Impact of advanced maternal age on neonatal morbidity: a systematic review

Abstract Objective This systematic review aimed to understand the impact of advanced maternal age (AMA) on the neonatal morbidity, based on the available scientific evidence. Methods A systematic search was conducted on 22 November 2021, using the PubMed and Scopus databases to identify studies that compared the morbidity of neonates delivered to AMA mothers with that of neonates delivered to non-AMA mothers. Results Sixteen studies that evaluated the effect of AMA on the neonatal morbidity were included in this review. Nine of these studies found some association between AMA and increased neonatal morbidity (with two of them only reporting an increase in asymptomatic hypoglycemia, and one only reporting an association in twins), six found no association between AMA and neonatal morbidity and one study found a decrease in morbidity in preterm neonates. The studies that found an increase in overall neonatal morbidity with AMA considered older ages for the definition of AMA, particularly ≥40 and ≥45 years. Conclusion The current evidence seems to support a lack of association between AMA and the neonatal morbidity of the delivered neonates. However, more studies focusing on the neonatal outcomes of AMA pregnancies are needed to better understand this topic.


Introduction
In the most developed countries there is a trend in delayed childbearing over recent decades [1].In these countries, advanced maternal age (AMA) became increasingly common and has been associated with a wide range of adverse obstetric, perinatal, and neonatal outcomes [2][3][4][5][6].
Most of the published literature reports on the obstetric and perinatal data, with relatively few studies assessing the effect of AMA on the morbidity and mortality of the neonates resulting from these pregnancies.Higher number of perinatal complications and a higher number of admissions to neonatal intensive care units (NICUs) have been described in the term and near-term infants [7].In preterm infants, especially very low birth weight (VLBW) infants, according to some studies, AMA is associated with an increased incidence of respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP) and periventricular leukomalacia (PVL) [8][9][10][11][12][13].On the other hand, other studies found that AMA was not associated with an increase of neonatal morbidity, or mortality, in preterm neonates [14,15].
The objective of this systematic review was to gather all the scientific evidence on the effect of AMA on the neonatal morbidity, in order to draw conclusions and to assess the need for further studies.More specifically, this review aims to assess if neonates born to mothers of AMA present higher morbidity than those born to non-AMA mothers.

Methods
A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for the search, with no limit of time.PubMed and Scopus databases were systematically searched, on 22 November 2021 using the following terms: maternal age, advanced maternal age, very advanced maternal age, delayed childbearing, neonatal morbidity, neonatal outcome, pregnancy outcome, respiratory distress syndrome, transient tachypnea of the newborn, pneumothorax, bronchopulmonary dysplasia, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, periventricular venous infarction, periventricular leukomalacia, retinopathy of prematurity, sepsis, pneumonia, meningitis, jaundice (Table 1).
After removing duplicates, two independent authors (GR and IR) screened the abstracts of 1083 articles.Disagreements were solved upon discussion with a third element (IA).At the end of this process, 26 articles were included.After an additional search, using the same methodology for the selection process, seven more articles were included.Thus, a total of 33 articles were eligible for full-text review, after which 16 articles were included in this systematic review.The selection process flowchart can be seen in Figure 1.
All studies prior to 22 November 2021 that met the inclusion criteria were included.The inclusion criteria were studies comparing the morbidity of neonates born to mothers of AMA with that of neonates born to mothers of non-AMA.Morbidity was defined as one or more of the following outcomes: RDS, pneumothorax, bronchopulmonary dysplasia (BPD), NEC, intraventricular hemorrhage (IVH), periventricular venous infarction (PVI), PVL, ROP, sepsis, pneumonia, meningitis, transient tachypnea of the newborn (TTN), seizures or convulsions, jaundice, and any metabolic disturbance.
Exclusion criteria included: studies that included only mothers with advanced age with hypertensive disorders or diabetes; studies that only included multiple gestations; articles written in languages other than English, Portuguese, French, or Spanish; studies that did not evaluate the outcomes defined for this review, namely studies that only assessed congenital anomalies.Review manuscripts were also excluded.
Data were extracted from the selected studies using a pre-determined model.Extracted data included: author name, study year(s) and country(ies), study design, sample size, maternal age ranges considered for the study, gestational ages of the included neonates, mean birth weight when available, the assessed outcomes and the main findings of the study.

Study quality assessment
The quality of the studies included in this review was assessed by two independent authors (GR and HS),  using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) [16] guidelines and a GRADE (Grading of Recommendations Assessment, Development and Evaluation) [17] level was attributed to each included article.

Results
Sixteen studies that evaluated the effect of AMA on the neonatal morbidity were included in this systematic review.A summary of the studies and their main findings can be seen in Table 2.In this set of studies, eight were retrospective cohort studies, six were retrospective case-control studies, one was a prospective case-control study, and one was a prospective cohort study.The oldest study included in this systematic review was from 1991 and the most recent was from 2021.
The studies differed in the definition of AMA.Most defined AMA as �35 or �40 years.Four studies assessed the neonatal outcomes of only preterm or VLBW infants, the others also included infants delivered at term.Four of the 16 studies found an association between AMA and overall increase in neonatal morbidity [3,5,6,18], two of which considered AMA a maternal age �45 years and the other two considered AMA a maternal age �40 years.One study also found an increase in neonatal morbidity but only in twins, when comparing a maternal age �50 years to a maternal age of 45-49 years [2].Other two studies found that AMA had an impact, not in the overall morbidity of the neonate, but specifically an increase in the incidence of cystic periventricular leukomalacia (cPVL) [8] and RDS [13], for maternal ages �35 and �32 years, respectively.The studies by Canto et al. [19] and Romero-Maldonado et al. [20] found an increase in the incidence of asymptomatic hypoglycemia in neonates delivered to mothers �40 and �35 years, respectively, but no increase in the overall neonatal morbidity.In the later, the increase in hypoglycemia was presumptively associated to an increased incidence of gestational diabetes mellitus in AMA pregnancies [20].
Six of the studies found no association between AMA and neonatal morbidity, including two studies that focused only on preterm or VLBW infants [4, 15,19,[21][22][23][24].Lastly, the results of one study showed that in preterm neonates, morbidity might even decrease with increasing maternal age, specifically a decreased incidence of mortality, NEC, and neonatal sepsis [14].

Risk of bias across studies
The major biases found were: most studies had a retrospective design; AMA definition was not uniformly used in all studies; definitions of the neonatal morbidities were different among the various studies and lack of definitions of the outcomes were found in some studies; the main objective of some studies was not to evaluate specific morbidities of the newborn; different epochs and countries across the different studies including some old articles not translating the current neonatal practices; most studies did not analyze all neonatal outcomes, and some articles analyzed only one or two outcomes.

Discussion
There are several studies and meta-analysis showing that a wide range of adverse obstetrical and perinatal outcomes are associated with women of AMA [7, [25][26][27][28][29][30][31][32].Most of the adverse outcomes can be explained through the physio-pathological changes due to aging in the female reproductive system and aging-associated comorbidities.But AMA can also be an independent risk factor according to current evidence [32].
This systematic review aimed to gather all the scientific evidence on the effect of AMA on the neonatal morbidity and mortality, more specifically, to assess if neonates born to mothers of AMA present higher prevalence of morbidities, during the neonatal period, than those born to non-AMA mothers.

RDS
RDS occurs mainly in very preterm infants with immature lungs and surfactant deficiency and is the most common cause of respiratory failure in preterm infants [33].
In this systematic review, 11 studies evaluated the impact of AMA on the incidence of RDS.The study of Dani et al. [13] that included 63,537 newborns and compared a maternal age �32 years to a maternal age <32 years, concluded that AMA was a risk factor for RDS.Shrim et al. [18] included 1108 neonates and found that a maternal age �40 years was associated with higher incidence of RDS when comparing with a maternal age of 20-39 years.The study by C¸etin et al.

Transitory tachypnea of the newborn
TTN is a benign condition that typically appears within the first two hours of life in term and late preterm neonates and is characterized by tachypnea and signs of respiratory distress [34].Although it is usually a selflimited condition, admission to a neonatal unit is frequently required [35].Infants born by C-section are at risk of TTN [36] and AMA has been associated to an increase in the number of prelabor C-section [37].In this review, the studies by Dani et al. [13], Romero-Maldonado et al. [20], and Cakmak Celik et al. [22] evaluated the effect of AMA on the incidence of TTN and no association was found in any of the studies.

BPD
BPD is a disease resulting from the interference of several prenatal and postnatal factors in the development of the lower respiratory tract of extreme preterm infants and it can lead to lifelong lung disease [38].
In this systematic review, three studies [14,15,21] evaluated the effect of AMA on BPD and none found an association between the two.

NEC
NEC is a gastrointestinal condition affecting mainly premature neonates that can have serious effects and for many years it has been a major cause of morbidity and mortality in NICUs worldwide [39,40].
In this systematic review, nine studies evaluated the impact of AMA on the incidence of NEC.The study by Kanungo et 15,[19][20][21]24] found no association between AMA and NEC.

Neonatal sepsis
Despite maternal intrapartum prophylaxis, which reduced its rates, early-onset sepsis (EOS) remains a severe problem, especially for preterm neonates [41,42].Risk factors include prematurity, low birth weight, chorioamnionitis, premature prolonged rupture of membranes, resuscitation, and low APGAR score [42].In this review, eight studies assessed the effect of AMA on the incidence of neonatal sepsis.In the study by Kanungo et al. [14], in preterm neonates, as maternal age increased by five years, the incidence of sepsis decreased by 9%.The study by C ¸etin et al. [5] showed an increase in sepsis incidence with AMA.The other six studies [4,8,19-21,24] found no association.Two studies [8,20] evaluated the effect of AMA on the incidence of pneumonia and one [8] evaluated the effect on meningitis and no association was found.

PVL and IVH
PVL is caused by dysregulation of cerebral blood flow causing ischemia of the periventricular white matter and it is a major cause of cerebral palsy in premature neonates [43,44].cPVL is the most severe form of the disease [43].
In preterm infants, particularly in extremely preterm neonates, IVH remains a clinically significant problem, increasing the risk of adverse neurological outcomes [45].
In this review, four studies evaluated the effect of AMA on PVL.The study by Rocha et al. [8] that included 499 neonates with a gestational age of 24-30 weeks found that a maternal age �35 years was associated with higher incidence of echographic cPVL, when compared with a maternal age <35 years.In this multicenter study, the main objective was not to assess cPVL and a confirmatory diagnosis by magnetic resonance was not performed.The other three studies [14,15,21] found no association between AMA and PVL.
[2] found an increase in incidence, but only in twins.

ROP
ROP is a leading cause of childhood blindness.It only occurs in preterm infants and is caused by a proliferation of retinal blood vessels [46].
In this review, four studies evaluated the effect of AMA in the incidence of ROP and none of them found any association [8, 14,15,21].

Asymptomatic hypoglycemia
It is common in healthy newborns to temporarily present low plasma glucose levels [47].There is no uniform definition of neonatal hypoglycemia but it is consensual that infants at risk should have their plasma glucose concentrations measured [47].There is a high incidence of hypoglycemia in asymptomatic neonates, although its significance is unclear [48].
In this review, five studies evaluated the effect of AMA on asymptomatic hypoglycemia, and all found an association.The study by Romero-Maldonado et al. [20] that included 420 neonates, showed a higher incidence of asymptomatic hypoglycemia in neonates delivered to mothers �35 years, when comparing to neonates born to mothers of 18-34 years.The authors associate this to the higher incidence of gestational diabetes in AMA pregnancies.The study by Canto et al. [19] included 682 neonates and found higher incidence of hypoglycemia in neonates born to mothers �40 years compared with neonates born to mothers of 20-29 years.The study by Yogev et al. [3] that included 5487 neonates found a higher incidence of metabolic complications (including hypoglycemia) in neonates delivered to mothers �45 years when comparing to neonates delivered to younger mothers.The study by C ¸etin et al. [5] also found an association between AMA and increased incidence of asymptomatic hypoglycemia, and Schwartz et al. [2] found this association but only in twins.

Jaundice and metabolic complications
In the neonatal period, jaundice is the most common morbidity, frequently requiring intervention [49].Another metabolic complication frequently observed in neonates is hypocalcemia, with risk factors including infants of diabetic mothers, preterm infants, and perinatal asphyxia [50].
Five studies included in this systematic review studied the effect of AMA on jaundice or other metabolic complications.The study by Yogev et al. [3] concluded that metabolic complications were significantly higher among neonates born to mothers �45 years.C¸etin et al. [5] showed that AMA was associated with higher rates of hyperbilirubinemia and hypocalcemia.The other three studies [19,20,24] found that these outcomes were not associated with AMA.

NICU admissions
A systematic review and meta-analysis by Lean et al. [7] including 63 cohort studies and 12 case-control studies, reported an increase in NICU admission among infants of AMA women.
Ten of the studies included in this review evaluated the effect of maternal age on the rate of NICU admissions.The studies by C ¸etin et al. [5] and Shrim et al. [18] associated a maternal age �40 years with a higher rate of NICU admissions.The study by Yogev et al. [3] found the same association but for a maternal age �45 years.Schwartz et al. [2] also found an association between the two variables, but only in twins.The other six studies [4, 19,20,[22][23][24] found no association between AMA and NICU admissions.

Mortality
Although the objective of this systematic review was not to evaluate the effect of AMA on neonatal mortality, eight of the included studies assessed this outcome.Shrim et al. [18] found an increase in mortality with AMA.Kanungo et al. [14] found a decrease of 8% in mortality of preterm neonates as maternal age increased by five years.The other six studies [2,3,15,19,21,24] found no association between the two variables.

Overall morbidity
Overall, nine studies [2,3,5,6,8,13,18-20] in this review found some association between AMA and neonatal morbidities, with two of them only reporting an increase in asymptomatic hypoglycemia [19,20] and the study by Schwartz et al. [2] only reporting a significative association in twins, which is an important finding, but does not fully support the association between AMA and neonatal outcomes.Six studies [4, 15,[21][22][23][24] found no association between AMA and neonatal morbidity and one study [14] found a protective effect of AMA in preterm neonates.
The studies that found an increase in overall neonatal morbidity with AMA [3,5,6,18] considered older ages for the definition of AMA, particularly �40 and �45 years.This might suggest that higher maternal ages have a higher impact on the morbidity of the neonates.On the other hand, two of the studies that found no effect of AMA only evaluated the outcomes for preterm or VLBW infants [15,21].Adding to the fact that the study by Kanungo et al. [14] found a protective effect of maternal age on the outcomes of preterm neonates, we might theorize that the effect of AMA might be different according to gestational age.
According to these results, although there seems to be a lack of association between AMA and neonatal morbidity, this relationship is not yet clearly understood.Our findings on neonatal morbidity contrast with those reported for antenatal and perinatal outcomes.A wide range of adverse pregnancy outcomes are associated with women of AMA, and these include increased risks for miscarriage, chromosomal abnormalities, stillbirth, fetal growth restriction, preterm birth, pre-eclampsia, gestational diabetes mellitus and cesarean section [7, [25][26][27][28][29][30][31][32].The effect of age on pregnancy outcome was investigated in a meta-analysis of 75 studies by Lean et al. [7], the largest and most comprehensive systematic review investigating AMA and pregnancy outcome up today.In this meta-analysis, AMA significantly increased the risk of stillbirth with a population attributable risk of 4.7%; similar trends were seen for risks of fetal growth restriction, neonatal death, NICU admission, and gestational diabetes mellitus.The relationship between AMA and stillbirth was not related to maternal morbidity or assisted reproductive therapies.The authors concluded that stillbirth risk increases with increasing maternal age, and that this is not wholly explained by maternal comorbidities and use of assisted reproductive therapies; they propose that placental dysfunction may mediate adverse pregnancy outcome in AMA.
Despite the evidence on the effect of maternal age on maternal and perinatal outcomes [7, [25][26][27][28][29][30][31][32], the studies focusing on the neonatal outcomes are not as many and the results are more heterogenous.More studies focusing on neonatal outcomes are needed to understand this effect, particularly paying attention to the role of gestational age and the cutoff of maternal age.

Strengths and limitations
There have been a lot of studies and some systematic reviews reporting the effects of maternal age on maternal and perinatal morbidity [7, [25][26][27][28][29][30][31][32].However, this systematic review focuses on neonatal outcomes and complications such as RDS, TTN, BPD, NEC, sepsis, PVL, and ROP, thus bringing some new insight into this topic.
Most of the studies included were retrospective and of moderate evidence, thus, there is a great risk of bias associated with these studies, limiting its conclusions.The fact that the studies included were quite variable in terms of what is considered AMA, the different outcomes evaluated in each study, the gestational ages included and the inclusion or not of twin pregnancies, also limited the conclusions reached in this systematic review.

Conclusion
The current evidence seems to support a lack of association between AMA and neonatal morbidity.
However, more well-designed prospective studies focusing on a thorough evaluation of neonatal outcomes are needed to clarify this association.
It is also important to highlight that the studied outcomes might be secondary to some maternal comorbidities and to preterm birth, and therefore, in future research it might be important to stratify the population by maternal comorbidities and gestational age to better understand their effects.The authors also consider that it is necessary to better define the category of AMA, to avoid the heterogeneity found in our results.It might also be important to filter the population according to the clinical and therapeutic management of pregnancies to understand if it accounts for the observed outcomes.

Figure 1 .
Figure 1.PRISMA flow diagram of the selection process for the systematic review.

Table 1 .
Queries used for search in PubMed and Scopus.

Table 2 .
Summary of findings.