIVF were compared with data from
610 after NC-IVF. For agonist and antagonist protocols, the odds ratio was 1.60–
1.72. The UK IVF registry study found data from 98,667 stimulated and 262
stimulated new cycles and showed a trend towards higher contrast only for LBT
(AOR 1.58, 95% CI 0.96 to 2.58) and PTB (AOR 1.43, 95% CI 0.91 to 2.26). In a
small US study of 174 stimulated and 190 unstimulated IVF cycles, birth weight
decreased by 163 g; the proportion of LBV infants was 1.0% in NC-IVF and 8.6%
in sivf. This may be explained by a significantly higher proportion of very
preterm births (<0.5 weeks gestation) in the sivf group (32% vs 6.3%).
Increased pressure-present on IVF analysis showed a risk for PTB (RR 1.32, 95%
CI 1.05 to 1.66) but not for LBV (RR 2.98, 95% CI 0.54 to 16.29) followed by
stimulated IVF. The reduced risk of PTB and LBV after frozen embryo transfer
may be due not only to cryopreservation but also to the absence of gonadotropin
use in the pre-transfer cycle. New studies comparing NC-IVF with natural
shedding cycles may shed more light on the specific impact of cryopreservation
on perinatal outcomes. The current study did not find a lower mean birth
weight, decreased gestational age, or higher risk of PTB and LBV in sivf
compared with NC-IVF. However, sivf births were found to have a higher risk of
low birth weight and SGA compared with slbr, while perinatal outcomes of NC-
IVF were similar to those of SLBR. After adjustment, the risk of LBV remained
high, but the risk of SGA was attenuated. It can be concluded that SIVF is
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associated with a slightly higher risk; maternal age and parity may partially
explain this. However, the risk difference in this study is much lower than in
other studies. Gonadotropin dose and individual ovarian response depend on
birth weight and SGA. Both superovulation and supraphysiological estradiol
concentrations are associated with adverse outcomes as they disproportionately
affect the endometrium, implantation, placentation and intrauterine growth. An
effect on endometrial gene expression has been demonstrated in endometrial
biopsy tissue analysis from SIVF and NC-IVF women, which is critical for tissue
remodeling and implantation. Another explanation may be the healthy lifestyle
of mothers in the Bern IVF cohort. Several studies have reported higher rates of
cesarean section or assisted vaginal delivery in IVF infants. Although there are
no high risk factors for operative and assisted vaginal delivery in IVF
pregnancies and preterm labor, shorter labor duration was reported by an
Italian study. The highest rates of cesarean section in singletons undergoing IVF
were reported by the Australian Newborn Registry Study. Conception by IVF
appeared to influence the gynecologist's and parents' decisions regarding
pregnancy monitoring, diagnostic interventions, and delivery mode. Pregnancies
after IVF are often closely monitored and undergo more diagnostic
interventions; this may result in primary cesarean section. This phenomenon
has been called the "precious baby effect". In an American study, pregnancy
complications and higher maternal age were the main reasons for the increased
cesarean section rate after IVF. Women with subfertility also had a higher
cesarean section rate than fertile women. Maternal age, subfertility and
comorbidities may be related to other treatments or the "precious baby effect".
In the current study, the high cesarean section rate in IVF was not observed after
adjusting for maternal age, parity and sex of the child. These findings may reflect
different characteristics of IVF mothers: this is not surprising, since women with
ODS have a higher rate of pregnancy complications and represent a high-risk
group. However, the high rate of primary cesarean section in IVF women may be
an indication to avoid risk during delivery. The caesarean section rates in the
ODS and Bern IVF cohort are higher than the 32% caesarean section rates in
Switzerland Federal Statistical Office. It is important to note that caesarean
section rates are also strongly influenced by cultural concepts and regional
differences such as urbanization. It is therefore difficult to conclude whether
pregnancy and birth are subject to the necessary medical interventions or
whether obstetricians and parents are especially careful in cases where
pregnancy is difficult to achieve.
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However, in primiparous women, the mode of delivery influences the
mode of delivery in subsequent pregnancies, and caesarean section also
influences the success of subsequent ART treatment, so it is particularly
important to avoid unnecessary caesarean sections in low-risk primiparous IVF
pregnancies. Further research into cesarean section in IVF pregnancies or after a
long period before conception will help to understand the underlying factors.
Overall, the children in the Bern IVF cohort did not show perinatal
outcomes due to infertility treatment. However, gonadotropin stimulation may
have additional effects on intrauterine growth and birth weight. The risk of low
birth weight and SGA was increased after stimulated IVF in the unadjusted
analysis and the risk of low birth weight in the adjusted analysis compared with
SLBR. An analysis including national data on all IVF children will be important to
verify these findings.
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