Evaluation of Soluble fms-Like Tyrosine Kinase 1 and Placental Growth Factor Ratio for Prediction of Preeclampsia and Its Correlation with Adverse Fetal Outcomes

Abstract

Background

sFlt-1/PlGF is a relatively recent biomarker for preeclampsia and for predicting adverse fetal outcomes. However, the marker has still not found its way in clinical practice in Pakistan.

Objectives

We aimed to determine positive and negative predictive values of sFlt-1/PIGF ratio for preeclampsia and its correlation with adverse fetal outcomes.

Design

Prospective cohort.

Methods

The study was conducted between September 2022 and January 2023. Blood samples for sFlt-1/PIGF ratio were taken from women at 28-30 weeks gestation with two or more risk factors of preeclampsia, and without known history of diabetes mellitus, hypertension, renal disease or hypothyroidism. Subjects were followed till delivery. Main outcome measures were negative predictive value (NPV) and positive predictive value (PPV) for sFlt-1/PIGF ratio and correlation of sFlt-1/PIGF ratio with adverse fetal outcomes.

Results

Out of total 180 women enrolled, 133(73.9%) had gestational diabetes mellitus (GDM), while 48(26.7%) had raised diastolic blood pressure at booking. sFlt-1/PlGF-ratio and its statistics were performed on 160 subjects. The ratio was ≤38 in 155 (96.8%) women. Preeclampsia was diagnosed in 12 participants. NPV of sFlt-1/PlGF ratio ≤38 to rule out Preeclampsia (PE) within a period of one week was 95.32% (95% CI 90.14%-97.84%) with sensitivity of 33.0% (95% CI 0.84%-90.57%) and specificity of 97.45% (95% CI 93.61%-99.30%). The PPV to rule in preeclampsia at the ratio cutoff of −38 within a period of 4 weeks was 41.18% (95% CI 9.03%-83.16%) with sensitivity of 25 (95% CI 0.63%-80.59%) and specificity of 97.44% (95% CI 93.57%-99.30%). Adverse fetal outcomes were seen in 43 (23.9%) deliveries, of which 7(16.3%) women were diagnosed to have preeclampsia. Women with adverse fetal outcomes had higher median (IQR) sFlt-1/PlGF ratio of 5.3(2.4-10.5), P-value = .008. There was a negative correlation of sFlt-1/PlGF-ratio with birthweight (P value .000), gestational age at delivery, and Appearance, pulse, grimace, activity, respiration (APGAR) Scores.

Conclusion

sFlt-1/PlGF ratio can be used to rule out preeclampsia and predict adverse fetal outcomes. Wider scale studies are required to truly assess its sensitivity for preeclampsia.

Keywords

Preeclampsia angiogenesis sFlt-1 PlGF biomarker low birth weight adverse fetal outcomes

Introduction

Preeclampsia (PE) is a multi-system disorder of pregnancy and a leading cause of maternal and fetal morbidity and mortality. It is defined as development of new onset hypertension in addition to proteinuria with or without end-organ dysfunction. The criteria of blood pressure for diagnosis of PE is equal to or exceeding 140/90 mm Hg on two separate occasions after twenty weeks of pregnancy. Proteinuria in PE is defined as presence of urinary proteins greater than 0.3 grams/24 h or spot urinary protein creatinine ratio greater than 300 mg/g.¹

Preeclampsia can progress to eclampsia which is characterized by onset of seizures. Both PE and eclampsia can further progress to multi- organ dysfunction, maternal death and poor fetal outcome. It is estimated that PE affects between 3%-12% of the pregnancies globally with 3.4% in the United States to 12% in Bangladesh.² The prevalence of PE in Pakistan is 5.6%.³ Some of the maternal complications of PE are placental abruption, postpartum hemorrhage, eclampsia, acute kidney damage and stroke which may lead to maternal mortality. Fetal adverse effects include intrauterine growth restriction (IUGR), low birth weight and intra uterine death. Admission to neonatal intensive care units, seizures and neonatal death are some other fetal complications.⁴

The high prevalence of PE and its implications for maternal and fetal complications mandate early diagnosis and management of these patients.⁴ However, current diagnostic criteria are neither sufficiently specific nor sensitive for clinical needs,^1,5,6 therefore, patients need to be intensively monitored and even admitted until PE can be ruled out. This impasse underscores the requirement for a suitable diagnostic biomarker for PE.

The pathogenesis of PE includes a state of anti-angiogenesis and dysregulation of angiogenic factors. Uterine arteries responsible for placental growth do not undergo the normal physiological change and fail to supply adequate blood supply leading to placental ischemia. The ischemic dysfunctional placenta releases proteins with proinflammatory and antiangiogenic effects. Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are two of such proteins released by the ischemic placenta.⁷

sFlt-1 is an antiangiogenic protein of placental origin. Its levels remain stable during early and mid-gestation and then increase in last trimester. In PE, its levels are disproportionately high. PlGF, a placental pro-angiogenic factor, normally increases during the first two trimesters, before decreasing in the third trimester. sFlt-1 is a soluble form of Flt-1 receptor and acts by antagonizing vascular endothelial growth factor (VEGF) and PlGF. It has been demonstrated that high serum levels of sFlt-1 and low levels of PlGF can predict subsequent development of PE. The measurement of sFlt-1/PlGF ratio can predict the risk of developing PE.⁶ The PRediction of short-term Outcome in preGNant wOmen with Suspected preeclampsIa Study (PROGNOSIS) conducted on a total of 1050 patients showed that sFlt-1/PlGF ratio ≤38 can accurately rule out PE within 1 week with 99.3% negative predictive value (NPV) and a ratio >38 can rule in PE within 4 weeks with positive predictive value (PPV) of 36.7%.⁸

sFlt-1/PlGF ratio has also been claimed to predict adverse fetal outcomes, although there are relatively fewer studies in this regard. Placental dysfunction and ischemia lead to fetal growth abnormalities and small for gestational age infants, with increased perinatal morbidity and mortality.⁹

Identification of patients with high probability of developing PE and at risk of adverse fetal outcomes will allow clinicians to follow these patients more vigilantly. On the other hand, identifying patients with low probability of these features will help to demarcate patients who do not require frequent monitoring, thus helping in resource conservation. PE can be either early onset (20-33 weeks) or late onset (34 weeks to end of pregnancy). Adverse fetal outcomes are potentially more serious in early onset PE.^10,11 Although the usefulness of sFlt-1/PlGF ratio has been addressed widely internationally but as of now little work has been done in our region. We aimed to determine the positive and negative predictive values of sFlt-1/PlGF ratio for early onset PE and the correlation of sFlt-1/PlGF ratio with adverse fetal outcomes.

Material and Methods

This prospective cohort study was conducted jointly by Section of Chemical Pathology and Department of Obstetrics and Gynecology at Indus Hospital and Health Network, Karachi. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for this study¹²; completed checklist is given in Supplementary File 1. Patients were recruited between September 2022 and January 2023. The institute is a free of cost, tertiary care hospital providing quality care to the underprivileged section of the society. The clinical laboratory is accredited by College of American Pathologists (CAP). The sample size, as calculated by OpenEpi, Version 3 open-source calculator, was 131 patients according to the referenced study findings of 86% incidence in suspected patients, keeping margin of error 5% and confidence interval 90%.¹³

Inclusion and Exclusion Criteria

Females between 28 and 30 weeks of gestation with at least two of the following associated factors or high clinical suspicion of PE were recruited: first pregnancy, personal history of PE, gestational diabetes mellitus (GDM) or pregnancy induced hypertension (PIH), age ≤20 years or ≥35 years, Body Mass Index (BMI) ≥ 35 kg/m², diastolic blood pressure ≥80 mm Hg at booking and patients with essential hypertension or GDM. Women who were booked after 18 weeks pregnancy, had history of hypothyroidism or renal disease with or without proteinuria and those lost to follow-up were excluded from the study.

Data Collection Procedure

Patients were recruited based on the inclusion and exclusion criteria. Consenting patients’ data was filled on REDCap (a secure web-based application for online surveys) forms. Three milliliters (mL) venous blood was aseptically drawn from these subjects. Serum was separated and stored at −40 °C until analysis. The tests were performed on Elecsys e411 by Roche Diagnostics, which is a random-access immunoassay analyzer based on electrochemiluminescence. The patients were longitudinally followed until delivery for the clinical development of PE and for any adverse fetal outcomes which included: stillbirth, IUGR (expected weight below 10^th percentile at the gestational age), low birthweight (<2.5 kg), neonatal mortality, neonatal seizures, requirement for admission to neonatal intensive care unit (NICU) and newborns requiring respiratory support. Results of any relevant lab investigations performed as per clinical requirements were also entered into REDCap forms periodically by the obstetrician. All patient information was kept deidentified.

Statistical Analysis

Data was analyzed on SPSS 24. Descriptive statistics, ie, Mean (SD) / Median (IQR) were calculated on quantitative data and frequencies/percentages on qualitative data. Chi square was applied to see association between categorical variables. Correlation was determined for sFlt-1/PlGF ratio and adverse fetal outcomes. A P-value of less than .05 was taken as significant. Diagnostic sensitivity, specificity, PPV, NPV and diagnostic accuracy were calculated for sFlt-1/PlGF ratio by MedCalc Software (MedCalc Software Ltd, Belgium).

Results

A total of 180 subjects were included in the study. The age range of the participants varied from a minimum of 18 to a maximum of 45 years, with the median (IQR) age of 27 (23-30) years. The median (IQR) BMI of the subjects was 26.9 (23.8-31.2) kg/m². Protein Creatinine Ratio was performed on 27 women only, of which 17 (63%) had less than 300 mg/g excretion. Overall demographics and relevant investigations performed on the study participants as per clinical requirement along with their frequencies and clinical cutoffs are mentioned in Table 1. There were 133(73.9%) women with GDM, 48(26.7%) women with booking diastolic BP 80 mm Hg or higher and 19 (10.6%) women with BMI of 35 kg/m² or higher. PE risk factors frequencies are shown in Table 2.

Table 1.

Overall Characteristics of the Study Participants.

Variables N = 180	Min-Max	Median (IQR)
Age (in years)	18−45	27 (23−30)
BMI (kg/m²)	15.8−42.5	26.9 (23.8−31.2)
Systolic blood pressure (mm Hg) at booking visit	90−160	118 (110−125.8)
Diastolic blood pressure mm Hg) at booking visit	59−100	70 (68−80)
Systolic blood pressure (mm Hg) at 28-30-week visit	90−155	110 (102.3−120)
Diastolic blood pressure (mm Hg) at 28-30-week visit	50−90	70 (61.3−80)
Variables	Frequency (n)	Percentage (%)
Urine Protein creatinine ratio mg/g (N = 27)
<300	17	63%
Alanine Transaminase U/L (N = 19)
<34	18	95%
Platelets count × 10⁹/L (N = 180)
>100	179	99%
Gestational age in weeks at delivery (N = 175)^a
>37	139	79.4%
APGAR score of babies (N = 172)^b
>7	64	37.2%

N refers to the total number of participants on whom the variable was measured, while n is the frequency observed at the cutoff mentioned.

There were 5 participants who delivered outside, ^bThere were 3 still births.

BMI, Body Mass Index; APGAR, appearance, pulse, grimace, activity, respiration.

Table 2.

Risk Factors for Preeclampsia.

Risk Factors	N(%)
History of Hypertension	9(5.0)
History of GDM	3(1.7)
History of PIH	4(2.2)
Age ≤20 years	18(10)
Age ≥35 years	17(9.4)
Primigravida	14(7.8)
GDM in current pregnancy	133(73.9)
Diastolic blood pressure at booking ≥80 mm Hg	48(26.7)
BMI ≥35 kg/m²	19(10.6)

GDM, gestational diabetes mellitus; PIH, pregnancy induced hypertension; BMI, Body Mass Index.

We conducted sFlt-1, PlGF testing and sFlt-1/PlGF ratio calculation on 160 patients from a cohort of 180 according to the availability of reagents. The sFlt-1/PlGF ratio was ≤38 in 155 (96.8%) while it was ˃38 in 5(2.8%) cases. NPV of sFlt-1/PlGF ratio ≤38 to rule out PE within a period of one week was 95.32% (95% CI 90.14%-97.84%) with sensitivity of 33.0% (95% CI 0.84%-90.57%) and specificity of 97.45% (95% CI 93.61%-99.30%). The PPV to rule in PE at the ratio cutoff of ˃38 within a period of 4 weeks was 41.18% (95% CI 9.03%-83.16%) with sensitivity of 25 (95% CI 0.63%-80.59%) and specificity of 97.44% (95% CI 93.57%-99.30%). Table 3 gives summary of the NPV and PPV statistics. Although a high proportion of our study population (73.9%) had GDM, yet no statistical difference was seen in sFlt-1, PlGF or sFlt-1/PlGF ratio in women with and without GDM.

Table 3.

Sensitivity and Specificity of sFlt/PIGF Ratio Cutoff 38 to Rule In and Rule Out Preeclampsia.

	Rule in Preeclampsia within 4 weeks		Rule out Preeclampsia within 1 week
Statistics	Value	95% CI	Value	95% CI
Sensitivity	25%	0.63%−80.59%	33.3%	0.84%−90.57%
Specificity	97.44%	93.57%−99.30%	97.45%	93.61%−99.30%
PPV	41.18	9.03%−83.16%	48.44.%	12.65%−85.91%
NPV	94.76%	91.13%−96.96%	95.32%	90.14%−97.84%
Accuracy	92.58%	87.37%−96.13%	93.16%	88.07%−96.54%

NPV, negative predictive value; PPV, positive predictive value.

Out of 180 enrolled patients, PE was clinically diagnosed in 12(6.7%) and 8(4.4%) patients developed pregnancy-induced hypertension. Among the study participants, 80(44.4%) women had spontaneous vaginal delivery (SVD), 95(52.8%) underwent a lower segment cesarean section while 5 (2.8%) women did not deliver at our institute. No specific adverse maternal outcomes were observed.

Adverse fetal outcomes were seen in 43 (24.6%) of the 175 study participants who delivered at our institute. Out of these, 7(16.3%) had PE during their pregnancy. It was noted that mothers who experienced adverse fetal outcomes had a higher statistically significant median (IQR) sFlt-1/PIGF ratio of 5.3 (2.4-10.5) compared to those who did not, 3.2 (2-5.5). Furthermore, Protein Creatinine Ratio was also high in the patients with adverse fetal outcomes (Table 4). The frequencies of observed adverse fetal outcomes are shown in Figure 1.

Figure 1.

Distribution of adverse fetal outcomes (N = 43). NICU, neonatal intensive care unit.

Table 4.

Characteristics of the Cohort with and Without Adverse Fetal Outcomes.

Variables	Descriptive	No Adverse outcome	Adverse outcome	P-value
Variables	Descriptive	132 (75.4%)	43 (24.6%)	P-value
Age (in years)	Median (IQR)	27 (23−30)	27 (24−32)	.245^a
Age (in years)	Min-Max	18−45	19−39	.245^a
Parity	Median (IQR)	1 (1−3)	1 (1−2)	.778^a
Parity	Min-Max	0−7	0−6	.778^a
BMI	Median (IQR)	27.1 (23.9−31.2)	26.2 (23.5−31.3)	.586^a
BMI	Min-Max	16−42.5	15.8−40.4	.586^a
Systolic blood pressure (mm Hg) at 28-30 week visit	Median (IQR)	110 (103.5−120)	110 (100−120)	.860^a
Systolic blood pressure (mm Hg) at 28-30 week visit	Min-Max	90−150	90−155	.860^a
Diastolic blood pressure (mm Hg) at 28-30 week visit	Median (IQR)	70 (60.5−80)	70 (62−75)	.418^a
Diastolic blood pressure (mm Hg) at 28-30 week visit	Min-Max	50−90	60−90	.418^a
Urine Protein Creatinine Ratio	Median (IQR)	192 (152−379)	1102 (256.5−1896)	.008^*a
Urine Protein Creatinine Ratio	Min-Max	84−6260	196−3776	.008^*a
Alanine Transaminase IU/L	Median (IQR)	17 (12.5−24)	16 (6.5−30)	.895^a
Alanine Transaminase IU/L	Min-Max	5−65	5−33	.895^a
Gamma Glutamyl Transferase IU/L	Median (IQR)	15 (10.3−25.5)	13 (10−0)	1.000^a
Gamma Glutamyl Transferase IU/L	Min-Max	8−36	10−26	1.000^a
Preeclampsia	N(%)	5 (4)	7 (16)	.009*^b
sFlt PIGF Ratio	Median (IQR)	3.2 (2−5.5)	5.3 (2.4−10.5)	.008*^a
sFlt PIGF Ratio	Min-Max	0.1−63.4	1.1−497.4	.008*^a

*P < .05, ^aMann Whitney U test, ^bFisher’s Exact test. Five patients did not deliver at the institute.

BMI, Body Mass Index.

There was a negative correlation of sFlt-1/PlGF-ratio with gestational age at delivery, weight of baby at birth (P value .000) and APGAR Scores (Table 5).

Table 5.

Correlation of sFlt/PIGF Ratio with Diastolic Blood Pressure, Gestational Age at Delivery, Birth Weight and APGAR Score of Babies.

Parameter	Correlation coefficient	P value
Diastolic blood pressure at booking visit	0.075	.347^a
Gestational age at delivery (in weeks)	−0.108	.181^a
Weight of baby at birth(kg)	−0.304	.000^**a
APGAR score	−0.135	.097^a

**P value < .0001, ^aSpearman correlation.

APGAR, appearance, pulse, grimace, activity, respiration.

Discussion

We found a high negative predictive value of sFlt-1/PlGF ratio for ruling out PE. In addition, we also observed a negative correlation of this marker with adverse fetal effects. Hence, our study reaffirms the findings of previous researchers.

The prediction of short-term outcome in pregnant women with suspected preeclampsia study Asia, PROGNOSIS Asia, was a hall mark, multicenter, prospective study to determine predictive value of sFlt-1 /PIGF ratio for PE and adverse outcomes in pregnancy.¹⁴ The authors used the ratio cutoff of 38 which had been previously validated by the original PROGNOSIS study.⁸ The frequency of PE in 764 pregnant females recruited in this study with high suspicion of PE was 14.4%. However, frequency of PE in our cohort of 180 patients with existent risk factors was 6.7%. The researchers of PROGNOSIS Asia demonstrated that sFlt-1/PlGF ratio of 38 or lower had a NPV of 98.6% for ruling out PE within 1 week, with 76.5% sensitivity and 82.1% specificity, while our NPV at the same ratio was 95.32% with sensitivity of 33.3 and specificity of 97.45%. Moreover, their PPV to rule in PE within 4 weeks was 30.3%, with 62.0% sensitivity and 83.9% specificity, in contrast to our PPV of 41.18% with sensitivity and specificity of 25 and 97.44% respectively. The low sensitivity of NPV in our study is due to the lower frequency of preeclamptic women in our cohort.

A recent study in North America to determine clinical utility of sFlt-1/PlGF ratio demonstrated that a cutoff of 38 had a diagnostic accuracy of 90.8% (95% CI, 85.8%-95.7%) for PE, which was better than that of new/worsening proteinuria or hypertension (71.9% and 68.6%, respectively). They also showed a NPV of 96.4% and a PPV of 84.8% for PE.¹⁵ This study included only women who were referred to or were admitted for evaluation of PE. Another study concluded that a ratio of 38 or lower can be used to rule out clinically suspected PE for at least a week with a NPV of 99.3%.¹⁶ The lower sensitivity of ruling out PE within one week in our study compared with other studies might be due to difference in study design; in our study the selected patients were potentially at higher risk of developing PE whereas in other studies the patients included were either those with high suspicion of having PE,¹⁵ with overt signs and symptoms of PE,¹⁷ or diagnosed cases of PE.^18,19

Increasing the cutoff sFlt-1/PlGF ratio improves the specificity while compromising the sensitivity of diagnosis as shown by Miller et al in their study on pregnant women with suspicion of PE.²⁰ They compared the sensitivity and specificity at various cutoffs and demonstrated that highest sensitivity of 93.5% was seen at the cutoff of ≥33, while a cutoff of ≥110 had the highest specificity of 100%.

GDM was present in 73.9% of our recruited population. No statistical difference was noted in the levels of sFlt-1, PlGF or sFlt-1/PlGF ratio in women with and without GDM. Our findings are supported by Walentowicz who also observed that GDM does not have a significant effect on sFlt-1 values.²¹ It is seen that sFlt-1/PIGF ratio remains a valid tool for prediction of PE in the presence of GDM.^22,23

sFlt-1/PIGF ratio has also been used to predict adverse fetal outcome.²⁴ We observed significantly higher sFlt-1/PlGF ratio in the pregnancies with adverse fetal outcome, and a negative correlation of sFlt-1/PIGF ratio with birth weight. Bian et al in the PROGNOSIS ASIA cohort demonstrated that at a ratio of 38, NPV for ruling out adverse fetal outcomes is 98.9% (95% CI, 97.6%-99.6%) while PPV is 53.5% (95% CI, 45.0%-61.8%) for ruling in fetal adverse outcomes within 1 and 4 weeks respectively.¹⁴ In another study on 616 suspected PE patients, the median sFlt/PlGF ratio was found to be 10.8 in patients who did not develop adverse effects compared to 47.0 in those who developed adverse maternal or perinatal outcomes¹³ A Polish study referred to earlier demonstrates that females with higher sFlt-1/PIGF ratios had more adverse fetal outcomes including IUGR, birth at lower gestational age, respiratory disorders and NICU admissions.⁹ Multivariate logistic regression analysis in this study revealed only two independent risk factors of combined adverse neonatal outcome which were neonatal birthweight, adjusted Odd's ratio (aOR) 0.98 and sFlt-1/PlGF ratio aOR 1.4. A retrospective analysis on 142 women with chronic hypertension and suspicion of superimposed PE revealed that 50% of women with angiogenic disbalance causing sFlt-1/PlGF ratio ≥85 or PlGF levels <100 pg/mL delivered within 1.6 weeks because of maternal or fetal indications.²⁵

As PE is a leading cause of preterm deliveries, high maternal and neonatal mortality and morbidity, using sFlt-1/PlGF ratio for high risk and suspected patients may be a feasible financial option. A study for investigating the impact of sFlt-1/PIGF ratio for short term risk of PE showed shorter hospitalization with potential economic benefits if used in routine clinical setting.²⁶ Cost effectiveness has been shown in multiple studies,^27,28 reducing unnecessary hospital admissions and antenatal surveillance in those with normal results. Pakistan is a resource limited country with a high frequency of adverse maternal²⁹ and perinatal outcomes³⁰ for which PE is a major factor. Implementation of sFlt-1/PlGF ratio in high-risk patients during antenatal checkups can possibly save undue hospitalizations and help target medical attention where required.

A major limitation of the study was the small sample size, which limits its current generalizability. We did not compare the diagnostic accuracy of sFlt-1 with other conventional markers of PE such as proteinuria or hypertension. A larger study is required to study the diagnostic accuracy and feasibility of sFlt-1/PIGF ratio for screening of high-risk patients.

Conclusion

sFlt-1/PIGF ratio has a strong negative predictive value for early onset PE. A higher ratio was also associated with adverse fetal outcomes. The sFlt-1/PlGF ratio might prove to be a clinically useful and financially viable parameter for prediction of adverse fetal outcomes and preterm deliveries if used consistently in high-risk antenatal workup.

Supplemental Material

sj-docx-1-bdx-10.1177_26348535261415802 - Supplemental material for Evaluation of Soluble fms-Like Tyrosine Kinase 1 and Placental Growth Factor Ratio for Prediction of Preeclampsia and Its Correlation with Adverse Fetal Outcomes – A Pilot Study

Supplemental material, sj-docx-1-bdx-10.1177_26348535261415802 for Evaluation of Soluble fms-Like Tyrosine Kinase 1 and Placental Growth Factor Ratio for Prediction of Preeclampsia and Its Correlation with Adverse Fetal Outcomes – A Pilot Study by Fatima Kanani, Nadia Asher, Moattar Majeed, Nida Ghouri, Adnan Mustafa Zubairi and Samia Shuja in Blood & Plasma

Footnotes

Abbreviations

Acknowledgements

We would like to acknowledge Roche Diagnostics for providing the reagent kits for the study. However, they had no input in any aspect of the study design or preparation of the manuscript.

ORCID iDs

Fatima Kanani

Nida Ghouri

Ethical Considerations

The study took place at Indus Hospital & Health Network, Karachi, Pakistan. The study was conducted after Indus Hospital & Health Network Institutional Review Board's approval (IHHN_IRB_2022_07_022), dated 12^th August 2022, which is in accordance with the ethical standards described in the 1975 Declaration of Helsinki, and revised in 2024.

Consent to Participate

Informed verbal consent from all participants was taken and signed by the attending obstetrician on IRB approved form.

Consent to Publish

Not required as anonymized data.

Author Contribution(s)

Fatima Kanani: Conceptualization; Formal analysis; Investigation; Methodology; Project administration; Supervision; Writing – original draft; Writing – review & editing.

Nadia Asher: Data curation; Investigation; Validation; Writing – review & editing.

Moattar Majeed: Data curation; Investigation; Methodology; Writing – review & editing.

Nida Ghouri: Data curation; Formal analysis; Software; Writing – review & editing.

Adnan Mustafa Zubairi: Conceptualization; Resources; Supervision; Writing – review & editing.

Samia Shuja: Methodology; Project administration; Supervision; Writing – review & editing.

Funding

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

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability

Data analyzed in the study is available from the corresponding author on reasonable request in line with the institutional policy.

Supplemental Material

Supplemental material for this article is available online.

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