Effetto dell'assistenza prenatale sugli esiti perinatali di donne in gravidanza con

Introduction

Diabetes mellitus (DM) is a public health problem of increasing magnitude among

adults in developed and developing countries. Due to the increase in prevalence

among women of reproductive age, and in parallel with the increase in obesity in

this population, an increase in the prevalence of DM diagnosed before or during

pregnancy has been observed [ - ].

Hyperglycemia in pregnancy (HIP) is the most common metabolic disorder in pregnancy

[ , ]. In 2021, an estimated 16.7% (about 21.1 million) of live births to

mothers aged between 20 and 49 years were affected by this condition. Among this

prevalence, 80.3% resulted from gestational diabetes mellitus (GDM), 10.6% resulted

from DM diagnosed before pregnancy and 9.1% due to overt DM, diagnosed primarily

during pregnancy [ ].

To protect the health of pregnant women and their newborns from the negative effects

of HIP, prenatal care (PC) has been recognized as an essential factor, as it allows

timely interventions on possible complications [ - ] commonly associated with this

condition, such as lack of glycemic control [ , ] and the birth of macrosomic

or large for gestational age (LGA) newborns [ - ]. Therefore, prenatal

health care is crucial to maximize the potential for a healthy life of both the

mother and the fetus and the inadequacy of this assistance has been related to

higher rates of maternal and infant morbidity and mortality [ , , ].

The World Health Organization (WHO) [ ] has

been reviewing PC strategies, recommending that all women and their newborns receive

quality care during the pregnancy-puerperal cycle, including specialized and

multidisciplinary follow-up. Among the strategies reviewed, there is the expansion

of the consultation calendar for pregnant women at usual risk to a minimum of eight

PC appointments throughout pregnancy, starting in the first trimester [ ]. In addition, it is recommended for cases of

DM prior to pregnancy, that this multi-professional follow-up is carried out before

or as early as possible until the levels of glycated hemoglobin (HbA1c) are

optimized for pregnancy, ideally 6.0%, with the objective of reducing the risk of

preeclampsia, congenital anomalies, macrosomia, and preterm birth [ ].

Related studies point to specialized nutritional therapy (NT) initiated concomitantly

with the initiation of PC as an important tool in the control of HIP, bringing

potential benefits to maternal-fetal health [ - ]. NT may be effective in

reducing pregnancy complications (preeclampsia, excessive weight gain, need for

insulin therapy, prematurity) and neonatal complications (neonatal hypoglycemia and

macrosomia) in addition to the adequacy of glycemic control, which is the main

factor that impacts the perinatal outcome [ , - ].

In this context, the objective of this study was to systematically review the

literature evaluating the effect of PC on the perinatal outcomes of pregnant women

with DM. This is particularly relevant regarding the benefits of this care to the

health of the mother and the fetus both in the short and in the long term.

Methods

### Study Design and Protocol Registration

This study employed a systematic review design and followed the Preferred

Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines,

and it was registered in the international prospective register of systematic

reviews (PROSPERO CRD 42020147826) [ ].

### Search Strategy and Data Sources

The search was carried out in PubMed, Scopus, and BIREME databases in July 2022.

A conceptual mapping of the study variables was elaborated based on the items of

the PICO strategy for the elaboration of search keys containing the most

recurrent terms in each database. After this step, the terms contained in the

DeCS (Health Descriptors) for the Portuguese terms and the MeSH (Medical Subject

Headings) for the English terms were considered for the research as descriptors,

in addition to the application of the Boolean operators “OR” and “AND” to

integration between terms and keys. There was no delimitation of the period of

publication of the studies for the search. The final keys are described in .

### Eligibility

The population, intervention, control, and outcomes (PICO) strategy was used to

define the question and variables to be analyzed. The study question defined

was: What is the effect of PC on the perinatal outcome of pregnant women with

DM? The population (P) consisted of pregnant women with GDM or DM before

pregnancy; the intervention (I) studied was PC, with specialized guidance and

appointments in groups or individuals by various health professionals, including

the nutritionist; control (C) consisted of pregnant women who received usual PC

without NT and the outcomes (O) analyzed were hypertensive disorders of

pregnancy (HDP), glycemic control, prematurity, hospitalization in the neonatal

intensive care unit (NICU), macrosomia (birth weight >4kg) and LGA

newborns.

As for the characteristics of PC mentioned by the studies, the most recurrent

were related to the number of appointments, frequency, adherence, participation

of a multidisciplinary team, and treatment of DM.

For the selection of publications, the following inclusion criteria were adopted:

controlled and/or randomized clinical trials (RCTs), observational studies

(cross-sectional, retrospective, and prospective cohort) and studies referring

to adult pregnant women, single-fetus pregnancy, diagnosis of DM or GDM who have

received PC and/or NT, and who had information on the effect of these criteria

on perinatal outcomes. Only publications in Portuguese, English, and Spanish

were selected. Studies were grouped according to the highest recurrence of

outcomes.

### Selection of Studies and Data Extraction

After the search, all references were imported into a reference manager

(EndNote®) and publications indexed in more than one database (duplicates) were

removed. After removing duplicates, 5079 records were analyzed for the

application of eligibility criteria described in above section Elegibility from the reading of titles and abstracts, which

resulted in the exclusion of 5028 records that did not meet the eligibility

criteria. After this step, 51 studies were read in their entirety, and the

inclusion criteria were applied. Subsequently, 15 manuscripts remained for final

analysis, as described in . Data

extraction from the included studies for final analysis was performed using a

Microsoft Excel® spreadsheet. The entire process of search and selection of

studies was carried out by two researchers independently and when there was

disagreement, a third researcher reviewed the entire process.

### Assessment of Study Quality and Risk of Bias

The quality of the studies included from the perspective of risk of bias was

assessed using the “Quality Assessment of Controlled Intervention Studies” tool

for intervention studies and the “Quality Assessment Tool for Observational

Cohort and Cross-Sectional Studies” for observational and cohort studies, both

from the National Heart, Lung and Blood Institute—National Institutes of Health

(NIH). Such tools can be accessed for free through the official link

( https://www.nhlbi.nih.gov /) and include 14 study quality questions, with “yes,”

“no,” and “not reported or not applicable.” Based on these responses, the

studies were classified as “Good,” “Fair,” or “Poor,” considering a study “good”

if it obtained eight or more “yes” responses. The ratings of these tools are not

based on summary scores but qualitative judgment. This evaluation was carried

out by two researchers independently and whenever there was inconsistency, a

third researcher contributed to a resolution.

Results

### Search Results

Initially, 5972 records were selected through electronic searches in the PubMed

(n=2224), BIREME (n=2536), and Scopus (n=1212) databases. There were 893

duplicate references, which were removed from the analysis, resulting in 5079

records. From this number, 5028 references were excluded from the reading of

titles and abstracts because they were considered irrelevant to the scope of

this review, for not meeting the eligibility criteria, such as population and

outcomes of interest, resulting in 51 studies, which were read in full.

Thirty-six studies were excluded and reasons described in the flow diagram

( ). So, we included a total of 15 studies, totaling 47 420 evaluated

pregnant women.

### Characteristics of Included Studies

presents general information about

the studies included in this systematic review, such as year of publication,

type of study, population studied, among others. presents a summary of the main findings of the studies,

including PC characteristics, when these were mentioned, in addition to the

presence of statistical adjustments.

Of all the studies included, four studies detailed the characteristics of PC

[ , - ], including information about the participation of

a multidisciplinary team, gestational age at onset, number and frequency of

appointments, adherence to the proposed program, information about insulin

therapy and other adopted therapies, guidelines for home blood glucose

monitoring, self-care and lifestyle changes for pregnant women.

NT as part of PC was considered in nine [ , , , , , - ] of the 15 included studies. Of these, only the study by Silva

et al. [ ] reported an average of five

appointments with the nutritionist.

Overall, there was a high variation in the sample size (n=45 to n=38 224) and the

mean age of the participants ranged from 22 to 35 years (Table 2).

As for the statistical analyses, 10 studies mentioned variable adjustments and

possible confounding factors from multivariate logistic regressions [ , , , - , , ] ( ).

Regarding the quality of the studies analyzed from the perspective of risk of

bias, it was observed that most studies met the criterion classification with a

“good” result, both the two clinical trials included and nine of the 13

observational studies included. The questions that most received “no” as an

answer were associated with the methodology of the studies regarding the

blinding of researchers and participants, as well as information on adherence to

the interventions applied and categorization of exposure variables. The summary

of the results of this analysis is shown in and 2.

The most recurrent perinatal outcomes were glycemic control, HDP, especially

preeclampsia, prematurity, LGA newborns, fetal macrosomia, and NICU

admission.

### Glycemic Control

Fourteen of 15 studies evaluated glycemic control (n=9096) [ , - , , , - , - ]. Of these, six studies considered

the oral glucose tolerance test (OGTT) as a tool to assess glycemic control,

measured in fasting, 1h, and 2h postprandial with 75g of glucose [ , , , , , ].

Two considered fasting and 2h postprandial glucose (15,28). Landon et al. [ ] evaluated glycemic control through

fasting, 1h, 2h, and 3h postprandial glycemia with a 100g glucose load. Huynh et

al. [ ] evaluated glycemic control from 2h

postprandial blood glucose with a 75g glucose load. In the study by Silva et al.

[ ] glycemic control was assessed

through fasting and 1h postprandial glucose with 75g glucose. In the study by

Pylypjuk et al. [ ] HbA1c was used to

assess glycemic control. Sunjaya and Sunjaya [ ] evaluated glycemic control through HbA1c and fasting and 2h

postprandial glucose. In the study by Carter et al. [ ] glycemic control was assessed through fasting glucose

and HbA1c. In general, adequate glycemic control was observed after PC,

especially in studies that applied NT as part of this assistance (n=9).

### HDP

HDP were evaluated in two studies (n=39 282) [ , ]. In Landon et

al. [ ], gestational hypertension was

defined as a systolic blood pressure >140 mm/Hg and diastolic blood pressure

>90 mm/Hg measured on two occasions at least 4 hours apart, or a change in

blood pressure that was subsequently treated with medication. Preeclampsia was

defined as an elevation in blood pressure (according to the definition of

gestational hypertension) associated with proteinuria (>300mg of protein in a

24-hour urine collection) or abnormal blood levels of liver enzymes (aspartate

aminotransferase level ≥70U/L) or thrombocytopenia (platelet count <100,000

per cubic millimeter).This study [ ]

found lower rates of gestational hypertension and preeclampsia in the group that

received specialized NT and self-monitoring of capillary blood glucose when

compared to the control group. Similarly, Allen et al. [ ] observed lower rates of preeclampsia in the group that

started PC in the first trimester when compared to the groups that did not

receive PC or that started PC only in the third trimester of pregnancy. Despite

this, Allen et al. [ ] do not describe

the diagnostic criteria used to classify preeclampsia, nor the characteristics

of the PC provided.

### Prematurity

Prematurity was evaluated in six studies (n=40 118) [ , , , , , ] and of these, only three associated it with PC (n=39

461) [ , , ]. Carter et al. [ ] observed 59% less probability of

premature birth among women who received 15 or more PC appointments when

compared to those who received eight or more appointments. Landon et al. [ ] observed a higher proportion of

prematurity among the control group when compared to the intervention group that

received NT as part of PC (11.6% versus 9.4%) (p=0.27). Allen et al. [ ] observed higher rates of preterm birth

in the group that started PC in the third trimester when compared to women who

started in the first or second trimester. In all these studies, prematurity was

considered as birth before 37 weeks of gestation.

### LGA and Fetal Macrosomia

The birth of LGA newborns was evaluated in four studies (n=1556) [ , , , ] however only two were associated with PC (n=1137)

[ , ]. Carter et al. [ ] did

not observe statistical differences between the groups. Landon et al. [ ]) observed a higher proportion of birth

weight LGA among the control group when compared to the intervention group that

received NT as part of the PC (14.5% versus 7.1%) (p<0.001). In all of these

studies, the classification was based on birth weight values above the 90th

percentile.

Fetal macrosomia was assessed in six studies (n=2022) [ , , , , , ]. Of these, two demonstrated an association with PC

(n=1446) [ , ]. Shi et al. [ ]

observed a higher proportion of macrosomia in the group that performed PC

without the participation of specialized NT (27.62% versus 9.77%; p<0.001).

Landon et al. [ ] observed a higher

percentage among the control group when compared to the intervention group that

received NT as part of the PC (14.3% versus 5.9%) (p<0.001).

### Hospitalization of the Newborn in a NICU

The admission of newborns to the NICU was evaluated in four studies (n=2382)

[ , , , ] being associated with PC in three of them (n=2079)

[ , , ]. Sperling et al.

[ ] observed that women in the

lowest quartile of PC adherence were more likely to be admitted to the NICU when

compared to those in the highest quartiles. Carter et al. [ ] reported an 85% lower proportion of NICU admissions

among pregnant women who received 15 or more appointments when compared to

pregnant women who received eight or more appointments from PC. Landon et al.

[ ] observed a higher proportion

among the control group when compared to the intervention group that received NT

as part of PC (11.6% versus 9.0%) (p=0.19).

Discussion

Most of the included studies were performed in the US. However, those focused on NT

were carried out in Southeast Asia and Brazil. The recent interest in the subject is

remarkable, given that more than 80% of studies were published after 2015, which may

be associated with the increasing prevalence of HIP cases in recent years as a

consequence of rapid urbanization, epidemiological transition and nutrition, a

global epidemic of obesity, and the change of diagnostic criteria for GDM [ ].

The number of RCTs is considerably lower when compared to the observational studies

included in this review. The sample size and the proper use of control groups are

positive characteristics found in all original research/intervention studies.

Another issue that can be considered homogeneous among the studies is the type of

HIP considered, most often resulting from GDM.

The scope of the original studies follows the trend in the literature regarding PC

for medium- and high-risk pregnant women, which focuses mainly on the assessment of

the impact of actions based on the multidisciplinarity of this care, including

medical doctors, nurses, psychologists, nutritionists, among other health

professionals, making the assistance complete, effective, and efficient [ , ].

Of the 15 studies included, only four detailed the characteristics of the PC

provided, such as the number of appointments, adherence to care and quality

assessment, and important information that makes up the planning of actions for this

care.

Methodologically, the improvement in the quality of PC strategies is noticeable over

time, with studies gradually incorporating more robust instruments in recent years,

such as quality indices of this care [ ],

which allows for more specific interventions. Nevertheless, these data as well as

instruments to assess adherence to the care provided were not mentioned in the

included studies, which can be considered a negative point. Another point considered

negative is the scarcity of studies on pregnant women with DM prior to pregnancy,

which points to the need for new studies on this population in view of the

complexity and severity of perinatal complications associated with this population

[ , , , , ].

One positive point to be highlighted, which is broadly related to the methodological

quality of the studies, is the performance of statistical adjustments that allow

more reliable results when analyzing the interference of possible confounding

variables.

Most studies considered the NT as part of the PC, however, there was no detail of

this follow-up regarding the number of appointments, gestational age at the

beginning, participation of pregnant women in collective appointments, adherence and

nutritional guidance methods applied, indicating the need of studies that address

these variables.

It is worth noting the importance of this follow-up for pregnant women with HIP,

which includes a complete and detailed nutritional assessment, considering

sociodemographic, obstetric, clinical, anthropometric, and dietary aspects that

guarantee the quality of care provided. The main goals of NT are based on the

adequacy of nutritional needs to promote adequate fetal growth, adequacy of

gestational weight gain, and glycemic control [ , ].

Glycemic control was assessed in most studies. Achieving goals in individuals with DM

is a potential challenge and, therefore, the main objective of PC for pregnant women

with DM, as the HIP is directly related to the development of obstetric and neonatal

complications [ , , ].

Horie et al. [ ] retrospectively evaluated

whether glucose intolerance in women diagnosed with GDM before the 20th week of

gestational age improved in mid-pregnancy after adequate NT and found that the group

of pregnant women who received this follow-up showed normalization of blood glucose

values in the OGTT performed after two weeks of diet and did not evolve with the

need for insulin therapy. These data point to the importance of early nutritional

care in achieving adequate glycemic control in pregnant women with an early

diagnosis of GDM. The sooner care begins, the greater the chances of adequacy.

Sunjaya and Sunjaya [ ] analyzed pregnant

women with DM and GDM and grouped the participants into three groups according to

the therapy applied, one group received only NT, another associated insulin therapy

and NT, and one group received oral antidiabetic drugs and NT. The findings showed

worse glycemic control in addition to a higher percentage of fetal deaths in the

oral antidiabetic treatment group when compared to the other groups. Within this

context of insulin use, a systematic review [ ] found higher proportions of macrosomia, LGA, NICU admission, preterm

birth, and other complications in the groups that used insulin when compared to

those that did not. These results reinforce the importance of NT as essential care

in the prevention of fetal morbidity and mortality, adequacy of glycemic control and

a possible delay in the use of insulin for pregnant women with HIP due to GDM [ , ].

Shi et al. [ ] also observed adequacy of

glycemic control, lower rates of macrosomia, higher rates of breastfeeding and lower

risk of developing Type 2 Diabetes Mellitus (T2DM) in the postpartum period in

pregnant women with GDM who received NT when compared to those who did not highlight

the importance of this specialized care and aimed at reducing timely treatable

complications.

Within this context, Allen et al. [ ] in a

retrospective cohort aimed to investigate the association of PC with adverse

perinatal outcomes in pregnant women with T2DM and classified the cohort according

to the onset of PC by gestational trimester. Among the results presented, it is

noteworthy that even after statistical adjustments, pregnant women who started PC in

the third trimester had a higher risk of prematurity and intrauterine fetal death,

when compared to pregnant women who started PC in the first or second trimester of

pregnancy, the which indicates and corroborates the recommendation and essentiality

of starting this care in the first trimester [ , ].

In addition to early PC, the number of appointments for this care deserves attention,

as it can determine the organization of a calendar to be followed, enabling the

adequacy of care for the different stages of pregnancy [ ].

Carter et al. [ ] aimed to associate the

number of PC appointments with pregnancy outcomes in pregnant women with DM and GDM,

according to percentiles of the number of appointments. Those with a percentile ≥ 75

were compared with those with a percentile ≤ 25, 15 and eight visits, respectively.

Mean HbA1c at delivery was significantly lower in pregnant women with more than 15

visits. In addition, the group that had more appointments had a lower risk of

hospitalization of newborns in the NICU, births of LGA newborns, and prematurity

when compared to the group that had fewer appointments, which points to the need to

establish an ideal number of PC appointments for pregnant women with the HIP. The

greater number of appointments may be associated with improved outcomes due to the

association with early, continuous, and periodic monitoring of clinical and

laboratory variables [ , ].

There is no specific recommendation for the number of PC visits for high-risk

pregnant women. Carter et al. [ ] indicate

that a number greater than the eight recommended by the WHO [ ] would result in better perinatal outcomes, given the

magnitude and complexity of medium- and high-risk pregnancies, it is believed that

the greater the number of appointments, the greater the possibility early detection

and timely treatment of possible complications [ , , ].

The occurrence of preeclampsia and gestational hypertension, complications commonly

associated with DM in pregnancy [ , ], was evaluated as an outcome in two studies

[ , ].

Insulin resistance, a characteristic commonly present in women with HIP due to GDM,

may be associated with the development of preeclampsia [ , ]. The

Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study showed a continuous linear

association between OGTT results and preeclampsia rates [ ]. Such findings reinforce the importance of NT and the

precocity of PC in preventing this outcome, which can cause complications to the

health of the maternal-fetal binomial and is considered the main cause of maternal

mortality worldwide [ ].

Regarding adherence to PC, only one study associated it with neonatal outcomes [ ]. Among women with DM, those classified in

the lowest adherence quartiles had higher rates of hospitalization of their newborns

in the NICU when compared to pregnant women in the highest quartiles. Related to

this, pregnant women with low adherence also had poor glycemic control, higher rates

of complications during pregnancy and postpartum, as well as hospitalizations. It

shows that the better the adherence of pregnant women to PC, the better the results

of pregnancy [ ].

Wong et al. [ ] studied the impact of PC

adherence on pregnancy outcomes among women with GDM. The lowest adherence to the PC

was defined as absence from at least two appointments. Those who met this criterion

had higher proportions of uncontrolled glycemic control, macrosomia, and a tendency

to increase admission of newborns to the NICU. Within this context, all efforts on

the part of the multidisciplinary team are valid to adapt the treatment to the

patient’s situation, making the care individualized and contributing to the

improvement of adherence [ ].

The most recurrent neonatal outcomes were macrosomia, LGA newborn, need for NICU

admission, and prematurity. These outcomes can increase hospitalization rates and,

consequently, expenses in the health sector, as the longer the hospitalization time,

the greater the need for treatment supplies, impacting the global economy on a large

scale [ , , ]. Within this context,

treating pregnant women with HIP becomes a challenge for health services, and PC can

directly contribute to the reduction of these expenses, based on early and

specialized care that allows timely detection and intervention of these and other

complications, favoring the perinatal outcome of these pregnant women.

Fetal macrosomia is an adverse outcome commonly associated with HIP because of the

high rate of placental transfer and is associated with complications for the

maternal-fetal binomial, such as cesarean delivery, postpartum hemorrhage, shoulder

dystocia, and need for admission to the NICU [ - ], in addition to the

increased risk of chronic non-communicable diseases in adulthood caused by

epigenetic changes and contributing to the intergenerational perpetuation of the

disease if birth weight is not controlled [ , , ].

A RCTs with pregnant women with 958 pregnant women with GDM [ ] showed a lower proportion of fetal macrosomia, mean birth

weight, and cesarean delivery in the intervention group compared to the control

group. The difference between the groups was the participation of the nutritionist

in the intervention group, which reinforces the importance of early nutritional care

and concomitant with the onset of PC in reducing this common outcome in pregnancies

with the HIP.

Limitations of this study are the scarcity of detailed information about PC and NT,

such as the number of appointments, gestational age at the beginning of the

follow-up, instruments that assess the quality and adherence of PC, the place of

performance, whether public or private institution, RCTs and studies with women with

DM prior to pregnancy. However, this is the first systematic review devoted to

systematically present available data regarding the effect of PC on the perinatal

outcomes of pregnant women with DM and it contributed to the identification of gaps

that still exist in research involving the topic.

Conclusion

The findings show that PC directly interferes with the perinatal outcome of pregnant

women with HIP, through timely and early intervention carried out by a

multidisciplinary team, including specialized NT, which can be considered beneficial

for the adequacy of glycemic control as well as a reduction in the occurrence of HDP

and fetal macrosomia. Therefore, it is essential to carry out studies that allow

organizing and systematizing the PC of these pregnant women, enabling more effective

specific actions during this period with the objective of reducing unfavorable

outcomes for the maternal-fetal binomial.