Pathological Insights into Placental Calcifications in HIV-Positive and HIV-Negative Pregnancies: Clinical Diagnostic Value of Ultrasound Versus Pathology in Obstetric and Perinatal Care in Uyo, Southern Nigeria

Abstract

Objectives

Placental calcifications are frequently noted on obstetric ultrasound, yet their diagnostic value and clinical significance remain uncertain, especially in human immunodeficiency virus (HIV)-positive pregnancies. This study compared clinical obstetric findings, ultrasound assessments, and pathological examinations to determine the reliability of ultrasound in detecting placental calcifications.

Materials and Methods

In this hospital-based case–control study, obstetric diagnoses, routine antenatal ultrasound reports, and detailed pathological evaluations of placentas from HIV-positive and HIV-negative mothers were analyzed. Diagnostic performance metrics, maternal factors, and the influence of HIV status, disease stage, and highly active antiretroviral therapy (HAART) use were assessed.

Statistical Analysis

Descriptive and inferential statistics assessed concordance between modalities, associations with gestational age, gravidity, parity, and miscarriage, and the influence of HIV status, disease stage, and HAART.

Results

Pathology confirmed placental calcifications in 114/145 cases (78.6%), with similar prevalence in HIV-positive (75.5%) and HIV-negative mothers (80.2%; p = 0.527). Ultrasound showed excellent specificity (100%) but extremely low sensitivity (0.9%), detecting only one case. Calcifications were not associated with gestational age, gravidity, parity, or miscarriage history. Among HIV-positive mothers, calcification prevalence did not differ by HIV stage (p = 0.824) or HAART use (p = 0.823).

Conclusion

Placental calcifications are common near term in both HIV-positive and HIV-negative pregnancies. Routine ultrasound has minimal diagnostic value for detecting these lesions and should not be used as a standalone indicator of placental pathology. Pathological examination remains the definitive diagnostic method and is essential for accurate placental evaluation, particularly in high HIV-prevalence settings.

Keywords

placenta pathology - calcinosis diagnostic imaging - ultrasonography prenatal methods - pregnancy complications infectious etiology - HIV infections complications - Uyo Nigeria epidemiology

Introduction

Placental health is critical to maternal and fetal well-being, functioning as the primary interface for nutrient exchange, gas transfer, and immune modulation during pregnancy.[1] [2] Placental calcifications, characterized by calcium-phosphate deposition within placental tissues, are frequently observed in late gestation and are often associated with placental maturation, uteroplacental insufficiency, and adverse perinatal outcomes.[3] Although calcifications are known to increase with gestational age, their biomedical significance remains incompletely understood. Distinct patterns and extents of calcification have been linked to preterm birth, preeclampsia, fetal growth restriction, and even long-term cardiovascular morbidity and mortality.[3] [4] A meta-analysis demonstrated associations between grade III placental calcifications and labor induction, meconium-stained liquor, low birth weight, and perinatal death, although no relationship was found with fetal distress or low APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) scores.[5]

Current prenatal assessment of placental calcifications primarily relies on ultrasound. However, ultrasound evaluation is inherently subjective, prompting calls for the development of more objective, computerized imaging tools.[6] Beyond its potential prognostic significance for immediate pregnancy outcomes, placental calcification may also serve as a biomarker for placental dysfunction and long-term cardiovascular health risks in both mothers and offspring.[4] Despite this, the clinical relevance and diagnostic accuracy of ultrasound for detecting calcifications remain debated, particularly in populations with additional obstetric risk factors.

Human immunodeficiency virus (HIV) infection is a well-established modifier of pregnancy outcomes, linked to increased risks of miscarriage, preterm birth, intrauterine growth restriction (IUGR), and neonatal death, even in settings with high antiretroviral therapy (ART) coverage.[7] Placental pathology is thought to play a crucial role in these adverse outcomes, with reported injuries including maternal vascular malperfusion, inflammatory lesions, and impaired immune regulation within the placental microenvironment.[2] [8] [9] HIV-associated immune dysregulation and ART exposure may alter key placental immune cell populations, such as natural killer cells, T cells, and macrophages, potentially contributing to preterm delivery and fetal growth restriction.[2] [9] However, the specific interactions between HIV infection, ART use, and placental calcifications remain poorly characterized.

In HIV-positive mothers, placental calcification may indicate underlying placental dysfunction and contribute to adverse perinatal outcomes, yet its true clinical diagnostic value is uncertain. While historical studies suggested radiological examination as an efficient tool for evaluating placental calcifications, contemporary obstetric practice primarily depends on ultrasound, whose reliability compared with pathological evaluation is unclear.[6] [10] Moreover, the prevalence, patterns, and prognostic implications of placental calcifications in HIV-positive versus HIV-negative mothers are insufficiently understood, particularly in regions with high HIV prevalence.

This study addresses these knowledge gaps by integrating clinical obstetric data, ultrasound findings, and pathological assessments to evaluate placental calcifications in HIV-positive and HIV-negative pregnancies in Uyo, Southern Nigeria. Specifically, we aimed to: (1) compare clinical obstetric diagnoses with ultrasound findings, (2) assess the concordance of ultrasound and pathological detection of placental calcifications, (3) examine associations between calcifications and maternal reproductive history, and (4) explore the impact of HIV status, disease stage, and highly active antiretroviral therapy (HAART) use on calcification prevalence. The findings are expected to refine diagnostic strategies and inform perinatal care practices in high HIV-prevalence settings.

Materials and Methods

Study Design and Setting

This was a hospital-based case–control study conducted in the Departments of Histopathology, and Obstetrics and Gynecology, University of Uyo Teaching Hospital (UUTH), Uyo, Southern Nigeria, a region with a moderate-to-high prevalence of HIV infection among women of reproductive age.[11] The study was designed to evaluate placental calcifications using three complementary approaches, clinical obstetric assessment, antenatal ultrasound scan (USS), and pathological examination of delivered placentas, in both HIV-positive and HIV-negative mothers.

Study Population

The study population comprised pregnant women who delivered at the Labor Ward of the Department of Obstetrics and Gynecology, UUTH over the study period of December 2015 to May 2016. Inclusion criteria were: (1) documented HIV status (positive or negative), (2) availability of complete obstetric clinical records, (3) antenatal ultrasound report performed during routine care, and (4) consent for placental pathological examination. Exclusion criteria included incomplete records, lack of antenatal ultrasound assessment, and unavailability of placenta specimens for pathological review. Consecutive HIV-positive mothers were paired with approximately two consecutive HIV-negative mothers who delivered within the same time for logistic sample (i.e., placenta) collection reasons.

Clinical Assessment

Clinical obstetric diagnoses were recorded at admission and delivery, including pregnancy complications such as prolonged rupture of membranes, hypertensive disorders, IUGR, and postdatism. These diagnoses were subsequently classified as either normal pregnancy or abnormal pregnancy for analytical purposes.

Ultrasound Assessment

Routine antenatal ultrasonography was performed by trained radiologists and sonographers using standard protocols for placental localization, morphology, and identification of calcifications. Placental calcification was documented based on visual echogenic foci suggestive of calcium deposits.

Pathological Assessment

Immediately after delivery, placentas were collected and examined grossly and histopathologically. Gross examination focused on disk morphology, fetal membranes, umbilical cord, and macroscopic calcifications.[1] [12] [13] Tissue samples were processed using standard hematoxylin and eosin staining for histopathologic confirmation of calcifications.

HIV Status, Stage, and HAART Use

HIV-positive mothers were staged according to the World Health Organization criteria and categorized by whether they were on HAART.[14] HIV-negative mothers served as controls.

Data Management and Statistical Analysis

Data were extracted into Microsoft Excel and analyzed using IBM SPSS (version 25) and Python (version 3.11) with panda. Descriptive statistics (means, standard deviations, frequencies, and percentages) were used to summarize data. Categorical variables were compared using chi-square or Fisher's exact tests, while continuous variables were analyzed with Mann–Whitney U tests due to nonnormal distribution. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for ultrasound detection of placental calcifications using pathological findings as the reference standard. Subgroup analyses compared HIV-positive and HIV-negative mothers, and the influence of HIV stage and HAART was evaluated. A p-value of < 0.05 was considered statistically significant.

Results

Study Population

A total of 145 pregnant women were included in the analysis: 49 (33.8%) were HIV-positive and 96 (66.2%) were HIV-negative. The mean gestational age at delivery was 38.2 ± 2.5 weeks, with no significant difference between HIV-positive and HIV-negative mothers (p = 0.918). HIV-positive mothers had significantly higher gravidity (mean 3.4 vs. 2.8; p = 0.025) and higher miscarriage rates (mean 1.1 vs. 0.6; p = 0.012), while parity did not differ significantly (p = 0.378) ([Table 1]).

Table 1 Maternal reproductive characteristics by HIV status and clinical obstetric diagnoses versus ultrasound assessment findings

Maternal reproductive characteristics by HIV status
Variable	HIV-positive mothers ( n  = 49)	HIV-negative mothers ( n  = 96)	p -Value[a]
Gestational age (wk)	38.22 ± 2.69	38.27 ± 2.48	0.918
Gravidity	3.39 ± 1.58	2.80 ± 1.48	0.025 [*]
Parity	1.45 ± 1.37	1.19 ± 1.01	0.378
Number of miscarriages	1.08 ± 1.20	0.64 ± 1.11	0.012 [*]
Clinical obstetric diagnoses versus ultrasound assessment findings
Clinical diagnosis for both groups ( n  = 145)		Normal ultrasound	Abnormal ultrasound[b]
Normal labor (n = 44)		44	0
Normal labor with RVD[d] (n = 13)		13	0
PROM/Postdatism/Hypertensive disorders		20	5
Others (e.g., breech, placenta previa)		46	5
Total		123	10
Comparative clinical diagnosis versus ultrasound assessment findings
Clinical diagnosis category	HIV-positive mothers ( n  = 49)	HIV-negative mothers ( n  = 96)	p -Value[c]
Normal clinical diagnosis	17 (34.7%)	44 (45.8%)	0.21
Abnormal clinical diagnosis	32 (65.3%)	52 (54.2%)
Normal ultrasound finding	48 (98.0%)	75 (78.1%)	0.003[*]
Abnormal ultrasound finding[b]	1 (2.0%)	21 (21.9%)

Abbreviations: HIV, human immunodeficiency virus; PROM, premature rupture of membrane; RVD, retroviral disease.

Note: ^a p-Values calculated using Mann–Whitney U test due to nonnormal distribution.

^b Abnormal ultrasound findings included oligohydramnios, breech presentation, placenta previa, and placental insufficiency.

^c p-Values calculated using chi-square or Fisher's exact test as appropriate.

^d RVD (or HIV infection).

^* Statistically significant.

Clinical Obstetric versus Ultrasound Assessments

Most clinical obstetric diagnoses were either normal labor (n = 44) or normal labor with retroviral disease (RVD) (n = 13). Ultrasound findings were predominantly reported as normal (n = 123), with fewer abnormal findings including oligohydramnios (n = 5), breech presentation (n = 3), and placenta previa (n = 3). Clinical and ultrasound assessments showed high agreement for normal pregnancies but poor correlation for structural placental abnormalities ([Table 1]).

Ultrasound versus Pathological Calcifications

Pathology confirmed placental calcifications in 114/145 (78.6%) placentas. Ultrasound detected only one case of calcification, resulting in a sensitivity of 0.9% and specificity of 100%. Pathology detected four placental calcification subtypes, namely: calcification of chorion of fetal membranes, sclerosing funisitis with perivascular calcification (of the umbilical cord), placental disk calcification, and chorionic plate blood vessels thrombosis with calcifications ([Table 2]), with placental disk calcification being the most frequent. Ultrasound failed to detect any subtype other than one extensive disk calcification. Using pathological findings as the reference standard, ultrasound detection of placental calcifications demonstrated a PPV of 100% and a NPV of 21.5%. This indicates that while ultrasound-reported calcifications were always confirmed pathologically, the absence of calcifications on ultrasound was unreliable due to the high proportion of false negatives.

Table 2 Ultrasound detection versus pathology for placental calcifications

Ultrasound detection versus pathology for placental calcifications
Combined for both groups	Pathology present ( n  = 114)	Pathology absent ( n  = 31)
Ultrasound detected (n = 1)	1 (TP)	0 (FP)
Ultrasound not detected (n = 144)	113 (FN)	31 (TN)
Sensitivity	0.9%
Specificity	100%
Comparative ultrasound detection of placental calcifications versus pathology by HIV status
Calcification status (pathology)	HIV-positive mothers ( n  = 49)	HIV-negative mothers ( n  = 96)	p -Value[a]
Pathology present (total)	37 (75.5%)	77 (80.2%)	0.54
Calcification of chorion of fetal membrane	1 (2.04%)	2 (2.08%)	1
Sclerosing funisitis with perivascular calcification	1 (2.04%)	1 (1.04%)	1
Placental disk calcification	35 (71.43%)	77 (80.20%)	0.295
Chorionic plate blood vessel thrombosis with calcification	2 (4.08%)	0 (0%)	0.113
Pathology absent (total)	12 (24.5%)	19 (19.8%)	0.54
Calcification of chorion of fetal membrane	48 (97.96%)	94 (97.92%)	1
Sclerosing funisitis with perivascular calcification	48 (97.96%)	95 (98.96%)	1
Placental disk calcification	14 (28.57%)	19 (19.79%)	0.295
Chorionic plate blood vessel thrombosis with calcification	47 (95.92%)	96 (100%)	0.113
Ultrasound detected	1 (2.7%)	0 (0%)	0.29
Ultrasound not detected	48 (97.3%)	96 (100%)
Sensitivity	2.7%	0%
Specificity	100%	100%

Abbreviations: FN, false negative; FP, false positive; HIV, human immunodeficiency virus; TN, true negative; TP, true positive.

^a p-Values calculated using chi-square or Fisher's exact test as appropriate.

Placental Calcifications and Maternal Factors

Placental calcification presence was not significantly associated with gestational age (p = 0.396), gravidity (p = 0.814), parity (p = 0.692), or number of miscarriages (p = 0.161).

HIV Status and Placental Calcifications

Placental calcification prevalence was similar in HIV-positive (37/49; 75.5%) and HIV-negative mothers (77/96; 80.2%, p = 0.527) ([Figs. 1] and [2]). Ultrasound sensitivity remained low in both groups (HIV-positive: 2.7%, HIV-negative: 0%).

Fig. 1 Boxplots comparing gravidity (A) and miscarriage history (B) between human immunodeficiency virus (HIV)-positive and HIV-negative mothers. Gravidity (p = 0.025) and miscarriage history (p = 0.012) were significantly higher in HIV-positive mothers.

Fig. 2 (A–F) Selected histopathological images of placental calcifications in human immunodeficiency virus (HIV)-positive and HIV-negative mothers. Representative histological sections of placental tissues showing diverse forms of calcification (indicated by yellow arrows) (hematoxylin and eosin stain, ×40 mag [top panels] with scale bar of 200 µm scale and ×100 mag [bottom panels] with scale bar of 100 µm, respectively). (A and D) Calcification of the chorion of the fetal membranes. (B and E) Calcification within the placental disk parenchyma. (C and F) Chorionic plate vessel thrombosis with perivascular calcification. These images highlight characteristic calcium deposits involving both fetal membranes and chorionic vessels, consistent with pathological calcification features.

Stage of HIV, HAART, and Placental Pathology

Among HIV-positive mothers, calcification frequency did not vary significantly by HIV stage (stage 1: 24/32; stage 2: 11/13; stage 3–4: 2/2; p = 0.824) or HAART use (on HAART: 35/43 vs. not on HAART: 2/6; p = 0.823) ([Table 3]).

Table 3 Placental calcifications by HIV stage and HAART status

Placental calcifications by HIV stage and HAART status
HIV stage ( n  = 49)	Placental calcification present	Placental calcification absent
Stage 1 (n = 32)	24 (48.98%)	8 (16.33%)
Stage 2 (n = 13)	11 (22.45%)	2 (4.08%)
Stage 3–4 (n = 2)	2 (4.08%)	0 (0%)
p-Value	0.824 (chi-square test)
HAART use ( n  = 49)	Placental calcification present	Placental calcification absent
On HAART (n = 43)	35 (71.43%)	8 (16.33%)
Not on HAART (n = 6)	2 (4.08%)	4 (8.16%)
p-Value	0.823 (Fisher's exact test)

Abbreviations: HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus.

Discussion

This study evaluated the diagnostic value of clinical obstetric assessment, USS, and pathological evaluation of placental calcifications, comparing HIV-positive and HIV-negative mothers, and exploring the influence of HIV disease stage and HAART. Placental calcifications were confirmed pathologically in 114 of 145 pregnancies (78.6%), with no significant difference between HIV-positive (37/49; 75.5%) and HIV-negative mothers (77/96; 80.2%; p = 0.527). Ultrasound demonstrated excellent specificity (100%) but extremely low sensitivity (0.9%) for placental calcification detection. Maternal reproductive factors such as gestational age (p = 0.396), gravidity (p = 0.814), parity (p = 0.692), and miscarriage history (p = 0.161) were not associated with placental calcification occurrence. However, HIV-positive mothers had significantly higher gravidity (mean 3.4 vs. 2.8; p = 0.025) and miscarriage history (mean 1.1 vs. 0.6; p = 0.012). Placental calcification frequency was not significantly influenced by HIV stage (p = 0.824) or HAART status (p = 0.823).

Most clinical diagnoses indicated normal labor (44/145; 30.3%) or normal labor with RVD (13/145; 9.0%). Despite 84 women having abnormal clinical diagnoses, ultrasound findings were predominantly normal (123/145; 84.8%), with few abnormalities such as oligohydramnios (n = 5), breech presentation (n = 3), and placenta previa (n = 3). More than 90% of women with abnormal clinical diagnoses had normal ultrasound findings, underscoring the limited utility of routine ultrasound in confirming clinically suspected placental pathology.

These findings are consistent with earlier studies by Bowie et al, Kukard and Freeman, and Chandra and Duff who showed that ultrasound is highly accurate for placental localization, particularly in placenta previa, but limited in detecting subtle or microscopic placental pathology such as ischemic villous necrosis and fibrin deposition.[15] [16] [17] Although Sebire and Sepulveda showed in their study that modern ultrasound and Doppler assessments have improved antenatal management, particularly for fetal growth restriction, histological examination remains indispensable for definitive placental diagnosis.[18] Our findings reinforce the complementary, rather than standalone, role of ultrasound in assessing placental health.

Pathology confirmed placental calcifications in 75.5% of HIV-positive and 80.2% of HIV-negative mothers (p = 0.527), yet ultrasound detected placental calcifications in only one case (0.9% overall), yielding sensitivities of 2.7% in HIV-positive mothers and 0% in HIV-negative mothers, with 100% specificity in both groups. These results clearly demonstrate that routine ultrasound fails to detect the majority of placental calcifications, regardless of HIV status, establishing pathological examination as the gold standard for placental calcification detection. A similar study by Shinde et al show poor ultrasound sensitivity for placental calcification and other lesions but high specificity, with positive findings linked to worse perinatal outcomes.[19] Furthermore, Mirza et al, in their study showed that grade III placental calcifications detected by ultrasound have been associated with labor induction, meconium-stained amniotic fluid, low birth weight, and perinatal death but not fetal distress or low APGAR scores.[5] The very low sensitivity observed in our study (0.9%) is even lower than previously reported by Kalk et al, in their study (2.7% in HIV-positive mothers), likely reflecting differences in ultrasound protocols and operator expertise.[20]

The extremely low sensitivity of ultrasound for placental calcification detection in this study (0.9%) is likely multifactorial. First, sonographer and radiologist variability may have contributed, as placental calcification detection is highly operator-dependent and subject to interpretive subjectivity.[21] Second, routine obstetric scans at our institution did not apply standardized grading systems such as the Grannum classification, which limits structured reporting and may reduce the likelihood of documenting subtle echogenic foci.[22] Third, the ultrasound machines available during the study period were conventional two-dimensional systems without advanced high-resolution or computerized texture-analysis capabilities, potentially reducing sensitivity for microcalcifications that were later confirmed histologically.[6] [23] Fourth, the gestational age at which scans were performed varied, and it is unclear if the scans occurred before late-gestation physiologic calcifications become more prominent. Therefore, a future retrospective study of stored ultrasound images, using standardized grading tools or computer-assisted software is recommended, as it may improve diagnostic yield.

Although HIV-positive mothers had higher gravidity (p = 0.025) and miscarriage history (p = 0.012), placental calcification prevalence was not associated with gestational age (p = 0.396), gravidity (p = 0.814), parity (p = 0.692), or miscarriage history (p = 0.161). These findings indicate that placental calcifications in late pregnancy are largely physiological rather than markers of maternal reproductive history or obstetric risk. Prior research by Santosa et al and Hung et al have linked HIV infection in pregnancy to higher rates of preterm birth, low birth weight, and small-for-gestational-age infants, even in settings with high ART coverage.[7] [24] Such adverse outcomes are often associated with maternal immunosuppression and other sociodemographic risk factors.[25] [26] However, our data suggest that placental calcification specifically does not drive these outcomes and is likely part of normal placental maturation.

Placental calcification prevalence did not differ between HIV-positive and HIV-negative mothers (75.5% vs. 80.2%; p = 0.527), and ultrasound detection sensitivity remained low in both groups. This finding supports the concept that placental calcifications primarily reflect physiological aging rather than HIV-specific pathology. Previous studies by Schuetz et al, Obimbo et al, and Bebell et al have shown mixed results regarding HIV and placental pathology.[27] [28] [29] Schuetz et al and Obimbo et al reported increased rates of chorioamnionitis, thrombosis, infarction, and abnormal cord insertion in HIV-positive placentas, whereas Bebell et al found no significant difference in chronic inflammation prevalence.[27] [28] [29] Our findings are consistent with the study by Kalk et al, who observed no difference in placental calcification prevalence by HIV status, indicating that placental calcification may not be a unique marker of HIV-related placental injury.[20]

Placental calcifications were observed in both clinically abnormal (65/84; 77%) and clinically normal (49/61; 80%) pregnancies, with no significant difference. Thus, placental calcifications, especially when detected incidentally on ultrasound, should not be interpreted as independent indicators for obstetric intervention but rather considered alongside broader clinical and fetal well-being parameters. While Dash et al and Schiffer et al, in their studies associated early or extensive calcifications (e.g., premature placental calcification before 36 weeks) with adverse pregnancy outcomes such as fetal growth restriction and preeclampsia, our findings show that calcifications in late pregnancy, regardless of HIV status, largely reflect physiological processes and lack independent diagnostic value.[30] [31]

Although four histopathological subtypes of placental calcifications were identified, their clinical implications differ.[32] Placental disk calcification was the most frequent subtype in this study, and, especially when premature, is a clinical indicator of potential complications such as preterm birth, fetal growth restriction, and lower APGAR scores.[3] It can also be associated with an increased risk for conditions like preeclampsia, placental abruption, and postpartum hemorrhage.[3] [33] While some calcification is normal, the degree and timing of its appearance can signal placental dysfunction and vascular issues, requiring careful monitoring.[3] Calcification of the chorion of the fetal membranes may indicate localized inflammatory or degenerative change but is not consistently linked to adverse outcomes.[4] Perivascular calcification associated with sclerosing funisitis has been described in inflammatory conditions and may occasionally correlate with fetal vascular malperfusion.[4] Chorionic plate vessel thrombosis with calcification may signify prior thrombotic events and has been associated in some studies with increased risk of fetal growth restriction or perinatal morbidity.[3] [4] [32] [34] However, in our cohort, these subtypes did not correlate with adverse obstetric outcomes, suggesting that most calcifications detected at term represent physiological aging rather than pathological placental dysfunction.

Among HIV-positive mothers, placental calcification prevalence did not differ significantly by HIV stage (stage 1: 24/32 [75%]; stage 2: 11/13 [84%]; stage 3–4: 2/2 [100%]; p = 0.824) or HAART status (on HAART: 35/43 [81%] vs. not on HAART: 2/6 [33%]; p = 0.823). These findings suggest that HIV disease severity and ART do not influence placental calcium deposition. Although Ikumi et al and Maswime et al, in their studies showed that HIV and ART exposure is linked to vascular malperfusion, inflammation, and other placental injuries, our data indicate that placental calcification is not among the lesions significantly modified by these factors.[2] [8] This supports evidence suggesting that while HIV infection alters placental immune and vascular biology, calcification remains predominantly a physiological aging marker.

A key limitation of this study is the small number of untreated HIV-positive mothers and the very limited representation of advanced HIV disease (stage 3–4). These small subgroup sizes reduce statistical power and may obscure true associations between HIV disease severity, HAART exposure, and placental calcification patterns. Therefore, the findings related to HIV staging and treatment status should be interpreted cautiously and validated in larger cohorts.

This study used routine clinical and ultrasound data, which may have introduced operator-dependent variability, and did not apply a standardized ultrasound placental calcification grading system. The relatively small number of untreated HIV-positive mothers and advanced-stage HIV cases limited subgroup statistical power. Furthermore, placental calcification severity and distribution patterns were not quantified, which may underestimate clinically meaningful subtypes.

Future research should adopt standardized ultrasound grading and advanced imaging modalities (e.g., three-dimensional ultrasound, Doppler flow analysis) to evaluate the prognostic role of placental calcifications in both high- and low-risk pregnancies. In clinical practice, incidental ultrasound placental calcifications should not alone dictate obstetric management decisions but instead be interpreted within the context of fetal growth, placental function, and maternal comorbidities. This study highlights the need for standardized ultrasound protocols for placental calcification assessment. Incorporating structured grading systems such as the Grannum classification may improve reporting consistency and diagnostic accuracy. Modern computer-assisted approaches have also demonstrated promising accuracy in quantifying calcifications and could enhance reproducibility in resource-limited settings. Adoption of such standardized or computer-assisted methods in future studies will help clarify the true diagnostic utility of antenatal ultrasound in placental evaluation. Pathological assessment remains essential for obstetric/perinatal care, research, and quality audits, especially in high HIV-prevalence settings, to further elucidate infectious disease-associated placental changes and improve perinatal care.

Conclusion

Placental calcifications were common in late gestation, occurring in 78.6% of cases, with similar prevalence in HIV-positive (75.5%) and HIV-negative mothers (80.2%, p = 0.527). Ultrasound demonstrated excellent specificity (100%) but extremely poor sensitivity (0.9%) for placental calcification detection compared to pathological examination, which remains the gold standard. Placental calcifications were not significantly associated with gestational age (p = 0.396), gravidity (p = 0.814), parity (p = 0.692), or miscarriage history (p = 0.161). HIV status, disease stage (p = 0.824), and HAART use (p = 0.823) did not significantly influence placental calcification occurrence. These findings suggest that routine ultrasound-reported placental calcifications alone should not guide obstetric decision-making but be interpreted within the context of overall maternal–fetal assessment. Pathological assessment remains essential for obstetrics/perinatal care, research, and quality improvement, particularly in high HIV prevalence regions.

Conflict of Interest

None declared.

Acknowledgments

The authors would like to acknowledge the support of the management and nursing staff of the UUTH in Uyo, Southern Nigeria, for their assistance in patient recruitment and data collection. The authors also thank the laboratory and histopathology personnel for their meticulous work in processing the placental specimens. Finally, they appreciate the contribution of all study participants, without whom this research would not have been possible.

Authors' Contributions

We confirm that this manuscript represents original work and has neither been published nor submitted elsewhere. U.B.E.: Conceptualization, methodology, investigation, funding acquisition, writing—original draft preparation, and writing—review and editing and final approval of the manuscript. M.W.R., I.J.K., C.O.N., N.M.U., O.O.A., E.O.E., E.D.E., E.I.A., and I.C.O.: Methodology, investigation, formal analysis, writing—review and editing, and final approval of the manuscript.

Compliance with Ethical Principles

Ethical approval for this study was granted by the Health Research Ethics Committee of the University of Uyo Teaching Hospital (Reference: UUTH/AD/S/96/VOL.XII/115) as part of a broader investigation into placental pathology in HIV-positive pregnancies. Written informed consent was obtained from all participating mothers prior to enrollment. All data were anonymized, and the study was conducted in strict compliance with internationally accepted ethical principles for human research, including respect for participant confidentiality and autonomy.

• References

• 1 Benirschke K, Kaufmann P, Baergen R. eds. Pathology of the Human Placenta. 5th ed.. Springer Science + Business Media, Inc; New York: 2006
• 2 Ikumi NM, Matjila M, Gray CM, Anumba D, Pillay K. Placental pathology in women with HIV. Placenta 2021; 115: 27-36
• 3 Correia-Branco A, Kallol S, Adhikari N. et al. Placental calcification: long-standing questions and new biomedical research directions. Published online. 2020:263–296
• 4 Wallingford MC, Benson C, Chavkin NW, Chin MT, Frasch MG. Placental vascular calcification and cardiovascular health: it is time to determine how much of maternal and offspring health is written in stone. Front Physiol 2018; 9 (1044): 1044
• 5 Mirza FG, Ghulmiyyah LM, Tamim H, Makki M, Jeha D, Nassar A. To ignore or not to ignore placental calcifications on prenatal ultrasound: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 2018; 31 (06) 797-804
• 6 Moran M, Higgins M, Zombori G, Ryan J, McAuliffe FM. Computerized assessment of placental calcification post-ultrasound: a novel software tool. Ultrasound Obstet Gynecol 2013; 41 (05) 545-549
• 7 Santosa WB, Staines-Urias E, Tshivuila-Matala COO, Norris SA, Hemelaar J. Perinatal outcomes associated with maternal HIV and antiretroviral therapy in pregnancies with accurate gestational age in South Africa. AIDS 2019; 33 (10) 1623-1633
• 8 Maswime S, Pule C, Mtshali Z, Chawana R, Matjila M. HIV, placental lesions, and adverse perinatal outcomes. J Infect Dis 2021; 224 (12, Suppl 2): S691-S693
• 9 Ikumi NM, Matjila M. Preterm birth in women with HIV: the role of the placenta. Front Glob Womens Health 2022; 3: 820759
• 10 Tindall VR, Scott JS. Placental calcification: a study of 3,025 singleton and multiple pregnancies. J Obstet Gynaecol Br Commonw 1965; 72 (03) 356-373
• 11 Nyoyoko NP, Umoh AV. The prevalence and determinants of HIV seroconversion among booked ante natal clients in the University of Uyo teaching hospital, Uyo Akwa Ibom State, Nigeria. Pan Afr Med J 2016; 25: 247
• 12 Khong TY, Mooney EE, Ariel I, Balmus NCM, Boyd TK, Brundler MA. et al. Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement. Arch Pathol Lab Med [Internet] 2016; 140 (07) 698-713 . Available from: https://meridian.allenpress.com/aplm/article/140/7/698/65370/Sampling-and-Definitions-of-Placental-Lesions
• 13 Lester SC. Gynaecologic and perinatal pathology. In: Lester SC. ed. Manual of Surgical Pathology. Churchill Livingstone: A Harcourt Health Sciences Company; 2001: 256-259
• 14 WHO. WHO Case Definition of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-Related Disease in Adults and Children. World Health Organization. Preprint posted online 2007
• 15 Bowie JD, Rochester D, Cadkin AV, Cooke WT, Kunzmann A. Accuracy of placental localization by ultrasound. Radiology 1978; 128 (01) 177-180
• 16 Kukard RFP, Freeman ME. The clinical application of ultrasonic placentography. J Obstet Gynaecol Br Commonw 1973; 80 (05) 433-437
• 17 Chandra M, Duff GB. Antenatal detection of placental pathology by ultrasound. Asia Oceania J Obstet Gynaecol 1982; 8 (02) 149-153
• 18 Sebire NJ, Sepulveda W. Correlation of placental pathology with prenatal ultrasound findings. J Clin Pathol 2008; 61 (12) 1276-1284
• 19 Shinde GR, Vaswani BP, Patange RP, Laddad MM, Bhosale RB. Diagnostic performance of ultrasonography for detection of abruption and its clinical correlation and maternal and foetal outcome. J Clin Diagn Res 2016; 10 (08) QC04-QC07
• 20 Kalk E, Schubert P, Bettinger JA. et al. Placental pathology in HIV infection at term: a comparison with HIV-uninfected women. Trop Med Int Health 2017; 22 (05) 604-613
• 21 Moran M, Ryan J, Higgins M, Brennan PC, McAuliffe FM. Poor agreement between operators on grading of the placenta. J Obstet Gynaecol 2011; 31 (01) 24-28
• 22 Siargkas A, Tsakiridis I, Michos G. et al. Impact of placental grading on pregnancy outcomes: a retrospective cohort study. Healthcare (Basel) 2025; 13 (06) 601
• 23 Lei B, Yao Y, Chen S. et al. Discriminative learning for automatic staging of placental maturity via multi-layer Fisher vector. Sci Rep 2015; 5 (01) 12818
• 24 Hung TC, Lu LC, Lin MH. et al. Characteristics of HIV-positive pregnant women and HIV- and antiretroviral therapy-exposed fetuses: a case-control study. J Infect Dev Ctries 2020; 14 (08) 901-907
• 25 Stratton P, Tuomala RE, Abboud R. et al. Obstetric and newborn outcomes in a cohort of HIV-infected pregnant women: a report of the women and infants transmission study. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20 (02) 179-186
• 26 Bodkin C, Klopper H, Langley G. A comparison of HIV positive and negative pregnant women at a public sector hospital in South Africa. J Clin Nurs 2006; 15 (06) 735-741
• 27 Schuetz AN, Guarner J, Packard MM, Zaki SR, Shehata BM, Opreas-Ilies G. Infectious disease immunohistochemistry in placentas from HIV-positive and HIV-negative patients. Pediatr Dev Pathol 2011; 14 (03) 180-188
• 28 Obimbo MM, Zhou Y, McMaster MT. et al. Placental structure in preterm birth among HIV-positive versus HIV-negative women in Kenya. J Acquir Immune Defic Syndr 2019; 80 (01) 94-102
• 29 Bebell LM, Siedner MJ, Ngonzi J. et al. Brief report: chronic placental inflammation among women living with HIV in Uganda. J Acquir Immune Defic Syndr 2020; 85 (03) 320-324
• 30 Dash S, Das B, Panda SR. et al. Perinatal outcomes in premature placental calcification and the association of a color Doppler study: report from a tertiary care hospital in eastern India. Clin Pract 2021; 11 (04) 841-849
• 31 Schiffer V, van Haren A, De Cubber L. et al. Ultrasound evaluation of the placenta in healthy and placental syndrome pregnancies: a systematic review. Eur J Obstet Gynecol Reprod Biol 2021; 262: 45-56
• 32 Rossi C, Gerosa C, Pampaloni P. et al. Placental Calcification Score: a new semiquantitative method to assess pattern and grading of placental calcifications. J Pediat Neonat Individual Med 2019; 8 (02) e080206-e080206
• 33 Ortega MA, Pekarek T, De Leon-Oliva D. et al. Placental tissue calcification and its molecular pathways in female patients with late-onset preeclampsia. Biomolecules 2024; 14 (10) 1237
• 34 Mastrolia SA, Weintraub AY, Sciaky-Tamir Y, Tirosh D, Loverro G, Hershkovitz R. Placental calcifications: a clue for the identification of high-risk fetuses in the low-risk pregnant population?. J Matern Fetal Neonatal Med 2016; 29 (06) 921-927

Publication History

Article published online:
23 January 2026