Maternal and neonatal systemic inflammatory indices and perinatal outcomes in methamphetamine-exposed pregnancies

Abstract

Objective

The aim of this study is to evaluate maternal hematological inflammatory indices such as (neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), and systemic inflammatory response index (SIRI)) in pregnant women using methamphetamine and to examine the relationship between these indices and neonatal inflammatory parameters.

Methods

This retrospective case-control study included 52 pregnant individuals with methamphetamine use and 93 matched controls delivering at a university training hospital. Maternal inflammatory indices were calculated from admission blood counts, and neonatal indices were assessed in 28 exposed neonates and compared with maternal indices using the Wilcoxon signed rank test. Among the 52 methamphetamine-exposed pregnancies, neonatal complete blood count data were available for only 28 neonates. Neonatal blood sampling was performed solely when clinically indicated according to routine neonatal practice. Therefore, neonates without available hematological data were not included in the paired maternal-neonatal analysis.

Neonatal outcomes were compared between groups, and multivariate logistic regression was used to identify factors associated with adverse perinatal outcomes.

Results

The case group demonstrated higher median NLR and PLR ratios. Furthermore, neutrophil, platelet, monocyte counts along with the systemic immune-inflammation index (SII (case vs. control, 1419.2 [1086.9-2231.3] vs. 883.7 [634.2-1076]); p<0.001), and systemic inflammatory response index (SIRI (case vs. control, 3.28 [2.2-5.55] vs. 2.12 [1.51-2.98]); p<0.001) levels were significantly higher than controls (all p<0.001). Furthermore, statistically significant differences were found between maternal and neonatal paired inflammatory indices (NLR, PLR, SII, and SIRI) (all p<0.001). In logistic regression analysis, prenatal methamphetamine exposure was identified as the strongest independent risk factor for adverse perinatal outcomes (odds ratio 2.742, 95% CI: 1.182-8.330; p=0.045).

Conclusion

Methamphetamine use during pregnancy can lead to changes in maternal inflammatory indices, and these changes may be correlated with neonatal inflammatory parameters.

Introduction

Methamphetamine is a potent synthetic psychostimulant belonging to the amphetamine class. It was first synthesized in 1887. It is a powerful psychostimulant that increases attention and alertness and can cross the placental barrier, potentially causing serious health problems for both the fetus and the mother. While used to keep soldiers alert during World War II, its use has diversified and been abused over time [1]. While methamphetamine use continues to increase worldwide data on maternal and neonatal outcomes, particularly those resulting from exposure during pregnancy, are limited [2]. Serotonin, norepinephrine, and dopamine (monoamine) transporters are present in high concentrations in the placenta and play an important role in the homeostasis of the fetal circulation. Because methamphetamine is a significant inhibitor of these transporters, it is thought to cause vasoconstriction in the placental vascular bed, leading to adverse neonatal effects such as oligohydramnios, intrauterine growth restriction, placental abruption, or preterm birth [3, 4].Methamphetamine readily crosses the placental barrier, and approximately half of the maternal dose reaches and persists in the fetal circulation. Metabolized in the liver, methamphetamine’s concentration in the fetal circulation increases over time, reaching levels higher than those in the maternal circulation, as the fetal liver is not yet fully developed [5, 6]. The Infant Development, Environment, and Lifestyle (IDEAL) study confirmed that infants who survive intrauterine exposure to methamphetamine may experience permanent growth retardation and neurobehavioral problems later in life [7]. Studies have also shown that methamphetamine increases oxidative stress (OS) and triggers systemic inflammation [8]. Hematological indices indicating systemic inflammation (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI) are low-cost and useful biomarkers that have become frequently used in recent years [9, 10].

Methamphetamine-induced systemic inflammation may contribute to adverse fetal outcomes through several biological mechanisms. Experimental and clinical studies have demonstrated that methamphetamine can induce oxidative stress, endothelial dysfunction, and vasoconstriction within the placental circulation, potentially impairing uteroplacental blood flow and fetal oxygen delivery. Furthermore, methamphetamine-associated inflammatory responses may promote cytokine dysregulation and placental immune activation, which have been linked to fetal growth restriction, preterm birth, and increased neonatal morbidity. These mechanisms may partly explain the adverse perinatal outcomes observed in methamphetamine-exposed pregnancies [3, 6, 11].

There is insufficient data in the literature demonstrating the relationship between methamphetamine exposure during pregnancy and systemic inflammatory responses. This study analyzed maternal and neonatal outcomes in patients who used methamphetamine during pregnancy and examined the relationship with hematological inflammatory indices. The aim of integrating readily available inflammatory biomarkers with perinatal clinical data is to provide insight into the potential role of maternal systemic inflammation in the biological link between prenatal methamphetamine exposure and adverse neonatal outcomes. The study fills a clinically significant gap, particularly by evaluating maternal and neonatal hematological inflammatory indices together, comparing the maternal inflammatory environment with the neonatal inflammatory environment, and correlating this with adverse neonatal outcomes.

The aim of this study was to evaluate maternal systemic inflammatory indices (NLR, PLR, SII, and SIRI) in pregnancies with methamphetamine exposure and to compare them with those of non-exposed controls. Additionally, we aimed to investigate the relationship between maternal and neonatal inflammatory indices and to determine their association with adverse neonatal outcomes.

Materials and methods

Study design

This retrospective case-control study was conducted to evaluate maternal and neonatal inflammatory indices in pregnancies with methamphetamine exposure. The study was performed at a tertiary care center, between January 2020 and December 2025. Clinical and laboratory data were obtained from the hospital electronic medical record system and institutional laboratory database. A total of 52 pregnant women with documented methamphetamine use during pregnancy and urine methamphetamine levels >500ng/mL during pregnancy were selected as the study group. 93 pregnant women with comparable maternal age and parity were selected as the control group from the same study period, resulting in an approximately 1:2 case-to-control ratio. In the prenatal methamphetamine exposure group, paired maternal-neonatal analysis was limited to 28 neonates for whom complete blood count parameters were available. Neonates without available hematological data were excluded from the paired analysis. Neonatal blood sampling was performed solely when clinically indicated according to routine neonatal practice. Figure 1 shows the flowchart of case selection and exclusion criteria for the study. Singleton pregnancies aged 18–40 years and 34–41 weeks gestation were included in the study. Multiple pregnancies, fetuses with congenital anomalies, those taking medication due to chronic disease, and those with missing data in the hospital information management system were excluded.

Fig. 1.

Flow chart of participant selection and allocation into methamphetamine-exposed and control groups

Variables

Demographic data such as maternal age, parity, and mode of delivery, as well as birth weight, gestational age, neonatal intensive care unit admission, 1- and 5- minute APGAR scores, adverse neonatal outcomes (IUGR, oligohydramnios, placental abruption, fetal distress), and hematological parameters (hemoglobin, neutrophil, lymphocyte, monocyte, and platelet counts) were obtained from the hospital automation system. A complete blood count (CBC) was performed using an automated hematology analyzer. All hematologic measurements were obtained from routine admission blood samples, no additional sampling was performed for research purpose. All maternal CBC parameters used for inflammatory indices calculations were obtained from routine blood samples collected at hospital admission for delivery, within the last 24 h prior to birth. Neonatal complete blood count parameters were recorded from samples taken immediately after birth for any clinical indication. Inflammatory parameters were calculated using the results obtained from the prenatal maternal CBC.

Data sources/measurement

Maternal complete blood count parameters obtained at admission for delivery were used for the calculation of inflammatory indices.

Systemic inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI), were recorded:

• NLR = Neutrophil/Lymphocyte counts.

• PLR = Platelet/Lymphocyte counts.

• SII = (Neutrophil×Platelet)/Lymphocyte counts.

• SIRI = (Neutrophil×Monocyte)/Lymphocyte counts.

Neonatal blood samples were obtained immediately after birth for clinical indications, and inflammatory indices were calculated using the same formulas. All hematological parameters were measured using standardized automated analyzers in the hospital laboratory.

Bias

Several points were taken into account to minimize potential sources of bias. Selection bias was mitigated by including all pregnant women with methamphetamine exposure confirmed by urine toxicology and selecting a control group matched for demographic characteristics such as maternal age and parity.

Misclassification bias was minimized by using urine toxicology screening rather than relying on patient report. CBC measurements were performed in the same hospital laboratory using the same automated hematology analyzer for all patients to reduce measurement variability. APGAR scores were determined by trained clinicians following standard institutional procedures; however, this assessment can be subjective to a certain extent because it was performed by different clinicians.

Information bias was addressed by excluding cases with incomplete electronic medical records or missing laboratory parameters in the hospital automation system.

Study size

Sample size estimation was performed using G*Power software (version 3.1; Heinrich Heine University, Dusseldorf, Germany). Assuming an adverse perinatal outcome rate of 8% in the control group and 30% in the methamphetamine-exposed group, with a two-sided α of 0.05, 80% power, and a control-to-case ratio of 2:1, the minimum required sample size was calculated as 102 pregnant women (34 cases and 68 controls). A total of 145 pregnant women (52 cases and 93 controls) were included in the final analysis, exceeding the estimated minimum sample size. Post hoc power analysis demonstrated a statistical power of approximately 93% for adverse perinatal outcomes and >99% for neonatal intensive care unit admission.

Statistical methods

SPSS v26.0 was used for statistical analysis. The distribution characteristics of the variables were evaluated using histograms, kurtosis, skewness, and the Kolmogorov-Smirnov test. Depending on the distribution characteristics, the results were presented as median with interquartile range (IQR) or 25^th−75^th percentiles for non-normally distributed data.

Chi-Square test was used to compare the percentage distributions of mother-infant categorical data between groups. For variables that were not normally distributed, differences between the methamphetamine and control groups were analyzed using the Mann-Whitney U test.

In the methamphetamine exposed group, the Wilcoxon Signed Rank test was used to compare maternal and neonatal inflammatory indices for paired data. Maternal and neonatal inflammatory indices were analyzed as matched pairs.

For logistic regression analysis, adverse perinatal outcome was defined as the presence of one or more of the following complications: intrauterine growth restriction (IUGR), oligohydramnios, placental abruption, or fetal distress. A multivariable logistic regression model was constructed to identify factors independently associated with adverse perinatal outcome (yes/no), and independent variables included methamphetamine exposure, maternal age, gestational age at delivery, and maternal SII.

A p-value <0.05 was considered statistically significant.

Results

A total of 145 pregnant women and 28 neonates were analyzed in the study. Of these pregnant women, 52 were included in the methamphetamine-exposed group, while 93 constituted the control group selected from the same study period. Table 1, which compares demographic and hematological data between the case and control groups, shows that no difference was observed between the two groups in terms of age (p=0.208) and parity (p=0.891), while gestational weeks at delivery were earlier in the case group than in the control group (38weeks [36–39] vs. 39weeks [38–40]; p<0.001). Despite the control selection process aimed at achieving comparable demographic and obstetric characteristics, gestational age at delivery remained significantly lower in the methamphetamine-exposed group. Birth weights were lower in the case group than in the control group (2910 g [2520-3300] vs. 3250 g [2930-3560]; p<0.001). A significant difference (p<0.001) was observed between the case and control groups in terms of APGAR scores at 1 and 5 min. When maternal hematological parameters and their derived inflammatory markers were examined in the same table, the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio showed a significant increase in the case group (both p=0.002). The median NLR and PLR values were higher in the case group than in the control group. Similarly, neutrophil, platelet, monocyte, SII, and SIRI levels were significantly higher in the case group than in the control group (all p<0.001).

Table 1.

Comparison of demographic and hematologic parameters by groups

Features	Control	Case	p
Age	25 (21–29)	23.5 (20.5–27)	0.208
Birth Weight	3250 (2930–3560)	2910 (2520–3300)	<0.001
Parity	1 (0–2)	1 (0–2.5)	0.891
Gestational Week	39 (38–40)	38 (36–39)	<0.001
Neutrophil	7.77 (6.44–9.33)	10.13 (8.7–13.62)	<0.001
Lymphocyte	1.87 (1.64–2.26)	2.02 (1.64–2.55)	0.133
Platelet	216 (179–253)	283 (236–372.5)	<0.001
Hemoglobin	12.4 (11.5–13.3)	11.05 (10.15–12.05)	<0.001
Monocyte	0.53 (0.39–0.61)	0.67 (0.5–0.8)	<0.001
APGAR 1 st Minute	9 (9–9)	9 (7–9)	<0.001
APGAR 5th Minute	10 (10–10)	10 (9–10)	<0.001
NLR**	4.05 (3.30–5.31)	4.65 (4.08–6.51)	0.002
PLRε	108.06 (87.37–149.09)	144.11 (108.19–176.48)	0.002
SIIγ	883.7 (634.2–1076)	1419.2 (1086.9–2231.3)	<0.001
SIRIϕ	2.12 (1.51–2.98)	3.28 (2.2–5.55)	<0.001

Data are presented as median (IQR). P values were calculated using the Mann-Whitney U test

** Neutrophil-to-Lymphocyte Ratio, ^ε Platelet-to-Lymphocyte Ratio, ^γSystemic Immune Inflammation Index, ^ϕSystemic Inflammation Response Index

According to Table 2, which evaluates the mode of delivery and perinatal outcomes, cesarean section rates were significantly higher in the case group compared to the control group (50% vs. 23.7%; p=0.002). The most striking result in this table was related to the neonatal intensive care unit admission rates.

Table 2.

Evaluation of characteristics between groups

Features	Subgroups	Control	Case	p∗
Delivery Mode	VB	71 (76.3%)	26(50.0%)	0.002
	CS	22 (23.7%)	26 (50.0%)
IUGR∗∗	Yes	6 (6.5%)	12 (23.1%)	0.007
	No	87 (93.5%)	40 (76.9%)
1 st Minute APGAR	Yes	4 (4.3%)	18 (34.6%)	<0.001
	No	89 (95.7%)	34 (65.4%)
Adverse perinatal outcomes	Yes	7 (7.5%)	16 (30.8%)	<0.001
	No	86 (92.5%)	36 (69.2%)
NICU∗∗∗	Yes	9 (9.7%)	28 (53.8%)	<0.001
	No	84 (90.3%)	24 (46.2%)

∗Fisher’s exact test p value, ∗∗ Intrauterine Growth Restriction, ∗∗∗Neonatal İntensive Care Unit

A significantly higher need for neonatal intensive care was observed in the case group compared to the control group (53.8% vs. 9.7%; p<0.001) (Fig. 2a).

Fig. 2.

a Comparison of NICU admission rates between methamphetamine-exposed and control pregnancies. b Distribution of adverse perinatal outcomes (Oligohydramnios, IUGR, Fetal distress, Placental abruption) in methamphetamine-exposed and control groups

Intrauterine growth restriction (IUGR) (23.7% vs. 6.5%; p=0.007), low 1-minute APGAR scores (34.6% vs. 4.3%; p<0.001), and perinatal adverse outcomes (30.8% vs. 7.5%; p=0.001) (Fig. 2b) were observed at higher rates in the case group compared to the control group.

Systemic inflammatory indices in methamphetamine-exposed mother–infant pairs were compared using the Wilcoxon Signed Rank test. Maternal inflammatory indices were significantly higher than neonatal indices for all evaluated parameters. Median maternal NLR was 4.58 (IQR: 3.93–6.22), compared with 1.81 (IQR: 0.91–2.86) in neonates (Z = −4.55, p < 0.001). Similarly, maternal PLR values were significantly higher than neonatal PLR values (145.3 [108.1–168.7] vs. 81.1 [52.1–108.1], p < 0.001). Significant differences were also observed for SII (1416.3 [1084.0–2340.4] vs. 531.5 [319.0–823.8], p < 0.001) and SIRI (3.19 [2.34–5.50] vs. 1.48 [0.88–4.11], p < 0.001) (Table 3). These findings indicate that maternal systemic inflammatory activity was significantly greater than neonatal inflammatory activity in methamphetamine-exposed pregnancies.

Table 3.

Comparison of maternal and neonatal systemic inflammatory indices in methamphetamine-exposed mother-infant pairs

Inflammatory Index	Maternal Median (IQR)	Infant Median (IQR)	Wilcoxon Z	p*
NLR**	4.58 (3.93–6.22)	1.81 (0.91–2.86)	−4.55	< 0.001
PLRз	145.3 (108.1–168.7)	81.1 (52.1–108.1)	−4.35	< 0.001
SII¥	1416.3 (1084.0–2340.4)	531.5 (319.0–823.8)	−4.28	< 0.001
SIRI£	3.19 (2.34–5.50)	1.48 (0.88–4.11)	−2.66	< 0.001

*Wilcoxon Signed Rank test was performed. ** Neutrophil-to-Lymphocyte, ^зPlatelet-to-Lymphocyte, ^¥Systemic Immune-Inflammation Index, ^£Systemic Inflammation Response Index

Multivariable logistic regression analysis identified prenatal methamphetamine exposure as an independent risk factor for adverse perinatal outcomes (OR 2.74, 95% CI 1.18–8.33, p = 0.045) (Table 4). Maternal age, gestational age at delivery, and maternal SII were included in the model but were not independently associated with adverse perinatal outcomes. These findings suggest that methamphetamine exposure itself was the primary factor associated with increased risk of adverse perinatal outcomes in the study population. The median NLR and PLR values and their distribution were higher in the methamphetamine-exposed case group than in the control group (Fig. 3a-b). This supports an increase in neutrophils and/or a decrease in lymphocytes in the case group, thus increasing inflammation and oxidative stress. The increase in platelet activation suggests endothelial stress. The median values of the SII and SIRI parameters were significantly higher in the case group (Fig. 3c-d). The dramatic increase in the SII parameter, known to best reflect inflammation, in the case group suggests a multisystem inflammatory response. This may be related to pregnancy complications.

Table 4.

Multivariable logistic regression model for adverse perinatal outcomes

Predictor Variable	B*	S.E.¥	Wald	df	p	Odds	95% C.I.**
Group (Case vs. Control)	1.203	0.567	3.167	1	0.045	2.742	1.182–8.330
Maternal Age (< 25 vs. > 25)	−0.176	0.482	0.133	1	0.715	0.839	0.326–2.156
Gestational Week	0.267	0.144	3.444	1	0.063	1.306	0.985–1.733
Maternal SIIα	0.000	0.000	0.216	1	0.642	1.000	0.999–1.000
Constant	−9.411	5.570	2.855	1	0.091	0.000	—

*B: Regression coefficient; ^¥ S.E.: Standard Error; ** CI: Confidence Interval; ^α SII: Systemic Immune-Inflammation Index

Fig. 3.

Box plots comparing inflammatory indices between methamphetamine-exposed pregnancies and controls. a Neutrophil-to-lymphocyte ratio (NLR): median 4.65 (IQR 4.08–6.51) vs. 4.05 (IQR 3.30–5.31), p = 0.002. b Platelet-to-lymphocyte ratio (PLR): median 144.11 (IQR 108.19–176.48) vs. 108.06 (IQR 87.37–149.09), p = 0.002. c Systemic immune-inflammation index (SII): median 1419.2 (IQR 1086.9–2231.3) vs. 883.7 (IQR 634.2–1076.0), p<0.001. d Systemic inflammatory response index (SIRI): median 3.28 (IQR 2.20–5.55) vs. 2.12 (IQR 1.51–2.98), p<0.001. The central line represents the median, the box indicates the interquartile range (IQR), and whiskers represent the data distribution

Discussion

This study demonstrated that methamphetamine exposure during pregnancy is associated with significantly increased maternal inflammatory indices and a higher rate of adverse perinatal outcomes. Notably, neonatal inflammatory indices paralleled maternal findings, suggesting a potential transplacental inflammatory effect.

Additionally, the higher rate of NICU admission in the exposed group further supports the clinical impact of these findings. Together, these results highlight the role of systemic inflammation as a potential mechanism underlying adverse outcomes in methamphetamine-exposed pregnancies.

To our knowledge, this is the first study evaluating paired maternal and neonatal systemic inflammatory indices in pregnancies complicated by prenatal methamphetamine exposure. This study makes a distinctive contribution to the literature by offering the first concurrent analysis hematologic inflammatory biomarkers and maternal-neonatal outcomes in methamphetamine-exposed pregnancies. One of the key strengths of the study is the simultaneous evaluation of both maternal and neonatal inflammatory indices. The significant differences observed in matched maternal and neonatal NLR, PLR, SII, and SIRI values suggest that methamphetamine exposure may influence not only the maternal inflammatory response but also the early inflammatory status of the newborn. These findings support the hypothesis that intrauterine methamphetamine exposure may alter the fetal inflammatory milieu, potentially through placental mechanisms. Although neonatal inflammatory indices were generally lower than maternal values, the presence of a measurable inflammatory profile in exposed neonates suggests early immune activation.

While existing literature does not associate intrauterine methamphetamine exposure with major fetal malformations [12, 13, 14], it is consistently linked to increased maternal and neonatal morbidity, including adverse perinatal outcomes such as intrauterine growth restriction (IUGR), neonatal intensive care unit (NICU) admission, and placental abruption [11]. The findings of the present study corroborate this established morbidity profile. Specifically, the methamphetamine-exposed cohort exhibited significantly lower birth weights and higher rates of NICU admission than the control group. These results demonstrate a strong association between prenatal methamphetamine exposure and adverse neonatal outcomes, low APGAR scores, fetal growth retardation, and increased requirement for intensive neonatal care.

A meta-analysis of eight studies comparing patients who used methamphetamine during pregnancy with controls reported that exposed newborns had higher incidence of premature birth, low birth weight, reduced head circumference, and lower APGAR scores; however no significant difference was observed in the rates of preeclampsia or hypertensive disease [11]. Our findings align with this synthesis, demonstrating significantly lower birth weight, gestational age, and mean APGAR scores in the exposed cohort. These results suggest a pattern of delayed postnatal adaptation in methamphetamine-exposed neonates.

The Infant Development, Environment, and Lifestyle (IDEAL) study is a longitudinal cohort study examining conditions and consequences related to intrauterine methamphetamine exposure.⁷ Analysis of data from the IDEAL cohort indicates a 5.2% estimated prevalence of prenatal methamphetamine use.

A recent study found methamphetamine in the urine toxicology of a newborn born to a mother who used methamphetamine immediately before birth [15]. Another similar study found that a newborn exposed to methamphetamine before birth developed seizures immediately after birth, followed by liver failure [16]. Another study emphasized the need for close postnatal monitoring due to early inadequate sucking, transient withdrawal symptoms, and neurological imbalances and withdrawal symptoms in newborns. The same study found a higher rate of NICU admission in the methamphetamine-exposed group [4]. This suggests a strong link between methamphetamine exposure and neonatal stress.

The neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR), have emerged as established biomarkers within obstetrics and gynecology, with NLR signifying acute inflammation and PLR reflecting platelet activation and immune response [17, 18, 19, 20]. More recently developed indices, such as the Systemic Immune-Inflammation Index (SII) and the Systemic Inflammatory Response Index (SIRI), offer further measures of systemic immune dysregulation. These biomarkers are utilized across numerous clinical domains, including oncology and cardiology [21, 22, 23, 24].

In the present study, elevated NLR, PLR, SII, and SIRI levels in the methamphetamine-exposed cohort indicate a pronounced inflammatory state. This provides a biological correlate for the observed adverse perinatal outcomes, suggesting that systemic inflammation may be a mechanistic link in pregnancies complicated by substance use. The findings of our study suggest that methamphetamine exposure during pregnancy may affect not only the maternal inflammatory response but also the neonatal inflammatory profile. This study contributes a novel contribution by providing the first concurrent evaluation of systemic inflammatory indices and maternal-neonatal outcomes in a cohort with prenatal methamphetamine exposure. Although these indices were not identified as independent predictors in multivariate analysis, they may reflect the underlying maternal inflammatory environment associated with methamphetamine exposure, rather than being direct causal determinants of neonatal outcomes. While NLR, PLR, SII and SIRI were not independent predictors of adverse neonatal outcomes in regression analysis, their significant and consistent elevation indicates their role as surrogate markers of maternal systemic inflammation associated with methamphetamine exposure, rather than primary mediators of perinatal morbidity. This distinction is clinically relevant, as such indices may help identify high risk pregnancies without implying a direct mechanistic causality.

Our findings are consistent with previous studies demonstrating that prenatal methamphetamine exposure is associated with adverse neonatal outcomes, including low birth weight, preterm birth, and increased NICU admission rates. These results are also in agreement with meta-analyses reporting impaired fetal growth and lower Apgar scores in exposed neonates. In addition to confirming these clinical outcomes, our study extends the existing literature by evaluating both maternal and neonatal inflammatory indices simultaneously. While previous studies have primarily focused on clinical outcomes, the present study provides novel evidence suggesting a potential inflammatory link between maternal exposure and neonatal response. However, unlike some studies that identified certain inflammatory markers as independent predictors of adverse outcomes, we did not observe independent predictive value in multivariate analysis. This discrepancy may be related to differences in sample size, study design, or population characteristics.

Limitations

The single-center, retrospective nature of our study limits causality. While the sample size was sufficient to detect key differences, multicenter, prospective studies are needed for generalizability. The consistency between the data obtained from this study and the literature supports the reliability of our study, despite all its limitations. Despite using matching and multivariable adjustment, residual bias may still exist. Several important confounding factors, such as smoking status, alcohol or other substance use, chronic maternal stress, socioeconomic conditions, and adequacy of prenatal care, were not controlled for. These variables are particularly important because they may independently influence both systemic inflammatory indices and adverse perinatal outcomes. Therefore, future prospective studies should systematically collect and adjust for these potential confounders to better clarify the independent effects of methamphetamine exposure. Because inflammation indices were obtained from a single blood sample at presentation, temporal fluctuations in maternal inflammation could not be assessed. In addition, neonatal complete blood count data were available for only 28 methamphetamine-exposed neonates, as laboratory testing was performed solely when clinically indicated according to routine neonatal practice. Therefore, selection bias cannot be excluded, and the neonatal inflammatory indices may not fully represent all exposed neonates. Another important limitation is the absence of placental histopathological evaluation. Placental inflammatory lesions such as chorioamnionitis, funisitis, chronic villitis, intervillositis, and vascular malperfusion may play a key role in mediating maternal-fetal inflammatory interactions. Because placental pathology data were not routinely available in this retrospective cohort, we were unable to investigate the relationship between placental inflammation and maternal or neonatal inflammatory indices. Future prospective studies incorporating detailed placental examination are warranted to better elucidate the maternal-placental-fetal inflammatory axis in methamphetamine pregnancies. Furthermore, even with the availability of toxicology screening, patient underreporting of methamphetamine use is likely. These factors may contribute to the remaining confounding factors and limit the ability to establish causal relationships.

The findings of this study may be generalizable to similar populations of pregnant women with methamphetamine exposure, particularly in tertiary care settings. The observed association between methamphetamine exposure, systemic inflammation, and adverse perinatal outcomes may also be applicable to other populations with substance use during pregnancy. However, caution should be exercised when generalizing these results to different populations, as this was a single-center study with a relatively limited sample size. Differences in demographic characteristics, healthcare systems, and patterns of substance use may influence the generalizability of the findings.

Further prospective, multicenter studies with larger sample sizes are needed to better clarify the relationship between methamphetamine exposure and systemic inflammation during pregnancy. In addition, future research should investigate the potential role of inflammatory indices as early biomarkers for identifying high-risk pregnancies and guiding clinical management in substance-exposed populations.

Conclusion

In conclusion, while existing literature has predominantly focused on neurodevelopmental sequelae of prenatal methamphetamine exposure, the present study contributes a novel perspective by incorporating systemic inflammatory indices into the evaluation of maternal and neonatal outcomes. Our findings suggest a potential biological pathway linking maternal methamphetamine use to adverse perinatal outcomes. The routine assessment of systemic inflammatory indices in this patient population may help identify high-risk pregnancies, and facilitate more targeted prenatal and postnatal care.

This study demonstrates that methamphetamine use during pregnancy may be associated not only with maternal inflammatory indices but also with neonatal inflammatory parameters. This relationship between maternal and neonatal inflammatory indices suggests potential effects of prenatal substance exposure on maternal-fetal inflammatory interactions.

Methamphetamine use during pregnancy constitutes a growing public health concern that extends beyond a social problem to a complex, multisystemic condition with enduring fetal consequences. Mitigating its impact requires a multifaceted strategy. This includes improving access to dedicated reproductive health services and care resources in this patient group, implementing a coordinated, multidisciplinary care model involving obstetrics, neonatology, psychiatry, and social work. Such an integrated approach is essential to minimize adverse maternal and neonatal outcomes associated with this exposure.

Authors’ contributions

MB conceived and designed the study, collected the data, performed statistical analyses, interpreted the results, and drafted the manuscript. MSD contributed to data collection, data interpretation, and critical revision of the manuscript. Both authors read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and ethical restrictions but are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was approved by the Aksaray University Health Science Ethics Committee (IRB No: 2025/178) and was conducted in accordance with the principles of the Declaration of Helsinki.

Informed consent was waived due to the retrospective design of the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.