Abstract
Background
Accurate interpretation of clinical laboratory test results relies on the application of appropriate reference intervals, which differs between populations. Despite this, there is no Kenyan-derived reference values for clinical management of both pregnant and non-pregnant women, potentially leading to diagnostic misclassification. This study established age- and trimester-specific reference intervals for lipid function tests and compare them with the current practice cut-offs.
Methods
Lipid parameters were determined in non-pregnant and pregnant women aged 19–29 and 30–40 years, partitioned by trimester. The measured parameters included total cholesterol, low and density lipoproteins, triglycerides, non-high-density lipoproteins, and their ratios. Differences between groups were assessed using Kruskal-Wallis and Mann-Whitney U tests. Out-of-range analysis were performed between the newly developed reference intervals and the current practice reference values.
Results
Significant age- and trimester-specific differences were noted in total cholesterol, low-density lipoproteins, triglycerides, and lipid ratios (p < 0.05), with incremental increases observed in later trimesters. High-density lipoproteins showed variable changes. Out-of-range comparison show significant misclassification: 54 % of pregnant women aged 30–40 years in the trimester two exceeded current low-density lipoproteins reference intervals, while 60 % were misclassified for triglycerides in third trimester. Remarkably, 100 % of women across all groups fell outside the standard high-density lipoproteins reference limits.
Conclusion
The current practice reference intervals are inappropriate for clinical assessment of pregnant and non-pregnant women in Nairobi, Kenya. Establishing age- and trimester-specific reference intervals provides a more accurate clinical decision-making tool, enhancing maternal care.
Keywords: Reference intervals, Lipid function tests, Women, Pregnancy, Age, Trimester
Graphical abstract
Highlights
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Progressive hyperlipidemia during pregnancy.
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Triglycerides increase 2–3 fold by third trimester.
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Older pregnant women showed higher atherogenic lipid levels.
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Standard lipid reference intervals misclassified many participants.
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Population-, age-, and trimester-specific lipid reference intervals are required.
1. Introduction
Accurate interpretation of clinical laboratory test results relies on the use of appropriate reference intervals (RIs) from biologically and contextually comparable population [[1], [2], [3]]. Nonetheless, in many low-income countries, including Kenya, laboratories continue to use foreign-derived or manufacturer-provided RIs [4,5] that may inadequately account for population-specific nutritional [6], demographic (age, trimester) [7], genetic [8], and lifestyle [9] factors. The absence of locally established reference values undermines evidence-based clinical decision-making and increase the risk of diagnostic misclassification [[10], [11], [12]].
The use of such inappropriate reference values increases the risk of misinterpreting normal alterations as pathological conditions [[13], [14], [15]] and of overlooking significant physiological changes attendant to pathological events that predict adverse pregnancy outcomes (APOs) [16] like preterm birth, gestational diabetes mellitus (GDM) and pre-eclampsia [17]. Further, this can lead to unnecessary and potentially dangerous clinical interventions, delayed treatment, and thus increased APOs [18,19].
Pregnancy is a unique physiological state characterized by dynamic, stage-dependent changes in lipid metabolism [20]. Progressive increases in total cholesterol (T-C), triglycerides (TG), and lipoproteins fractions (low and high-density lipoproteins) occur across pregnancy [[21], [22], [23]], reflecting hormonal regulation and adaptive energy redistribution in support of placental function and fetal development [24]. These alterations are neither linear nor uniform, making the use of non-pregnant reference limits or pooled pregnancy RIs clinically inappropriate [25]. The International Federation for Clinical Chemistry and the Clinical and Laboratory Standards Institute C28-A3 (IFCC-CLSI) guidelines therefore recommend pregnancy-, age- and trimester-specific RIs; however, no data exist on RIs for pregnant and non-pregnant women based on Kenyan women [26].
Non-pregnant women of reproductive age represent an essential physiological baseline for meaningful interpretations of gestational alterations [27]. Age-specific metabolic changes further necessitates partitioning, as lipid markers are altered by both reproductive status and advancing maternal age [28]. Clinically relevant differences may be obscured by failure to account for these dimensions, and thus compromise the diagnostic utility of the laboratory measurements [29].
In this context, the present study establishes age- and trimester-specific RIs for lipid profile parameters and related ratios among health pregnant and non-pregnant women in Nairobi, Kenya. By conducting an in-depth comparative study across pregnancy status, age and gestational stage, this study generated clinically relevant reference values that will enhance diagnostic accuracy, improve clinical decision-making, and support evidence-based laboratory practice within the local context.
2. Materials and methods
2.1. Study design and setting
This was a descriptive cross-sectional study carried out from June 2019 to January 2020 at Pumwani Maternity Hospital and Kenyatta National Hospital (KNH) in Nairobi City, Kenya. The study was conducted as per CLSI-IFCC C28-A3 guidelines.
Ethical approval
All procedures were performed in compliance with relevant laws and institutional guidelines and have been approved by the appropriate institutional committee. Ethical approval was obtained from Kenyatta University Ethics Review Committee: KU/ERC/APPROVAL/VOL.1 (272). Valid from March 12, 2019 to July 20, 2021.
2.2. Study population
Apparently healthy pregnant women were recruited from the Pumwani Maternity Hospital antenatal clinic. Non-pregnant women were recruited from Nairobi National Blood Transfusion Center, Kenyatta National Hospital (KNH) and at KENCOM Bus stop Nairobi during blood donation drives by Kenya Red Cross Society (KRCS) and St John Ambulance Kenya. All participants received a review of medical history.
2.3. Inclusion criteria
Participants were included in the study if apparently healthy (as determined by clinical officer), female (pregnant and non-pregnant), aged 19–40 years, residents of Nairobi for at least 6 months (for acclimatization), and able to provide informed consent.
2.4. Informed consent
The privacy rights of human subjects was observed and an informed written consent was obtained.
2.5. Exclusion criteria
Participants were evaluated by a Clinical Officer. Participants were excluded if febrile, on medication, seropositive for HIV, syphilis, hepatitis B and C surface antigens. Subject samples were coded. Participants with abnormal results were recalled for referral.
2.6. Sample size
To establish reference interval, the IFCC-CLSI guidelines recommends a priori nonparametric determination from a minimum of 120 reference individuals, per partition (per age and trimester) [14]. A total of 316 non-pregnant women and 1142 pregnant women were recruited for this study.
2.7. Blood collection and processing
A blood sample was drawn by a phlebotomist in two separate 10 mL Becton Dickson (BD) EDTA vacutainer tubes. Another blood sample (5 mL) was drawn and screened for pregnancy, HIV, syphilis, Hepatitis B and C virus. The specimens were coded with donor number, age and trimester. The specimens were kept in coolers. Serum extraction was performed at Pumwani Maternity Hospital laboratory within three (3) hours. The serum samples were stored at −80 °C awaiting analysis at KNH Clinical Chemistry Laboratory.
2.8. Laboratory analysis
2.8.1. Serology analysis
HIV, Syphilis, Hepatitis B and Hepatitis C status was determined from whole blood using rapid test kits follows: HIV test was carried out using Alere Determine™ HIV-1/2 Ag/Ab Combo (Abbot Laboratories, Tokyo, Japan) as primary kit, and Uni-Gold™ HIV Complete (Trinity Biotech Plc, Bray, Ireland) as a confirmatory test, with Bioline HIV-1/2 (Standard Diagnostics Inc., Korea) as a tie breaker for specimens with indeterminate test results. Syphilis test was carried out using SD Bioline Syphilis 3.0 (Standard Diagnostics, Suwon City, South Korea). Hepatitis B virus (HBV) was carried out using Alere determine™ HBsAg 2 (Abbot Laboratories, Tokyo, Japan). The HCV test was carried out using SD Bioline HCV test (Abbot Laboratories, Tokyo, Japan). All the diagnostics were performed as per the manufacturer's instructions.
2.8.2. Pregnancy testing
A serum pregnancy test was administered to all females prior to collection of blood samples, using SD Bioline hCG (Abbot Laboratories, Tokyo, Japan) as per the manufacturer's instructions.
2.8.3. Lipid analysis
Routine biochemical tests included T-C, LDL-C, HDL-C, TG, and non-HDL. These parameters were analyzed using the Cobas Integra 400 plus biochemistry analyzer (Roche, Germany) as per the manufacturer's instructions. The related calculated ratios were TC/HDL-C, LDL-C/HDL-C, TG/HDL-C, and non-HDL-C/HDL-C.
2.8.4. Quality control
Internal quality control (QC) protocols involved daily QC runs and participation in external quality assessment (EQA) scheme (Randox International Quality Assessment Scheme (RIQAS®))
2.9. Statistical analysis
Data were analyzed in SPSS v26. Since normality tests (Kolmogorov-Smirnov, Shapiro-Wilk W, skewness, kurtosis) showed non-normal distributions, medians with 2.5th-97.5th percentiles (95 % confidence interval) were used to establish RIs. Group differences were tested using Mann-Whitney U, and for more than 2 groups, Kruskal-Wallis H with Bonferroni-adjusted Mann-Whitney U (adjusted ρ = 0.0083). Out-of-range analysis compared the developed RIs against current practice RIs using Chi-square, with significance set at ρ < 0.05.
3. Results
3.1. Establishment of reference values
The study participants were 1458 women, aged 19–40 years, stratified into two age groups 19–29 years, and 30–40 years. Non-pregnant women were 316, and pregnant women were 1142 (trimester 1: 321; trimester 2: 499; and trimester 3: 322). Fig. 1 presents the flow chart of study participants. The lipid function tests (LFTs) evaluated included T-C, LDL-C, HDL-C, TG, non-HDL-C and their ratios; T-C/HDL-C, LDL-C/HDL-C, TG/HDL-C, and non-HDL-C/HDL-C.
Fig. 1.
Flow chart of study participants.
3.2. Reference intervals of lipid profiles and related ratios for pregnant and non-pregnant women aged 19-40-years
Table 1 present the combined age (19–40 years) median, trimester and 95 % RI for lipid parameters for non-pregnant and pregnant women obtained from this study. In non-pregnant women aged 19–40 years, the median (95 % range) lipid panel values were as follows: T-C 4.4 (2.6–7.6) mmol/L, LDL-C 1.9 (0.7–4.8) mmol/L, HDL-C 1.3 (0.6–2.5) mmol/L, TG 0.9 (0.0–2.4) mmol/L, non-HDL-C 3.2 (1.0–6.0) mmol/L, T-C/HDL-C 3.5 (1.4–8.2), LDL-C/HDL-C 1.4 (0.4–4.5), TG/HDL-C 0.7 (0–2.3), and non-HDL-C/HDL-CHO 2.5 (0.4–7.2).
Table 1.
Combined age (19–40 years) reference intervals for lipid profile and related ratios in pregnant and non-pregnant women.
| Age/Parameter |
Non pregnant |
Pregnant women |
Kruskal Wallis test |
|||||
|---|---|---|---|---|---|---|---|---|
| 19-40-years |
Trimester 1 |
Trimester 2 |
Trimester 3 |
Combined trimesters |
||||
| N | 343 | 321 | 499 | 322 | 1142 | df | χ2 | Sig |
| T-C (mmol/L) | 4.4 (2.6–7.6) | 4.8 (2.9–7.6)a | 5 (3.1–7.4)a | 5.3 (3–8.7)ab | 5.0 (3.0–8.0)a | 3 | 78.597 | 0.000 |
| LDL-C (mmol/L) | 1.9 (0.7–4.8) | 2.4 (1.2–5.2)a | 2.6 (1.4–5.1)ab | 2.5 (1.4–5.7)ab | 2.5 (1.4–5.3)a | 3 | 110.675 | 0.000 |
| HDL-C (mmol/L) | 1.3 (0.6–2.5) | 1.7 (1–3)a | 1.6 (0.9–2.9)a | 1.6 (1–2.7)ab | 1.6 (0.9–2.9)a | 3 | 90.180 | 0.000 |
| TG (mmol/L) | 0.9 (0.0–2.4) | 1.4 (0.6–3.1)a | 1.6 (0.8–3.3)ab | 1.8 (0.9–3.6)abc | 1.6 (0.7–3.4)a | 3 | 268.436 | 0.000 |
| Non HDL-C(mmol/L) | 3.2 (1.0–6.0) | 3.2 (1.0–6.0) | 3.4 (1.5–5.8)ab | 3.7 (1.3–6.9)abc | 3.4 (1.3–6.1)a | 3 | 41.834 | 0.000 |
| T-C/HDL-C | 3.5 (1.4–8.2) | 2.9 (1.2–5.2) | 3.1 (1.6–5.5)ab | 3.4 (1.7–6.3)abc | 3.1 (1.5–5.7) | 3 | 50.887 | 0.000 |
| LDL-C/HDL-C | 1.4 (0.4–4.5) | 1.4 (0.6–3.5)a | 1.5 (0.8–3.7)ab | 1.6 (0.9–4.1)abc | 1.5 (0.7–3.7)a | 3 | 41.406 | 0.000 |
| TG/HDL-C | 0.7 (0–2.3) | 0.9 (0.2–2.2)a | 1.0 (0.4–2.6)ab | 1.1 (0.5–2.8)abc | 1 (0.4–2.5)a | 3 | 177.001 | 0.000 |
| Non HDL-C/HDL-C | 2.5 (0.4–7.2) | 1.9 (0.2–4.2)a | 2.1 (0.6–4.5)ab | 2.4 (0.7–5.3)abc | 2.1 (0.5–4.7)a | 3 | 50.887 | 0.000 |
Results are expressed as median and 95 % range for the number of referent participants in the column labeled N. Significant differences in medians of each of the measured parameters within and between non-pregnant and pregnant women in the three trimester were carried out using Kruskal-Wallis H test followed by Mann-Whitney U test with adjusted significant ρ-value of less than 0.0083. Significant differences between the medians of the non-pregnant and combined pregnant data were assessed using Mann-Whitney U test at a ρ-value <0.05 and marked with a letter (a). Note: (a) represent significant difference to non-pregnant; (b) represent significant difference to Trimester 1; (c) represent significant difference to Trimester 2.
In pregnant women aged 19–40 years, significant trimester-specific changes in lipid values were noted. T-C increased from 4.8 (2.9–7.6) mmol/L in trimester 1 to 5.3 (3–8.7) mmol/L in trimester 3 (p < 0.001). LDL-C increased from 2.4 (1.2–5.18) mmol/L in trimester 1 to 2.5 (1.4–5.7) mmol/L in trimester 3 (p < 0.001). HDL-C had higher values in trimester 1 and 2 [1.7 (1.0–3.0) mmol/L] compared to trimester 3 [1.6 (1.0–2.7)] and non-pregnant women [1.3 (0.6–2.5)] (p < 0.001). TG values doubled from 0.9 (0.0–2.4) mmol/L in non-pregnant women to 1.8 (0.9–3.6) mmol/L in the third trimester (p < 0.001).
There was no significant difference in non-HDL-C values between non-pregnant [3.2 (1.0–6.0)] and pregnant women in trimester 1 [3.2(0.97–5.95)], however non-HDL-C values progressively elevated during pregnancy to 3.7 (1.3–6.9) in trimester 3 (p < 0.001). T-C/HDL-C decreased in trimester 1 [2.9 (1.2–5.16)] compared to non-pregnant women [3.5 (1.4–8.2)] but increased in trimester 2 [3.1 (1.6–5.5)] and trimester 3 [3.4 (1.7–6.3)]. There was no significant difference in LDL-C/HDL-C values between non-pregnant and pregnant women, and across the trimesters.
LDL-C/HDL-C decreased from 1.4 (0.4–4.5) in non-pregnant women to 1.4 (0.6–3.5) mmol/L in trimester 1 then progressively increased to 1.6 (0.9–4.1) mmol/L in trimester 3 (p < 0.001). Similarly, TG-CHOL/HDL-C decreased from 0.7 (0–2.3) in non-pregnant women to 0.9 (0.2–2.2) mmol/L in trimester 1 then progressively increased to 1.1 (0.5–2.8) mmol/L in trimester 3 (p < 0.001). Further, non-HDL-C/HDL-C decreased from 2.5 (0.4–7.2) in non-pregnant women to 1.9 (0.2–4.2) mmol/L in trimester 1 then progressively increased to 2.4 (0.7–5.3) mmol/L in trimester 3 (p < 0.001).
3.3. Reference intervals of lipid profile and related ratios for pregnant and non-pregnant women aged 19–29, and 30-40-years
Table 2 present the median, age, trimester and 95 % RI for lipid parameters for non-pregnant and pregnant women obtained from this study. In non-pregnant women aged 19–29 years, the median (95 % range) lipid panel values were as follows: T-C 4.0 (2.0–7.0) mmol/L, LDL-C 2.0 (1.0–4.9) mmol/L, HDL-C 1.0 (1.0–3.0) mmol/L, TG 1.0 (0.0–2.9) mmol/L, non-HDL-C 3.1(1.0–5.9) mmol/L, T-C/HDL-C 3.5 (1.3–8.4), LDL-C/HDL-C 1.4 (0.4–4.8), TG/HDL-C 0.7 (0.0–2.7), and non-HDL-C/HDL-CHO 2.5 (0.3–7.4). In the 30–40 years group, most of the parameter RIs were comparable except for T-C, and LDL-C, which were significantly higher, and HDL-C that was significantly lower compared to the 19–29 years.
Table 2.
Reference intervals for lipid profile and related ratios in pregnant and non-pregnant women by age and trimester.
| Age/parameter |
Non-pregnant women |
Pregnant women |
Kruskal Wallis test |
|||||
|---|---|---|---|---|---|---|---|---|
| 19-29-years |
Trimester 1 |
Trimester 2 |
Trimester 3 |
Combined trimesters |
||||
| N | 162 | 184 | 277 | 125 | 585 | df | χ2 | Sig |
| T-C (mmol/L) | 4.0 (2.0–7.0) | 5.0 (2.6–7.0)a | 5.0 (3.0–8.0)ab | 5.0 (3.0–10.0)a | 5.0 (3.0–8.0)a | 3 | 45.754 | 0.000 |
| LDL-C (mmol/L) | 2.0 (1.0–4.9) | 2.0 (1.0–5.0)a | 2.0 (2.0–5.0)ab | 2.0 (1.0–5.0)ac | 2.0 (1.0–5.0)a | 3 | 67.344 | 0.000 |
| HDL-C (mmol/L) | 1.0 (1.0–3.0) | 2.0 (1.0–3.0)a | 2.0 (1.0–3.0)a | 2.0 (1.0–3.0)a | 2.0 (1.0–3.0)a | 3 | 84.651 | 0.000 |
| TG (mmol/L) | 1.0 (0.0–2.9) | 1.0 (1.0–3.0)a | 2.0 (1.0–3.0)ab | 2.0 (1.0–4.0)ab | 2.0 (1.0–3.0) | 3 | 117.020 | 0.000 |
| Non HDL-C (mmol/L) | 3.1 (1.0–5.9) | 3.3 (1.5–5.7) | 3.3 (1.5–5.7) | 3.6 (1.1–8.1)ab | 3.3 (1.1–6.5)a | 3 | 17.988 | 0.000 |
| T-C/HDL-C | 3.5 (1.3–8.4) | 3.0 (1.6–6.2)a | 3.0 (1.6–6.2)a | 3.4 (1.5–7.2)bc | 3 (1.5–6.1)a | 3 | 29.420 | 0.000 |
| LDL-C/HDL-C | 1.4 (0.4–4.8) | 1.5 (0.9–3.3) | 1.5 (0.9–3.3)b | 1.5 (0.9–2.7) | 1.4 (0.8–3.3) | 3 | 8.189 | 0.042 |
| TG/HDL-C | 0.7 (0–2.7) | 0.9 (0.4–2.3)a | 0.9 (0.4–2.3)ab | 1.0 (0.5–3.4)ab | 0.9 (0.4–2.4)a | 3 | 68.750 | 0.000 |
| Non-HDL-C/HDL-C | 2.5 (0.3–7.4) | 2.0 (0.7–5.2)a | 2.0 (0.7–5.2)a | 2.4 (0.5–6.2)bc | 2.0 (0.5–5.1)a | 3 | 29.420 | 0.000 |
| 30-40-years |
Non-pregnant women |
Trimester 1 |
Trimester 2 |
Trimester 3 |
Combined trimesters |
Kruskal Wallis test |
||
|---|---|---|---|---|---|---|---|---|
| N | 181 | 137 | 222 | 197 | 556 | df | χ2 | Sig |
| T-C (mmol/L) | 4.0∗ (3.0–8.0) | 5.0 (3.0–8.0)a | 5.0 (3.0–7.0)a | 5.0 (3.0–9.0)a | 5.0 (3.0–8.0)a | 3 | 36.885 | 0.000 |
| LDL-C (mmol/L) | 2.0∗ (1.0–5.0) | 2.0∗ (1.0–6.0)a | 3.0 (1.0–5.0)a | 3.0∗ (2.0–6.0)ab | 3.0∗ (1.0–6.0)a | 3 | 54.882 | 0.000 |
| HDL-C (mmol/L) | 1.0∗ (0.6–2.0) | 2.0 (0.5–3.0)a | 2.0 (1.0–3.0)a | 2.0 (1.0–3.0)b | 2.0 (1.0–3.0)a | 3 | 23.073 | 0.000 |
| TG (mmol/L) | 1.0 (0.0–2.0) | 2.0∗ (1.0–3.0)a | 2.0 (1.0–3.0)a | 2.0 (1.0–4.0)ab | 2.0∗ (1.0–4.0)a | 3 | 152.540 | 0.000 |
| Non HDL-C | 3.2 (1.3–6.4) | 3.2 (1.3–6.4) | 3.40 (1.5–5.9) | 3.7 (1.5–6.7)ab | 3.4∗ (1.5–6.1)a | 3 | 21.728 | 0.000 |
| T-C/HDL-C | 3.4 (0.6–6.4) | 2.8 (1.1–4.9)a | 3.3∗ (1.6–5.6)b | 3.4 (1.9–6.3)b | ∗3.2 (1.5–5.8) | 3 | 23.550 | 0.000 |
| LDL/HDL-C | 1.3 (0.2–4.5) | 1.3 (0.2–3.5)a | 1.6∗ (0.7–3.8)ab | 1.8∗ (0.8–4.4)ab | 1.6∗ (0.7–3.9)a | 3 | 34.745 | 0.000 |
| TG/HDL-C | 0.7 (0–2.2) | 0.9 (0.0–2.0)a | 1.0∗ (0.7–2.6)ab | 1.1 (0.5–2.7)ab | 1.0∗ (0.4–2.5)a | 3 | 108.142 | 0.000 |
| Non HDL-C/HDL-C | 2.4 (0.1–5.4) | 1.8 (0.0–3.9)a | 2.3∗ (0.6–4.6)b | 2.4 (0.9–5.3)b | 2.2∗ (0.5–4.8) | 3 | 23.550 | 0.000 |
Results are expressed as median and 95 % range for the number of referent participants in the column labeled N. Significant differences in medians of each of the measured parameters within and between non-pregnant and pregnant women in the three trimester were carried out using Kruskal-Wallis H test followed by Mann-Whitney U test with adjusted significant ρ-value of less than 0.0083. Significant differences between the medians of the non-pregnant and combined pregnant data were assessed using Mann-Whitney U test at a ρ-value <0.05 and marked with a letter (a). Significant differences between medians of the two age categories (19-29-years versus 30-40-years) for each of the measured parameters were by Mann-Whitney U test with significant ρ-value of less than 0.05 marked with an asterisk (∗). Note: (a) represent significant difference to non-pregnant; (b) represent significant difference to Trimester 1; (c) represent significant difference to Trimester 2.
In pregnant women aged 19–29 years, significant trimester-specific changes in lipid values were noted. T-C increased from 5.0 (2.6–7.0) mmol/L in trimester 1 to 5.0 (3.0–10.0) mmol/L in trimester 3 (p < 0.001). LDL-C increased from 2.0 (1.0–5.0) mmol/L in trimester 1 to 3.0 (1.9–6.0) mmol/L in trimester 3 (p < 0.001). HDL-C had higher values in trimester 1 and 2 [2.0 (1.0–3.0) mmol/L] compared to non-pregnant women (p < 0.001). TG values almost doubled from 1.0 (0–2.0) mmol/L in non-pregnant women to 2.0 (1.0–4.0) mmol/L in the third trimester (p < 0.001).
There was no significant difference in non-HDL-C values between non-pregnant and pregnant women, and across the trimesters. T-C/HDL-C decreased in trimester 1 [3.0 (1.6–6.2)] compared to non-pregnant women [3.5 (1.3–8.4)] but increased in trimester 3 [3.4 (1.5–7.2)]. There was no significant difference in LDL-C/HDL-C values between non-pregnant and pregnant women, and across the trimesters. The TG/HDL-C increased significantly from 0.9 (0.4–2.3) in trimester 1 to 1.0 (0.5–3.4) in trimester 3.
In the 30–40 years group, most of the RIs were comparable except for T-C (non-pregnant women), LDL-C (non-pregnant women and trimester 1), TG (trimester 1), and LDL/HDL-C (trimester 2 and 3) which were significantly higher, and HDL-C (non-pregnant women), TC/HDL-C (trimester 2), TG/HDL-C (trimester 2), and non-HDL-C/HDL-C (trimester 2) which were significantly lower than 19–29 years.
The Kruskal-Wallis test revealed significant trimester-related variations in all lipid parameters (p = 0.042). For most parameters, post-hoc Mann-Whitney U tests indicated that pregnant women had significantly higher RI values than non-pregnant women (p < 0.05). Age-partitioned comparison showed that women aged 30–40 years had markedly higher LDL-C and TG compared to younger women (p < 0.05).
3.4. Out of range comparison of this study RIs and the current practice RIs
Table 3 present combined 19–40 age group OOR values determined by comparing this study RI with the current practice RIs, showing substantial differences across all lipid analytes and partitions. Among the non-pregnant women, 24.8 %, 27.7 %, 100.0 %, and 43.4 % of T-C, LDL-C, HDL-C, and TG, respectively, were out of range (OOR). For the pregnant participants, the OOR percentage increased with pregnancy, peaking at different trimesters. T-C (22.3 %) and TG (66.1 %) peaked in trimester 3, LDL-C (50.7 %) in trimester 2, while HDL-C (69.2 %) peaked in trimester 1.
Table 3.
Out of range comparison of this study RIs and current practice RIs for the combined 19–40 age group.
| This study 95 % RI |
N | Current practice 95 % RI |
Out of Range | % Out of Range | ||
|---|---|---|---|---|---|---|
| T-C (mmol/L) | Non-pregnant | 2.6–7.6 | 343 | 3.5–6.7 | 85 | 24.8 |
| Trimester 1 | 2.9-7.6 | 321 | 3.5–6.7 | 58 | 18.0 | |
| Trimester 2 | 3.1–7.4 | 499 | 3.5–6.7 | 91 | 18.2 | |
| Trimester 3 | 3.0–8.7 | 322 | 3.5–6.7 | 72 | 22.3 | |
| Combined | 3.0–8.0 | 1142 | 3.5–6.7 | 221 | 19.4 | |
| LDL-C (mmol/L) | Non-pregnant | 0.7-4.8 | 343 | 0.0–2.6 | 95 | 27.7 |
| Trimester 1 | 1.2–5.2 | 321 | 0.0–2.6 | 132 | 41.1 | |
| Trimester 2 | 1.4–5.1 | 499 | 0.0–2.6 | 253 | 50.7 | |
| Trimester 3 | 1.4–5.7 | 322 | 0.0–2.6 | 162 | 50.3 | |
| Combined | 1.4–5.4 | 1142 | 0.0–2.6 | 547 | 47.9 | |
| HDL-C (mmol/L) | Non-pregnant | 0.6-2.5 | 343 | 1.1–1.7 | 343 | 100.0 |
| Trimester 1 | 1.0–3.0 | 321 | 1.1–1.7 | 222 | 69.2 | |
| Trimester 2 | 0.9-2.9 | 499 | 1.1–1.7 | 325 | 65.1 | |
| Trimester 3 | 1.0–2.7 | 322 | 1.1–1.7 | 198 | 61.4 | |
| Combined | 0.9-2.9 | 1142 | 1.1–1.7 | 745 | 65.2 | |
| TG (mmol/L) | Non-pregnant | 0.0–2.4 | 343 | 0.5-1.8 | 149 | 43.4 |
| Trimester 1 | 0.6-3.1 | 321 | 0.5-1.8 | 162 | 50.5 | |
| Trimester 2 | 0.8-3.3 | 499 | 0.5-1.8 | 290 | 58.1 | |
| Trimester 3 | 0.9-3.6 | 322 | 0.5-1.8 | 213 | 66.1 | |
| Combined | 0.7-3.4 | 1142 | 0.5-1.8 | 665 | 58.2 |
Table 4 presents out of range comparison of this study RIs and the current practice RIs showing substantial variations across all lipid parameters. T-C values were higher during gestation, with 12–23 % of cohorts being OOR, peaking in trimester 3. LDL-C showed great variation, with 38–60 % of pregnant participants being OOR, particularly in late pregnancy. HDL-C exhibited 100 % OOR across all partitions. TG increased with gestational age, with 45–67 % being OOR, specifically in trimester 3.
Table 4.
Out of range comparison of this study RIs and the current practice RIs for ages 19-29- and 30-40-years.
| Parameter | Women | Age | This study 95 % RI |
N | Current practice 95 % RI |
Out of Range | % Out of Range | |
|---|---|---|---|---|---|---|---|---|
| T-C (mmol/L) | Non-pregnant women | 19–29 | 2.0–7.0 | 162 | 3.5–6.7 | 55 | 34.0 | |
| 30–40 | 3.0–8.0 | 181 | 3.5–6.7 | 30 | 16.6 | |||
| Pregnant women | Trimester 1 | 19–29 | 2.6–7.0 | 184 | 3.5–6.7 | 41 | 22.3 | |
| 30–40 | 3.0–8.0 | 137 | 3.5–6.7 | 17 | 12.4 | |||
| Trimester 2 | 19–29 | 3.0–8.0 | 277 | 3.5–6.7 | 49 | 17.7 | ||
| 30–40 | 3.0–7.0 | 222 | 3.5–6.7 | 42 | 18.9 | |||
| Trimester 3 | 19–29 | 3.0–10.0 | 125 | 3.5–6.7 | 27 | 21.6 | ||
| 30–40 | 3.0–9.0 | 197 | 3.5–6.7 | 45 | 22.8 | |||
| Combined trimesters | 19–29 | 3.0–8.0 | 586 | 3.5–6.7 | 117 | 19.9 | ||
| 30–40 | 3.0–8.0 | 556 | 3.5–6.7 | 104 | 18.7 | |||
| LDL-C (mmol/L) | Non-pregnant women | 19–29 | 1.0–4.9 | 162 | 0.0–2.6 | 37 | 22.8 | |
| 30–40 | 1.0–5.0 | 181 | 0.0–2.6 | 58 | 32.0 | |||
| Pregnant women | Trimester 1 | 19–29 | 1.0–5.0 | 184 | 0.0–2.6 | 71 | 38.6 | |
| 30–40 | 1.0–6.0 | 137 | 0.0–2.6 | 61 | 44.5 | |||
| Trimester 2 | 19–29 | 2.0–5.0 | 277 | 0.0–2.6 | 133 | 48.0 | ||
| 30–40 | 1.0–5.0 | 222 | 0.0–2.6 | 120 | 54.1 | |||
| Trimester 3 | 19–29 | 1.0–5.0 | 125 | 0.0–2.6 | 44 | 35.2 | ||
| 30–40 | 2.0–6.0 | 197 | 0.0–2.6 | 118 | 59.9 | |||
| Combined trimesters | 19–29 | 1.0–5.0 | 586 | 0.0–2.6 | 248 | 42.3 | ||
| 30–40 | 1.0–6.0 | 556 | 0.0–2.6 | 299 | 53.8 | |||
| HDL-C (mmol/L) | Non-pregnant women | 19–29 | 1.0–3.0 | 162 | 1.1–1.7 | 162 | 100.0 | |
| 30–40 | 0.6-2.0 | 181 | 1.1–1.7 | 181 | 100.0 | |||
| Pregnant women | Trimester 1 | 19–29 | 1.0–3.0 | 184 | 1.1–1.7 | 184 | 100.0 | |
| 30–40 | 0.5-3.0 | 137 | 1.1–1.7 | 137 | 100.0 | |||
| Trimester 2 | 19–29 | 1.0–3.0 | 277 | 1.1–1.7 | 277 | 100.0 | ||
| 30–40 | 1.0–3.0 | 222 | 1.1–1.7 | 222 | 100.0 | |||
| Trimester 3 | 19–29 | 1.0–3.0 | 125 | 1.1–1.7 | 125 | 100.0 | ||
| 30–40 | 1.0–3.0 | 197 | 1.1–1.7 | 197 | 100.0 | |||
| Combined trimesters | 19–29 | 1.0–3.0 | 585 | 1.1–1.7 | 586 | 100.0 | ||
| 30–40 | 1.0–3.0 | 556 | 1.1–1.7 | 556 | 100.0 | |||
| TG (mmol/L) | Non-pregnant women | 19–29 | 0.0–2.9 | 162 | 0.5-1.8 | 75 | 46.3 | |
| 30–40 | 1.0–2.0 | 181 | 0.5-1.8 | 74 | 40.9 | |||
| Pregnant women | Trimester 1 | 19–29 | 1.0–3.0 | 184 | 0.5-1.8 | 82 | 44.6 | |
| 30–40 | 1.0–3.0 | 137 | 0.5-1.8 | 80 | 58.4 | |||
| Trimester 2 | 19–29 | 1.0–3.0 | 277 | 0.5-1.8 | 157 | 56.7 | ||
| 30–40 | 1.0–3.0 | 222 | 0.5-1.8 | 133 | 60.0 | |||
| Trimester 3 | 19–29 | 1.0–4.0 | 125 | 0.5-1.8 | 81 | 64.8 | ||
| 30–40 | 1.0–4.0 | 197 | 0.5-1.8 | 132 | 67.0 | |||
| Combined Trimesters | 19–29 | 1.0–3.0 | 585 | 0.5-1.8 | 320 | 54.6 | ||
| 30–40 | 1.0–4.0 | 556 | 0.5-1.8 | 345 | 62.1 | |||
3.5. Comparison of this study reference intervals with those found in literature
Table 5 present a comparison of developed lipid panel test RIs for pregnant and non-pregnant women of Nairobi County, Kenya with those reported in medical literature. This study's trimester dependent lower RI limit for T-C was lower than the trimester independent RI limit reported in Denmark [30], U.S [31], Beijing-China [32], Hangzhou-China [33], Beijing-China [34] and Nigeria [35]. The upper limit RI was higher than those of Denmark [30], Beijing-China [32], Changzhou-China [36] and Nigeria [35]. In non-pregnant women, the lower and the upper RI limit for T-C were lower and higher, respectively than those from Denmark [30] and Nigeria [35].
Table 5.
Comparison of this study RIs for pregnant and non-pregnant women with those found in literature.
| Parameter | Women | Age | This study | Denmark [30] | US [31] | Germany [37] | Beijing, China [32] |
Changzhou, China [36] |
Hangzhou, China [33] | Beijing, China [34] |
Nigeria [35] | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T-C (mmol/L) | Non-pregnant women | 19–29 | 2.0–7.0 | 2.9-6.1 | <11.1 | 3.1–5.6 | ||||||
| 30–40 | 3.0–8.0 | |||||||||||
| Pregnant women | Trimester 1 | 19–29 | 2.6–7.0 | 3.5–7.1 | 7.8–11.7 | 3.2–5.4 | 3.7-6.9 | 3.1–6.1 | 4.0–5.5 | |||
| 30–40 | 3.0–8.0 | |||||||||||
| Trimester 2 | 19–29 | 3.0–8.0 | 3.9-8.2 | 9.7–16.6 | 4.5–9.0 | 4.64-7.56 | 5.1–6.4 | 5.3–7.1 | ||||
| 30–40 | 3.0–7.0 | |||||||||||
| Trimester 3 | 19–29 | 3.0–10.1 | 4.3–8.2 | 12.2–19.4 | 4.8–9.7 | 4.9-8.2 | 5.2–6.8 | 4.1–8.6 | 4.6–9.3 | 1.7-6.1 | ||
| 30–40 | 3.0–9.0 | |||||||||||
| LDL-C (mmol/L) | Non-pregnant women | 19–29 | 1.0–4.9 | 1.2–4.3 | <5.6 | |||||||
| 30–40 | 1.0–5.0 | |||||||||||
| Pregnant women | Trimester 1 | 19–29 | 1.0–5.0 | 1.1–4.2 | 3.3–8.5 | 1.33-2.98 | <2.27 | 1.3–3.8 | ||||
| 30–40 | 1.0–6.0 | |||||||||||
| Trimester 2 | 19–29 | 2.0–5.0 | 1.1–5.1 | 4.3–10.2 | 2.1–6.1 | 2.0–4.4 | 2.4–4.0 | |||||
| 30–40 | 1.0–5.0 | |||||||||||
| Trimester 3 | 19–29 | 1.0–5.0 | 1.4–5.1 | 5.6–12.4 | 2.4–7.0 | 2.0–4.9 | 2.7-4.6 | <3.95 | 1.9-5.9 | |||
| 30–40 | 2.0–6.0 | |||||||||||
| HDL-C (mmol/L) | Non-pregnant women | 19–29 | 1.0–3.0 | 1.0–2.7 | 2.2–3.3 | |||||||
| 30–40 | 0.6-2.0 | |||||||||||
| Pregnant women | Trimester 1 | 19–29 | 1.0–3.0 | 1.3–3.0 | 2.2–4.3 | 1.1–2.2 | 1.1–2.5 | 1.1–2.2 | ||||
| 30–40 | 0.5-3.0 | |||||||||||
| Trimester 2 | 19–29 | 1.0–3.0 | 1.2–3.3 | 2.9-4.8 | 1.3–3.1 | 1.3-2.5 | 1.8-2.4 | |||||
| 30–40 | 1.0–3.0 | |||||||||||
| Trimester 3 | 19–29 | 1.0–3.0 | 1.4-3.4 | 2.7-4.8 | 1.2–3.1 | 1.2–2.3 | 1.9-2.6 | 1.1–2.4 | 1.2–2.6 | |||
| 30–40 | 1.0–3.0 | |||||||||||
| TG (mmol/L) | Non-pregnant women | 19–29 | 0.0–2.9 | 0.5-2.6 | <8.3 | 0.6-2.1 | ||||||
| 30–40 | 1.0–2.0 | |||||||||||
| Pregnant women | Trimester 1 | 19–29 | 1.0–3.0 | 0.7-2.6 | 2.2–8.8 | 0.4-1.8 | 0.7-2.9 | 0.5-2.3 | 0.9-1.8 | |||
| 30–40 | 1.0–3.0 | |||||||||||
| Trimester 2 | 19–29 | 1.0–3.0 | 0.8-1.0 | 4.2–2 | 0.9-3.0 | 1.14-3.5 | 1.5-2.6 | 1.3–3.1 | ||||
| 30–40 | 1.0–3.0 | |||||||||||
| Trimester 3 | 19–29 | 1.0–4.0 | 0.8-4.3 | 7.3–3 | 1.4–4.8 | 1.6-4.6 | 2.42-4.2 | 1.3–4.0 | 1.7-5.7 | 0.9-2.3 | ||
| 30–40 | 1.0–4.0 | |||||||||||
The present study trimester dependent lower RI limit for LDL-C was comparable with that reported in Denmark [30], lower than those reported in U.S [31], Germany [37], Changzhou-China [36], and higher than that reported in Beijing-China [32]. Meanwhile, the upper limit was comparable with that from Denmark [30], lower than those from U.S [31] and Germany [37], and higher than those from Beijing-China [32] and Beijing-China [34]. In non-pregnant women, the lower and the upper RI limit for LDL-C were lower and higher, respectively than that from Denmark [30].
This study's trimester dependent lower RI limit for HDL-C was lower than the trimester independent RI limit reported in Denmark [30], U.S [31], Germany [37], Beijing-China [32], Changzhou-China [36] and Beijing-China [34]. The upper limit was lower than those reported in Denmark [30], U.S [31] and Germany [37], and higher that those from Beijing-China [32], Changzhou-China [36], Hangzhou-China [33] and Beijing-China [34]. In non-pregnant women, the lower RI limit for HDL-C was comparable with that from Denmark [30], and lower than that from U.S [31]. Meanwhile, the upper limit was comparable with that from Denmark [30], and lower than that from U.S [31].
The current study's trimester dependent lower RI limit for TG was higher than that from Denmark [30], and lower than the trimester independent RI limit reported in U.S [31], Germany [37], Beijing-China [32], Changzhou-China [36], Hangzhou-China [33] and Beijing-China [34]. Meanwhile, the upper limit was higher than that from Denmark [30], and lower than those reported in U.S [31], Germany [37], Beijing-China [32], Changzhou-China [36], Hangzhou-China [33] and Beijing-China [34]. In non-pregnant women, the lower and upper RI limits for TG were comparable with those from Denmark [30].
4. Discussion
This study provides a comprehensive account of alterations in lipid metabolism during pregnancy across two age groups (19–29 years and 30–40 years), demonstrating significant deviations from non-pregnant physiology and highlighting the clinical importance of establishing population-appropriate RIs. Across almost all lipid parameters, pregnant cohorts had significantly higher values than non-pregnant controls, with a progressive increase across the trimesters. These findings are consistent with physiological hyperlipidemia of pregnancy, where marked hypertriglyceridemia and enhanced cholesterol-rich lipoprotein synthesis support fetal energy demands and placental steroidogenesis [3,14]. This aligns with previous reports of increases in both atherogenic and anti-atherogenic lipoproteins during pregnancy [7,15].
Relative to non-pregnant cohorts, pregnant women in all trimesters presented higher TC, LDL-C, HDL-C, and TG, with significance differences across both age sets. These elevations reflect the combined influence of hepatic lipoprotein synthesis due to estrogen stimulation [1], modulation of lipid handling induced by insulin resistance [11], and metabolic shift towards prioritization of fetal nutrition [10]. The magnitude of increment was more pronounced for TG, with pregnant RIs exceeding non-pregnant values by 2-3-fold. This steep increase in TG mirrors global epidemiological data reporting the near-universality of gestational hyperlipidemia, especially in the second and third trimesters [[5], [6], [7], [8], [9]].
Significantly, the consistently raised HDL-C in pregnant compared with non-pregnant cohorts reflect a positive estrogenic effect during pregnancy [6]. However, the magnitude of the elevation in this study were most of women were out of range compared to the currently used RIs, indicates substantial deviation from conventional RIs derived from Western population. Similar observations in East African [9,25], European [37] and South Asian [2,7] cohorts suggest that environmental and ethno-genetic factors probably contribute to the variability of lipid physiology [1].
The comparison across trimesters revealed that TC and LDL-C rose progressively to peak in the third trimester, consistent with global studies indicating 30–50 increase during pregnancy [[20], [21], [22], [23], [24], [25],36]. The late pregnancy LDL-C elevations, especially in older women, are clinically relevant because of their association with adverse gestational outcomes, including preterm birth and hypertensive disorders [17,23].
TG exhibited the highest trimester-related elevation, with values almost doubling by trimester 3 across both age categories. This excessive increment reflect increased production of VLDL and developing insulin resistance [20,37], characteristic features of late pregnancy. Such elevations are associated with increased risks of preeclampsia [22], macrosomia [11], and GDM [13,18]. This metabolic risk pattern is further reinforced by the high TG/HDL-C ratios in second and third trimesters.
HDL-C demonstrated a biphasic pattern characterized by elevation from non-pregnancy to first trimester, stability in second trimester, and a marginal decline or plateau in third trimester. This distinct trajectory is documented globally [[1], [2], [3], [4], [5], [6]], and reflects antagonistic action of estrogen in first trimester and insulin resistance in second and third trimesters [10,12,16].
Younger women (19–29 years) presented lower LDL-C, TG, and lipid ratios than older women (30–40 years) across almost all trimesters. This is consistent with global studies documenting age-related decrease in lipid clearance [1], elevated central adiposity [10], and increased cardio-metabolic susceptibility in older women [13,17]. This finding aligns with age-dependent lipid patterns seen in Denmark [30], Germany [37], US [31] Nigerian [35], and China [34]. These findings are clinically relevant for maternal health risk stratification given the growing global trend of delayed childbearing.
The out-of-range (OOR) analysis revealed great divergence between this study RIs and the currently used RIs. For LDL-C, >40 % of pregnant participant, and 60 % of older women in the third trimester fell outside the standard practice limits. TG exceeded conventional RIs in >50 % of pregnant cohorts, peaking above 60 % in third trimester. Even among non-pregnant participants, OOR values for TG and LDL-C were 40–60 %, and 20 % respectively, underscoring population-specific variations extending beyond gestation [1].
Remarkably, 100 % of the HDL-C values were OOR in all categories indicating that the current practice RIs are wholly inappropriate for this population. This is in agreement with reports from Asian [34] and African [24,28] cohorts where the conventional HDL cut-offs (1.1–1.7 mmol/L) fails to reflect true population values. The implications are clinically significant in that misclassification can lead to erroneous cardio-metabolic risk assessment, unnecessary or delayed clinical investigations and interventions, and thus negative clinical outcomes [11,29].
The significant physiological variations documented in this study mirror global findings [[8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]] and further highlight regional differences in baseline and pregnancy lipid values. Thus, WHO increasingly advocate for population-specific RIs in clinical assessment [38]. This study's findings support that call, especially in low-income settings of sub-Saharan Africa, where reference data is limited despite high morbidity and mortality rates [[24], [25], [26]].
Accordingly, these study findings contribute to the global precision-medicine imperative to adopt context-appropriate lipid reference values, to enhance clinical decision-making and maternal cardio-metabolic surveillance.
In summary, this study generated robust age- and trimester-specific lipid profile RIs for health pregnant and non-pregnant women in Nairobi City, Kenya. The high incidence of OOR values when applying the standard RIs underscore the need for population-specific RIs to ensure accurate clinical interpretation. These findings carry significant implications for maternal health strategies and clinical practice globally.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors acknowledge Pumwani Maternity Hospital Laboratory and Kenyatta National Hospital Clinical Chemistry Laboratory for their invaluable assistance in this study.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.athplu.2026.01.005.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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