Perinatal outcome of growth restricted fetuses with abnormal umbilical artery Doppler waveforms compared to growth restricted fetuses with normal umbilical artery Doppler waveforms at a tertiary referral hospital in urban Ethiopia.

BACKGROUND: Intrauterine growth restriction is defined as a fetal weight below the 10th percentile for a given gestational age and can be identified using umbilical artery Doppler velocimetry which is a non-invasive technique. The objective of this study was to determine the perinatal outcome of growth-restricted fetuses with abnormal umbilical artery Doppler study compared to those with normal umbilical artery Doppler waveforms at a tertiary referral hospital in Ethiopia.
METHODS: A prospective cohort study was conducted among pregnant mothers with fetal growth restriction admitted for labour and delivery from September 2018-February 2019. The data were entered and analyzed using SPSS version 23. After conducting descriptive analysis, exploring the entire data, and checking for, statistical associations between abnormal umbilical artery Doppler and outcome variables, multiple logistic regression was conducted to control for confounders.
RESULTS: A total of 170 pregnant mothers complicated with growth-restricted fetuses were included in the study, among which 133 were with normal umbilical artery Doppler studies and 37 were with abnormal umbilical artery Doppler studies. Four (3%) of normal and 9(24.3%) of abnormal umbilical artery Doppler studies ended in perinatal death-value = 0.001. Twenty (15%) of normal and 24(64.9%) of abnormal umbilical artery Doppler study neonates required neonatal intensive care admission-value = 0.002. Growth restricted fetuses complicated with abnormal Doppler were two times more likely to require neonatal intensive care unit admissions compared to growth-restricted fetuses with normal umbilical artery Doppler flow, P-value 0.002, (OR = 2.059,95%CI 1.449-2.926). Growth restricted fetuses complicated with abnormal Doppler were four times more likely to end in early neonatal death compared to growth-restricted fetuses with normal umbilical artery Doppler flow, P-value 0.001, (OR = 4.136, 95%CI 3.423-4.998). However, the study is unmatched and there is a possibility of gestational age confounding the result and should be seen with the context of preterm morbidity and mortality.
CONCLUSION: The abnormal umbilical artery Doppler waveform is associated with cesarean section delivery, neonatal intensive care unit admission, respiratory distress syndrome, neonatal sepsis, neonatal hyperbilirubinemia, and early neonatal death compared to normal umbilical artery Doppler flow.

Background

Intrauterine growth restriction (IUGR) is defined as a fetal weight below the 10th percentile for a given gestational age [1, 2]. Some fetuses are constitutionally small, and they don't have an increased risk of perinatal morbidity and mortality. [1, 2]. Growth restricted fetuses who may or may not be small for the date are at increased risk of morbidity and mortality [2-4]. Identification of growth-restricted fetuses at high risk of complications is very important for management purposes. Doppler ultrasound in IUGR fetuses is used for diagnosis(differentiation of health small for date and growth-restricted fetuses) and in-utero monitoring of the progression of the disease [5]. The commonly studied and used vessels are umbilical artery(UA) and vein(UV) followed by the middle cerebral artery(MCA) [6]. The systolic/diastolic (S/D) ratio, the resistance index (RI), and the pulsatility index (PI) are the three Doppler indices most widely used to analyze arterial blood flow resistance and diagnose IUGR [2, 5, 7, 8].

Perinatal mortality rates in growth-restricted neonates are 6 to 10 times that of those with normal growth [2]. Many studies reported that respiratory distress syndrome(RDS), Necrotizing enterocolitis (NEC), Intraventricular hemorrhage (IVH), clotting disorders, and multi-organ failure are significantly more likely to occur in growth-restricted neonates [1, 8, 9]. High perinatal mortality has been reported in association more with absent and reversed end-diastolic flow velocities in the umbilical arteries [2, 5, 9–15].

The high perinatal morbidity and mortality associated with growth-restricted fetuses mandate monitoring and evaluation using different parameters. Appropriate prenatal identification and management are very important to prevent some perinatal complications that could lead to adverse outcomes in growth-restricted fetuses. It has been reported that UA Doppler significantly reduces perinatal mortality and iatrogenic premature interventions by differentiating pathologic growth restriction from constitutionally small fetuses. A metanalysis of randomized controlled studies has shown that UA Doppler in combination with standard antepartum testing, was associated with a decrease of up to 38% in perinatal mortality [16].

The aim of the current study is, therefore, to determine the perinatal outcome of growth-restricted fetuses with abnormal umbilical artery Doppler waveforms compared to normal umbilical artery Doppler waveforms at Saint Paul’s Hospital Millennium Medical College.

Materials and methods

Study area, period, and design

This was a hospital-based prospective cohort study. The study was conducted at Saint Paul’s Hospital Millennium Medical College(SPHMMC), Addis Ababa, Ethiopia from September 2018-February 2019. SPHMMC is a tertiary teaching referral hospital under the Federal Ministry of Health (FMOH). According to the statistics office of the hospital, around 10,000 deliveries were attended in 2018 and 35% of deliveries being by cesarean section. According to hospital protocol growth restriction is suspected when birth weight percentile is below 10th percentile and or femoral length to abdominal circumference is greater than 23.5%. UA artery Doppler is done for all pregnant women suspected to have a growth-restricted fetus. Sagittal view color Doppler interrogation of the free loop of the umbilical artery is used to monitor Doppler indices and diastolic flow. At each episode 2 or 3 waveforms are seen and the worst waveform is taken to inform subsequent follow-up. Those with normal Doppler flow will have weekly follow up. Those with abnormal Doppler are classified in to early (raised Doppler indices) and late (reversed or absent Doppler flow). Patients will have 1–2 times antenatal visits if the abnormality is raised Doppler indices and admitted for strict inpatient follow up if its reversed or absent umbilical artery diastolic flow. The follow up involves antepartum surveillance (biophysical profile) and umbilical artery Doppler study to evaluate fetal wellbeing and progress in the abnormality. If Doppler flow remains persistently (more than two weeks) normal the fetus is considered as constitutionally small but the follow up will continue. The target timing of delivery is 32, 34, and 37–39 weeks for reversed, absent, and raised umbilical artery Doppler flow respectively. The Doppler study is also done on the date of delivery to inform the mode of delivery. The delivery is by cesarean section for reversed and absent Doppler flow and determined by obstetric factors for those with raised indices and normal Doppler study.

We considered the following inclusion criteria: singleton intrauterine pregnancy having Antenatal care (ANC) follow up, delivery and neonatal care at SPHMMC whose gestational age was ≥28 completed weeks by reliable last normal menstrual period (LNMP) or by early ultrasound of fewer than 24 weeks, diagnosed to have IUGR according to hospital protocol. Patients with lethal congenital anomalies, intrauterine fetal death before having Doppler studies and unknown last normal menstrual period, and no ultrasound before 24 weeks were excluded. Additionally, pregnant mothers with comorbid chronic medical disorders like diabetes, severe anemia, renal disease, cardiac disease, antiphospholipid antibody syndrome, and those with known TORCH infections were also excluded. We considered the following perinatal outcomes as outcome variables: prematurity, birth weight, APGAR score, the need for resuscitation, NICU admission, RDS, neonatal sepsis, perinatal mortality. The exposure variable of interest is abnormal umbilical artery Doppler waveform compared to normal umbilical artery Doppler waveform. We considered age, place of residence, level of education, occupation, marital status, parity, gestational age, mode of delivery, and hypertension as confounding variables.

Operational definitions

Normal UA Doppler waveform: Normal Doppler indices (less than 95th centile) and positive end-diastolic velocities.

Abnormal UA Doppler waveform: Raised (above 95th centile) indices (S/D ratio, RI, and or PI) or absent or reversed UA Doppler flow.

Prematurity: delivery after 28 weeks but before 37 weeks of gestational age.

Non-Reassuring Fetal Heart Rate Pattern (NRFHRP): abnormal fetal heart rate is considered as a non-reassuring fetal heart rate pattern in this study.

Low 5th Apgar score: 5th minute Apgar score of < 7.

Neonatal Intensive Care Unit(NICU) admission: those neonates admitted to NICU.

Respiratory Distress Syndrome(RDS): also known as hyaline membrane disease (HMD), is a respiratory disorder of premature babies, in this study is a clinical diagnosis considered by the neonatal care team.

Neonatal sepsis: is a type of neonatal infection and the diagnosis of which is considered by the neonatal care team clinically or confirmed microbiologically as the presence of bacterial bloodstream infections such as meningitis, pneumonia, urinary tract infection, or gastroenteritis, in the setting of fever.

Perinatal mortality: in this study its antepartum fetal death after fetal viability (above 28 weeks) intrapartum fetal death plus the death of neonates in the first seven days (early neonatal deaths) per 1000 live Birth.

Intrauterine growth restriction: birth weight below the 10th percentile for a given gestational age.

Sample size and sampling procedure

The sample size was calculated using info stat calc version 7, for cohort study. Pregnant mothers complicated with IUGR which had abnormal UA Doppler studies were labeled as an exposed group, and pregnant mothers complicated with IUGR which had normal UA Doppler studies were labeled as a non-exposed group. Considering perinatal mortality of 28% in the exposed group and 6% in non-exposed groups [14], using the power of 80% and confidence interval (CI) of 95%, the calculated sample size was 150, adding a 10% loss to follow up gave a total sample size of 170. The ratio of non-exposed to exposed was taken as 3.6:1. So 37 cases of the exposed group and 133 cases of the non-exposed group were collected consecutively for comparison for six months.

Data collection procedure and instrument

A structured and pretested English questionnaire was used to assess sociodemographic characteristics, obstetric factors, umbilical artery Doppler waveforms, and neonatal outcomes. Two trained midwives, who were not involved in patient care, collected data by interviewing the mother and reviewing the maternal and neonatal charts. The phone number of mothers and their card numbers were recorded for the latter tracing of neonatal outcomes.

Data collection was started at the time the women were admitted to the labor and delivery room and were continued through the intrapartum course until delivery. The neonates who were not referred to Neonatal Intensive Care Unit (NICU) were followed until mothers discharged and those neonates which were referred to NICU were followed in the NICU. The status of all neonates was checked at the seventh neonatal day. Those admitted to NICU were checked at NICU for the outcome and all those discharged home before the 7th day was checked during follow up visits. Those who didn’t appear on follow up were reminded by cell phone call. Principal investigator supervised data collection and checked for completeness, accuracy, and consistency of all questionnaires.

Data processing and analysis

Data cleaning was performed to check for outliers, missed values, and any inconsistencies before the data were analyzed using the software. Data were entered and analyzed using SPSS version 23. A chi-square test was used to check statistical associations between abnormal UA Doppler and outcome variables and covariates. Outcome variables with P value less than 0.05 were selected, and cross-tabulation was done to determine the strength and direction of the association between abnormal UA Doppler and each outcome variable. All covariates with P value less than 0.05 (covariates associated with exposure variable) were selected for multiple regression to determine their association with each outcome variable. Statistical significance of the association between exposure and outcome variables were determined by a 95% confidence interval and p-value set at 0.05. Adjusted Risk Ratio (RR) was used to determine the strength and direction of the association between exposure and outcome variables.

Ethical consideration

Ethical approval was obtained from Saint Paul's Hospital Millennium Medical College ethical review committee. All the datasets used and/or analyzed during the current study are included in the manuscript.

Results

Maternal socio-demographic characteristics of the study participants

There was a total of 5000 births managed at SPHMMC during the study period of which 170 pregnant mothers complicated with IUGR were identified. Among 170 growth-restricted fetuses, 133 were with normal UA Doppler studies and 37 were with abnormal UA Doppler studies. From abnormal UA Doppler studies, 14 of them are AED, and or REDF while 23 of them were affected Doppler indices (raised indices).

The mean gestational age at the time of diagnosis was between 34 ± 2 weeks in normal UA Doppler studies and 32 ± 2 weeks in the abnormal UA groups. The average duration of follow up is 2 weeks in the abnormal UA Doppler group and 3 weeks in the normal umbilical artery follow up. There was no loss to follow up nor missing outcome data in both groups.

There is no statistically significant difference in socio-demographic characteristics in terms of maternal age, ethnicity, religion, level of education, occupation, marital status and place of residence (See Table 1).

Table 1

Socio-demographic characteristics of mothers complicated with IUGR at SPHMMC, Addis Ababa, Ethiopia from September 2018-February 2019 (n = 133 for normal UA Doppler group, n = 37 for abnormal UA Doppler group).

Variable	Category	Normal UA Doppler, N (%)	Abnormal UA Doppler, N (%)	Chi-square (p-value)
Maternal age	<20	2(1.5)	2(5.4)
	20–25	64(48.1)	9(24.3)
	26–30	30(22.6)	13(35.1)	2.802(0.241)
	31–35	19(14.3)	9(24.3)
	>35	9(6.8)	1(2.7)
Ethnicity	Oromo	56(42.1)	11(29.7)
	Amhara	34(25.6)	12(32.4)	0.281(0.962)
	Tigre	3(0.2)	4(10.8)
	Gurage	32(24.1)	8(21.6)
	Others	8(6)	2(5.4)
Religion	Orthodox	69(51.9)	23(62.2)
	Muslim	34(25.6)	9(24.3)	6.405(0.063)
	Protestant	30(22.6)	5(13.5)
Level of education	Illiterate	9(6.8)	3(8.1)
	Elementary	49(36.8)	15(40.5)	2.065(0.721)
	High school	59(44.4)	13(35.1)
	College/university.	16(12)	6(16.2)
Occupation	Housewife	92(69.2)	26(70.3)
	Government employee	14(10.5)	5(13.5)	4.663(0.193)
	Private employee	16(12)	6(16.2)
	Merchant	6(4.5)	0
	Daily laborer	4(3)	0
	Student.	1(0.8)	0
Marital status	Married.	130(97.7)	35(94.6)	3.402(0.431)
	Single.	2(1.5)	0
	Divorced.	0	1(2.7)
	Widowed.	1(0.8)	1(2.7)
Place of residence.	Rural	11(8.3)	4(10.8)	1.281(0.762)
	Urban	122(91.7)	33(89.2)

Maternal reproductive and obstetric characteristics of the study participants

About 37(27.8%) of participants with normal UA Doppler were para I compared to 10(27%) of those with abnormal UA Doppler but the difference is not statistically significant. The two groups were statistically different in terms of gestational age, mode of delivery, indications for cesarean section, and hypertension. About 26(70.3%) of abnormal UA Doppler patients gave birth by cesarean section compared to 43(32.3%) of patients in the normal UA Doppler. In the abnormal UA group 11(29.7%) of the cesarean section were done for absent and or reversed end-diastolic velocity (AEDV/REDV), while 8(21.6%) of them were done for NRFHR compared to 24(18.02%) of cesarean section for NRFHR in those with normal UA. Eleven (29.7%) of the abnormal UA group had hypertension compared to 15(11.3%) of IUGR with normal UA Doppler. There is no statistically significant difference between the two groups in terms of birth weight (Table 2).

Table 2

Maternal reproductive and obstetric characteristics of the pregnant mothers complicated with IUGR with normal and abnormal Doppler studies at SPHMMC, Addis Ababa, Ethiopia from September 2018-February 2019.

Variable	Category	Normal UA Doppler, N (%) N (%)	Abnormal UA Doppler, N (%)N (%)	Chi-square (P-value)
Parity.	I	37(27.8)	10(27.0)
	II	6(4.5)	4(10.8)	2.870(0.238)
	III	6(4.5)	0
	IV	2(1.5)	1(2.7)
	V and above	2(1.5)	0
Gestational age at delivery.	(28–32)	2(1.5)	2(5.4)
	(32–34)	5(3.8)	6(16.2)	7.283(0.007)
	(34–37)	21(15.8)	10(27.0)
	37 and above	105(78.9)	19(51.4)
Mode of delivery.	Vaginal	90(67.7)	11(29.7)	14.682(0.005)
	Cesarean delivery	43(32.3)	26(70.3)
Indications for cesarean delivery.	NRFHRP	24(18.0)	8(21.6)	4.532(0.023)
	AEDF/REDF	0	11(29.7)
	Mal-presentation	7(5.3)	0
	Dystocia.	14(10.5)	5(13.5).
Hypertension.	No	118(88.7)	26(70.3)	8.237(0.044)
	Yes	15(11.3)	11(29.7)
	[1000–1500]	5(3.8)	9(24.3)
EFW	(1500–2000]	22(16.5)	15(40.5)	8.237(0.144)
	(2000–2500]	75(56.4)	12(32.4)
	>2500	31(23.3)	1(2.7)

Comparison of perinatal outcome of neonates with normal and abnormal UA Doppler waveform

All the abnormal UA Doppler waveform groups were born alive compared to one (0.75) intrapartum (stillbirth) in those with normal UA Doppler, but the result was not statistically different. Five (3.2%) of normal and 9(24.3%) of abnormal UA Doppler studies ended in perinatal death. Apgar scores of 9(6.8%) of normal and 11(29.7% of abnormal Doppler groups were less than seven. About 22(16.5%) of neonates with normal UA Doppler required resuscitation compared to 25(67.6%) of abnormal UA Doppler neonates. Two (5.4%) neonates with abnormal UA Doppler studies developed meconium aspiration syndrome compared to six (4.5%) of normal UA Doppler waveforms and the difference is not statistically different, P-value of 0.431.

Twenty (15%) of normal and 24(64.9%) of abnormal UA Doppler study neonates required NICU admission. Fetuses complicated with IUGR with abnormal Doppler were two times more likely to require neonatal NICU admissions compared to IUGR fetuses with normal UA Doppler flow, P-value 0.002, (OR = 2.059,95%CI 1.449–2.926). Fetuses complicated with IUGR with abnormal Doppler were four times more likely to end in END compared to IUGR fetuses with normal UA Doppler flow, P-value 0.001, (OR = 4.136, 95%CI 3.423–4.998) (Table 3).

Table 3

Perinatal outcome of fetuses complicated with IUGR with normal and abnormal Doppler studies at SPHMMC, Addis Ababa, Ethiopia from September 2018-February 2019 ((n = 133 for normal UA Doppler group, n = 37 for abnormal UA Doppler group).

Variable	Normal UA Doppler	Abnormal UA Doppler	Chi-square (P-value)	RR (95% CI)
Stillbirth.	1 (0.75%)	0	2.802(0.241)	-
Low 5th minute APGAR score.	11 (8.3%)	11(29.7%)	30.475(0.001)	2.142(1.669–2.748)
The need for resuscitation.	22 (16.5%)	25 (67.6%)	9.782(0.002)	2.350(1.648–3.352)
NICU admission.	20 (15%)	24 (64.9%)	9.631(0.002)	2.059(1.449–2.926)
Respiratory distress syndrome.	17 (12.8%)	19 (51.4%)	8.001(0.005)	2.267(1.539–3.340)
Meconium aspiration syndrome.	6 (4.5%)	2 (5.4%)	3.402(0.431)	-
Neonatal sepsis.	12 (9.0%)	9 (24.3%)	17.388(0.001)	2.598(1.972–3.424)
Neonatal hyperbilirubinemia	2 (1.5%)	2 (5.4%)	22.685(0.001)	2.161(1.660–2.813)
Early neonatal death(END). Died(END)	6 (3%)	9 (24.3%)	21.657(0.001)	4.136(3.423–4.998)

Mode of delivery, gestational age, and hypertension was associated with abnormal UA Doppler studies (Table 2). Multiple logistic regression was done to determine the effect of those independent variables on perinatal outcomes in addition to UA Doppler abnormality. Mode of delivery and the presence of hypertension was not associated with any of the perinatal outcomes. Gestational age is associated with NICU admission, respiratory distress syndrome(RDS), and early neonatal death. Neonates born between 28 and 32 weeks of gestational age were two times more likely to be admitted to NICU, four times more likely to have respiratory distress syndrome, and three times more likely to end up with END (Table 4).

Table 4

Multiple logistic regression of perinatal outcomes with the mode of delivery, gestational age, and hypertension among mothers complicated with IUGR with normal and abnormal Doppler studies at SPHMMC, Addis Ababa, Ethiopia from September 2018-February 2019.

Perinatal outcome.	Independent variable.	P-value.	Adjusted RR (95% CI)
Low 5th minute Apgar score	Mode of delivery	0.391	2.009(0.409–9.878)
	Hypertension	0.815	0.865(0.090–52.439)
	Gestational age	0.773	1.023(0.124–3.336)
Early neonatal death.	Mode of delivery	0.998	2.583(0.007–73941)
	Hypertension	0.496	3.407(0.100–11.590)
	Gestational age	0.025	2.103(2,048–9.884)
Neonatal hyperbilirubinemia	Mode of delivery	0.998	7.443(0.704–4.951)
	Hypertension	0.998	2.2730.412–368.583)
	Gestational age	0.921	1.000(0.219–16.886)
The need for resuscitation.	Mode of delivery	0.998	1.000(0.257–2.917)
	Hypertension	0.998	1.000(0.090–32.439)
	Gestational age	0.921	1.000(0.072–63.987)
Neonatal sepsis.	Mode of delivery	0.200	0.200(0.024–1.683)
	Hypertension	0.953	0.953(0.140–6.483)
	Gestational age	0.430	0.430(0.063–4.505)
NICU admission.	Mode of delivery	0.142	4.640(0.597–36.061)
	Hypertension	0.225	2.509(0.568–11.079)
	Gestational age	0.035	3.425(1.219–5.886)
Respiratory distress syndrome	Mode of delivery	0.921	3.407(0.100–11.590)
	Hypertension	0.773	2.059(1.449–2.926)
	Gestational age	0.012	4.136(3.423–4.998)

Discussion

The present study was conducted to compare perinatal outcomes of IUGR with normal and abnormal UA Doppler waveforms. A total of 170 pregnant mothers having a complicated IUGR were included in the study, among which 133 were with normal UA Doppler studies and 37 were with abnormal UA Doppler studies. The two groups were statistically different in terms of gestational age, mode of delivery, indications for cesarean section, and presence of hypertension. In this study, 21.1% of the preterm deliveries had normal UA Doppler studies, whereas 48.6% of the preterm deliveries had abnormal UA Doppler studies. Comparing to the previous study, the percentage of preterm deliveries with normal UA Doppler study was higher (21.1% versus 14%), but the percentage of preterm deliveries with abnormal UA Doppler studies was less (48.6% versus 96%) [9].

About 70.3% of abnormal UA Doppler patients gave birth by cesarean section compared to 32.3% of patients in the normal UA Doppler. Most (29.7%) of the cesarean section in abnormal UA group was done for absent and or reversed end-diastolic velocity (AEDV/REDV), while 21.6% of them were done for NRFHR compared to 18.02% of cesarean section for NRFHR in those with normal UA. About 29.7% of the abnormal UA group had hypertension compared to 11.3% of IUGR with normal UA Doppler. This is consistent with previous study findings [1, 17, 18].

In the current study newborns with abnormal UA, Doppler studies were 2.3 times more likely to develop RDS and require resuscitations respectively compared to those with normal UA Doppler studies. This is comparable with other previous studies [11-13]. Neonates from abnormal UA Doppler studies group were two times more likely to require NICU admission compared to those with normal UA Doppler studies, which is comparable to other study findings [9, 12, 14].

In the current study newborns with abnormal UA Doppler studies were 2,2.5 and 2 times more likely to have low 5th minute APGAR score, neonatal sepsis, and neonatal hyperbilirubinemia respectively compared to those with normal UA Doppler studies. This finding is consistent with other similar studies [9, 11–13].

Concerning neonatal mortality in this study, a total of 15(8.8%) neonates died, 24.3% from those with abnormal UA Doppler studies and 4.5% from those with normal UA Doppler studies i.e. neonates from abnormal Doppler study were 4 times more likely to end up in END compared to neonates with normal UA Doppler studies. This finding is slightly higher compared to other related studies [9, 13, 14]. This might be because of the difference in the level of neonatal care in different countries and institutions as care for preterm babies is poor in low and middle-income countries [19-21]. There is only one stillbirth from the normal UA Doppler group but there is no stillbirth from abnormal UA group. This difference is not significant and is intrapartum death as patients were recruited in labour which might be related to intrapartum care and the different threshold health professional use for operative intervention for fetuses with normal and abnormal Doppler in labour. Mode of delivery and the presence of hypertension was not associated with perinatal outcomes. However, those neonates born at gestational age less than 34 weeks were more likely to require NICU admission, develop respiratory distress syndrome, and end in early neonatal death. This is perinatal morbidity and mortality associated with preterm delivery and is consistent with other study findings [9, 11–13].

The current study has its limitations. The study was limited to short term intrapartum events and neonatal outcomes during the first 7 days of neonatal life. Additionally, in the current study decision was made based on UA Doppler flow abnormality only. If possible, it would have been good to include umbilical vein and ductus venosus Doppler flow abnormality, special evaluating their impact on reducing iatrogenic preterm delivery. The study is unmatched and there is also a possibility of gestational age confounding the outcome as the study shows growth-restricted fetuses with abnormal umbilical artery born at gestational age less than 34 weeks were more likely to require NICU admission, develop respiratory distress syndrome and end in perinatal death. It would have been better if the study was done by incorporating antenatal fetal surveillance, change patterns of umbilical artery Doppler flow, and outcomes of neonates in the first month of neonatal life.

Conclusions

The abnormal umbilical artery Doppler waveform is associated with cesarean section delivery, neonatal intensive care unit admission, respiratory distress syndrome, neonatal sepsis, neonatal hyperbilirubinemia, and early neonatal death compared to normal umbilical artery Doppler flow.

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5 May 2020

PONE-D-20-03283

Perinatal Outcome of Growth Restricted Fetuses with Abnormal Umbilical Artery Doppler waveforms compared to Growth Restricted Fetuses with Normal Umbilical Artery Doppler Waveforms at a tertiary referral hospital in urban Ethiopia.

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Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

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Reviewer #1: With interest, I’ve read the manuscript “Perinatal outcome of growth restricted fetuses with abnormal umbilical artery Doppler waveforms compared to growth restricted fetuses with normal umbilical artery Doppler waveforms at a tertiary hospital in urban Ethiopia”.

This is a prospective cohort study which defines the population, exposure, comparison and outcomes as follow:

Population: Pregnant women with a suspected small fetus by estimated fetal weight below the 10th centile.

Exposure: Abnormal umbilical artery Doppler

Controls: Normal umbilical artery Doppler

Outcome: several adverse perinatal outcomes

The objective of the study is to assess the perinatal outcome among suspected small fetuses exposed and non-exposed to abnormal UA Doppler.

The narrative is a little difficult to follow and the reporting somehow confusing. The overall English quality is good.

I will be dividing my revision in three main parts: reporting, critical appraisal, and general comments.

Reporting: I will be comparing the manuscript using the STROBE criteria blinded to your own list. This is to ensure I’m not bias to your results since we may have different interpretations for each given point.

Title and abstract:

1) The authors adequately mention the study design. Also, the abstract is adequately structured

Introduction:

1) Citations should be place at the end of each line that requires such, not at the end of each paragraph.

2) Introduction must be cut down in half and just stating the essential (disease, rationale, hypothesis, objective)

Methods:

1) Please state the study design at the first line of the methods section, then followed by the setting where the study was conducted, then the eligibility criteria.

2) The studies population is supposed to be pregnant women with diagnosis of suspected small-for-gestational-age fetus by estimated fetal weight measurement below the 10th percentile. This population must be adequately defined.

3) Exposures are adequate (normal and abnormal UA).

4) After eligibility criteria, variables must be stated in a narrative way, starting with outcomes, then exposures, predictors, potential confounders, effect modifiers. All in a narrative way, without headers.

5) Please describe the procedure of how pregnant women with abnormal Doppler are handle. What classification do you use? How do you end a pregnancy with abnormal UA Doppler at a certain age?

6) Describe any efforts to address potential sources of bias.

7) Sample size must be stated before statistical analysis. Which by the way, I want to congratulate the authors for adequately calculating the sample size.

8) Ethical considerations should be reduced to 2 lines maximum.

9) Statistical methods are ok. The only limitation is How did you adjust for confounders? When describing pregnancy cohorts is almost impossible not to adjust for gestational age at birth as the most important effect modifier.

Results:

1) For prospective cohorts, please state the number of individuals potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analyzed. Preferably, use a flow diagram.

2) Tables should be placed at the end of the manuscript and not embedded in the middle of it.

3) Continuous variables such as maternal age, gestational age... should be stated as mean and standard deviation or median and interquartile range. Continuous variables should not be only categorized or we miss the idea of the description of the population.

4) Indicate the number of participants with missing data for each variable of interest (if any)

5) State and summarize the follow-up and time of follow. A good way to do so is by describing the mean (and SD) age at diagnosis and the mean age at delivery for each group.

6) Thank you for using RRs instead of ORs. As part of the quality assessment, please, describe the adjusted RRs. You can use the Mantel-Haenzel method. The second option is to produce a multiple regression analysis adding the confounders the logistic regression.

7) Consider translating relative risk into absolute risk for the given time period of the study. This will allow readers to give a meaning idea of the magnitude of the effect.

8) Table 4. It seems clear to me that gestational age is the most important component for adverse outcome. All analyses need to be adjusted for gestational age at birth. Also, those RR with “0” are incorrect. Maybe the analysis was not robust enough. I suggest using bootstrapping to estimate those confidence intervals due to the extremely small sample.

Discussion:

1) Please, discuss more in depth the limitations of the study. Take into account the management of women with abnormal UA Doppler.

2) Conclusions must be cut by half at least.

Critical appraisal

Selection:

1) Representativeness of the exposed cohort is adequate (Abnormal UA Doppler by different definitions)

2) Selection of the non-exposed cohort is also adequate since it was drawn from the same population

3) Ascertainment of exposure is adequate because it was obtained from a structured interview.

Comparability:

1) Adequate study controls for the most important factor (Abnormal UA and normal UA). No additional factors were used

Outcome:

1) There is unclear risk of bias on assessment of outcome. There is no explanation in whether those performing the ultrasound were the ones assessing the outcomes.

2) Adequate follow-up for outcomes to occur

3) Adequate follow-up of the whole cohort. For most described adverse perinatal outcomes, a 7-day follow-up seems adequate except for neonatal death. But this does not seem to compromise the overall quality of the study.

General comments:

1) It is important to follow the same order as the STROBE tool in a narrative way.

2) Please, add an explanation of possible confounders and how were they handled.

3) Adequately define and explain the selected population (suspected SGA).

4) Use the term suspected small-for-gestational-age for all fetuses below the 10th percentile, and fetal growth restriction for those suspected SGA + abnormal Doppler.

5) Clearly state the hospital’s protocol on how FGR fetuses are handle

6) Please use mean and SD (or median and IQR) for continuous variables

7) Add the gestational age at diagnosis and the gestational age at delivery

Minor:

1) Tables should be at the end of the article

2) Use the same font type and number for the whole manuscript. Do not use bigger fonts for the headers

Reviewer #2: The manuscript by Lemi B Tolu. et al. addressed the issue on the association between Umbilical Artery Doppler and perinatal outcome in fetal growth restriction (IUGR). Placental dysfunction is one of the main complications of pregnancies and and the risk of death or neurodevelopmental impairment is high in these cases .

During the study period the authors collected 170 patients with fetal growth restriction and they were divided into fetuses with of normal umbilical artery Doppler 133 and fetuses with abnormal umbilical artery Doppler 37 and they found, On the 7th neonatal day, 129 (97%) of normal and 29 (78.4%) of abnormal umbilical artery Doppler were alive whereas 4 (3%) of normal and 9 (24.3%) of abnormal umbilical artery Doppler studies ended in early neonatal death , however although for almost 20 years, the umbilical artery (UA) has been widely accepted as the standard to identify IUGR, this assumption was based on false premises, because it extended observations that are valid in the most severe subset of IUGR fetuses to the whole group of IUGR. While UA identifies severe placental disease, if fails to pick up instances of mild placental disease, which constitute a proportion of early-onset cases, and virtually all instances of late-onset IUGR.

Evidence during the last two decades has demonstrated that SGA, as defined by a normal UA PI, contains a large proportion of fetuses with worse perinatal outcomes than normally grown fetuses

Thus, UA Doppler cannot be used as standalone criterion to differentiate IUGR from SGA.

The authors do not provide a complete outline of the current literature in this field and the articles used as references are not complete.

Major limitations are the following:

1-Introduction

It is very long and must be trimmed

2-Materials and methods:

In general, there is a important information that should be given by the authors. The specific points are:

The definition for the late and early IUGR fetuses, SGA and non SGA are required .

2.1Among the exclusion criteria did they also consider the presence of diabetes ,hypertension?

2.2 More information are required regarding the management of time of delivery, according to the local management guidelines .

2.3Was fetal well-being tests performed in all cases as standard protocol? please describe the monitoring and management protocol for IUGR

2.4Doppler results of the middle cerebral artery and uterine arteries should be added.

3-Discussion:

It should be clarified why the Doppler values of MCA and uterine artery were not taken into account for the classification and management of IUGR cases .

The following references should be added and commented in the discussion

1LINDQVIST PG, MOLIN J. Does antenatal identification of small-for-gestational age fetuses significantly improve their outcome? Ultrasound Obstet Gynecol 2005;25:258-64.

2. GARDOSI J, MADURASINGHE V, WILLIAMS M, MALIK A, FRANCIS A. Maternal and fetal risk factors for stillbirth: population based study. BMJ 2013;346:f108.

3. SKOVRON ML, BERKOWITZ GS, LAPINSKI RH, KIM JM, CHITKARA U. Evaluation of early thirdtrimester ultrasound screening for intrauterine growth retardation. J Ultrasound Med 1991;10:153-9.

4. FIGUERAS F, EIXARCH E, GRATACOS E, GARDOSI J. Predictiveness of antenatal umbilical artery Doppler for adverse pregnancy outcome in small-for-gestational-age babies according to customised birthweight centiles: population-based study. Bjog 2008;115:590-4.

5. RICHARDUS JH, GRAAFMANS WC, VERLOOVE-VANHORICK SP, MACKENBACH JP, EURONATAL INTERNATIONAL AUDIT P, EURONATAL WORKING G. Differences in perinatal mortality and suboptimal care between 10 European regions: results of an international audit. BJOG 2003;110:97-105.

6. ALFIREVIC Z, STAMPALIJA T, GYTE GM. Fetal and umbilical Doppler ultrasound in high-risk pregnancies. Cochrane Database Syst Rev 2010:CD007529.

7. SOOTHILL PW, BOBROW CS, HOLMES R. Small for gestational age is not a diagnosis. Ultrasound Obstet Gynecol 1999;13:225-8.

8. OROS D, FIGUERAS F, CRUZ-MARTINEZ R, MELER E, MUNMANY M, GRATACOS E. Longitudinal changes in uterine, umbilical and fetal cerebral Doppler indices in late-onset small-for-gestational age fetuses. Ultrasound Obstet Gynecol 2011;37:191-5.

9. DOCTOR BA, O'RIORDAN MA, KIRCHNER HL, SHAH D, HACK M. Perinatal correlates and neonatal outcomes of small for gestational age infants born at term gestation. Am J Obstet Gynecol 2001;185:652-9.

10. MCCOWAN LM, HARDING JE, STEWART AW. Umbilical artery Doppler studies in small for gestational age babies reflect disease severity. Bjog 2000;107:916-25.

11. SEVERI FM, BOCCHI C, VISENTIN A, et al. Uterine and fetal cerebral Doppler predict the outcome of third-trimester small-for-gestational age fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 2002;19:225-8.

12. BAHADO-SINGH RO, KOVANCI E, JEFFRES A, et al. The Doppler cerebroplacental ratio and perinatal outcome in intrauterine growth restriction. Am J Obstet Gynecol 1999;180:7506.

Reviewer #3: PONE-D-20-03283

Perinatal Outcome of Growth Restricted Fetuses with Abnormal Umbilical Artery Doppler waveforms compared to Growth Restricted Fetuses with Normal Umbilical Artery Doppler Waveforms at a tertiary referral hospital in urban Ethiopia.

The following study describes the use of umbilical artery (UA) Doppler to predict abnormal findings and worse perinatal outcomes in intrauterine growth restriction (IUGR). The study has a good number of patients, however it lacks information which may be novel and contribute to the subject; in reality, the idea that UA Doppler is associated with worse outcomes is something that is known and this study only confirms current previously published knowledge. Furthermore, the study does not include other variables which are relevant to the study and prognosis of IUGR. I believe that the study may be relevant locally, but provides little information otherwise.

• The Introduction provides outdated information and lacks references; i.e. the concepts that UA is the only vessel used for IUGR, or the classification for symmetric and asymmetric IUGR.

• I am not sure the sample size calculation is adequate, since they claim it is 150, but usually this would be per study group. Since the proportion of IUGR with abnormal UA Doppler is rare, this would seem logical.

• The definition of IUGR is never provided, the authors claim that the diagnosis was by attendings or ObGyn residents. This would be unacceptable due to the variability and lack of expertise, and this population would have to be confirmed or supervised.

• The Methods section lacks the information for statistical analysis; Chi squared is only used for comparison of parametric proportions, however the authors present comparisons of medians(range), do not specify if they tested normality and do not describe their analysis adequately.

I would suggest the authors redefine their population because their results are very strange; for starters they have a high proportion of abnormal UA Doppler near term than preterm, which is not what commonly happens. Secondly, they do not provide basic information for delivery (Gestational age at delivery, birth weight, birth weight centile). Thirdly, they do not provide their criteria for diagnosis of the problem (IUGR) but rather assume it was previously diagnosed. I think the data requires revision and it would be more suitable for publication in a local journal.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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11 May 2020

May 10, 2020

To: PLOS ONE Editor in chief.

Dear Editor in chief.

We would like to thank the reviewers for their thoughtful review of the manuscript. They raise important issues and their inputs are very helpful for improving the manuscript. We agree with almost all their comments and we have revised our manuscript accordingly. We respond below in detail to each of the reviewer’s comments. We hope that you find our responses satisfactory and that the manuscript is now acceptable for publication

Looking forward hearing from you soon

Sincerely,

Lemi B Tolu (MD, Assistant prof of obstetrics and gynecology).

Saint Paul’s Millennium Medical College(SPHMMC)

Department of Obstetrics and Gynecology

Addis Ababa, Ethiopia.

Email: lemi.belay@gmail.com

Dear editor and reviewer

Thanks for thoughtful review of the manuscript. Below is point by point response to raised concerns and how we changed the manuscript according to the comments.

Editor comments:

1. Thank you for including your funding statement; "no"

Authors: Dear editor thank you very much, we have corrected as “The authors received no specific funding for this work.”

2. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical.

Authors: Dear editor thank you very much, we have corrected.

Reviewer #1

Title and abstract:

1) The authors adequately mention the study design. Also, the abstract is adequately structured

Introduction:

1) Citations should be place at the end of each line that requires such, not at the end of each paragraph.

2) Introduction must be cut down in half and just stating the essential (disease, rationale, hypothesis, objective)

Authors: Dear author thank you very much, almost we rewrite introduction (page 4, lines 69-117)

Methods:

1. Please state the study design at the first line of the methods section, then followed by the setting where the study was conducted, then the eligibility criteria.

Authors: Dear reviewer corrected as per your recommendation (Page 6-7, lines 128-169).

2. The studies population is supposed to be pregnant women with diagnosis of suspected small-for-gestational-age fetus by estimated fetal weight measurement below the 10th percentile. This population must be adequately defined.

Authors: Edited and population well defined, hospital protocol included (Page 6, lines 135-140)

3. Exposures are adequate (normal and abnormal UA).

Authors: thank you very much for the comment.

4. After eligibility criteria, variables must be stated in a narrative way, starting with outcomes, then exposures, predictors, potential confounders, effect modifiers. All in a narrative way, without headers.

Authors: Dear reviewer comment well taken, and correction made (Page 8, lines 163-169)

5. Please describe the procedure of how pregnant women with abnormal Doppler are handle. What classification do you use? How do you end a pregnancy with abnormal UA Doppler at a certain age?

Authors: Dear reviewer thank you very much comment well taken, and protocol of the hospital stated on page 7, lines 135-148.

6. Describe any efforts to address potential sources of bias.

Authors: we collected data using structured questionnaire’s, data collectors were not involved in patient care and well trained on the tool, supervisors cross check data collection (Line 232-237).

7. Sample size must be stated before statistical analysis. Which by the way, I want to congratulate the authors for adequately calculating the sample size?

Authors: Dear reviewer thank you very much, the manuscript is structed accordingly.

8. Ethical considerations should be reduced to 2 lines maximum.

Authors: Comment well taken and addressed (Page 13, 262-264)

9. Statistical methods are ok. The only limitation is How did you adjust for confounders? When describing pregnancy cohorts is almost impossible not to adjust for gestational age at birth as the most important effect modifier.

Authors: Dear reviewer thank you very much, we also used multiple regression to control confounders.

Results:

1. For prospective cohorts, please state the number of individuals potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analyzed. Preferably, use a flow diagram.

Authors: Dear reviewer the comment is well taken and addressed (page 13, line 271-276)

2. Tables should be placed at the end of the manuscript and not embedded in the middle of it.

Authors: Thank you very much and we moved tables to end of the manuscript.

3. Continuous variables such as maternal age, gestational age... should be stated as mean and standard deviation or median and interquartile range. Continuous variables should not be only categorized, or we miss the idea of the description of the population.

Authors: Dear reviewer gestational age is described in mean and average duration of follow up.

4. Indicate the number of participants with missing data for each variable of interest (if any)

Authors: Dear reviewer we didn’t come across missed data (page 13, lines 277-281)

5. State and summarize the follow-up and time of follow. A good way to do so is by describing the mean (and SD) age at diagnosis and the mean age at delivery for each group.

Authors: Thanks, comment is well taken and addressed (Page 13, lines 277-281)

6. Thank you for using RRs instead of ORs. As part of the quality assessment, please, describe the adjusted RRs. You can use the Mantel-Haenzel method. The second option is to produce a multiple regression analysis adding the confounders the logistic regression.

Authors: Dear reviewer, thank you very much, we also multiple logistic regression.

7. Consider translating relative risk into absolute risk for the given time of the study. This will allow readers to give a meaning idea of the magnitude of the effect.

Authors: Dear reviewer thank you very much for the suggestion, but we didn’t think that translating in to absolute risk is as such applicable in the current manuscript.

8. Table 4. It seems clear to me that gestational age is the most important component for adverse outcome. All analyses need to be adjusted for gestational age at birth. Also, those RR with “0” are incorrect. Maybe the analysis was not robust enough. I suggest using bootstrapping to estimate those confidence intervals due to the extremely small sample.

Authors: Dear reviewer this is an amazing catch, loved it. Thank you very much, we have corrected it (Table 4)

Discussion:

2. Please, discuss more in depth the limitations of the study. Consider the management of women with abnormal UA Doppler.

3. Conclusions must be cut by half at least.

Authors: Dear reviewer thank you very much manuscript is modified accordingly (Page 21, lines 388-394 and Page 22, lines 400-404)

Critical appraisal

Authors: Dear reviewer thank you very much for such input which helped us to improve the manuscript.

General comments:

1. It is important to follow the same order as the STROBE tool in a narrative way.

2. Please, add an explanation of possible confounders and how were they handled.

3. Adequately define and explain the selected population (suspected SGA).

4. Use the term suspected small-for-gestational-age for all fetuses below the 10th percentile, and fetal growth restriction for those suspected SGA + abnormal Doppler.

5. Clearly state the hospital’s protocol on how FGR fetuses are handle

6. Please use mean and SD (or median and IQR) for continuous variables

7. Add the gestational age at diagnosis and the gestational age at delivery

Authors: Dear reviewer these general comments are addressed in the above explanations.

Minor:

1. Tables should be at the end of the article

2. Use the same font type and number for the whole manuscript. Do not use bigger fonts for the headers

Authors: Dear reviewer we have moved tables to the end of manuscript and the manuscript is also prepared according to PLOS ONE requirement.

Reviewer#2

General

1. Thus, UA Doppler cannot be used as standalone criterion to differentiate IUGR from SGA.

Author: Dear reviewer we never said UA is a standalone criterion, but we said its most commonly used. MCA, UA, UV and DV are often used together. Our only aim in the current study is to compare perinatal outcome of abnormal UA to normal UA, we have also included the protocol used in our hospital (Page 7, lines 133-147). Special in low and middle-income countries Umbilical artery is very commonly used for diagnosis and follow up growth restriction.

2. The authors do not provide a complete outline of the current literature in this field and the articles used as references are not complete.

Authors: Dear reviewer we have revised the introduction part by including updated information we came across in our search.

Introduction.

1. Introduction is very long and must be trimmed

Authors: dear reviewer thanks for the comment, we have revised and rewrote introduction accordingly.

Materials and methods:

1. The definition for the late and early IUGR fetuses, SGA and non-SGA are required.

Authors: Dear reviewer the comment is well taken and addressed on page 7, lines 135-149.

2. Among the exclusion criteria did they also consider the presence of diabetes, hypertension

Authors: Dear reviewer we excluded diabetes, but we included hypertension and did multiple logistic regression to control its confounding effect.

3. More information is required regarding the management of time of delivery, according to the local management guidelines.

Authors: Dear reviewer, the comment is well taken and addressed on page 7, lines 135-148.

4. Were fetal well-being tests performed in all cases as standard protocol? please describe the monitoring and management protocol for IUGR

Authors: Dear reviewer we have included hospital protocol which includes follow up of fetal wellbeing (Page 7, lines 135-148)

5. Doppler results of the middle cerebral artery and uterine arteries should be added.

Authors: Dear reviewer in the hospital we conducted study MCA is done for patients with suspected IUGR but normal UA doppler flow to measure cerebroplacental ratio to see brain sparing which is expected to occur before umbilical artery abnormality, but not considered as universal standard practice. Uterine artery doppler is used for prediction of preeclampsia and growth restriction (predicting uteroplacental insufficiency). The hospital doesn’t use uterine artery for diagnosis or follow up of growth restriction, we didn’t come across literature suggesting such practice otherwise. Dear reviewer that’s why we focus on comparing growth restriction with normal and abnormal umbilical artery. Thanks for understanding us.

Discussion

1. It should be clarified why the Doppler values of MCA and uterine artery were not considered for the classification and management of IUGR cases.

Authors: Dear reviewer please see the explanation under question number 5.

2. The following references should be added and commented in the discussion.

Authors: Dear reviewer thank you very much we have used the following references in our manuscript from the suggestions.

a. GARDOSI J, MADURASINGHE V, WILLIAMS M, MALIK A, FRANCIS A. Maternal and fetal risk factors for stillbirth: population-based study. BMJ 2013;346: f108.

b. FIGUERAS F, EIXARCH E, GRATACOS E, GARDOSI J. Predictiveness of antenatal umbilical artery Doppler for adverse pregnancy outcome in small-for-gestational-age babies according to customised birthweight centiles: population-based study. Bjog 2008; 115:590-4.

c. ALFIREVIC Z, STAMPALIJA T, GYTE GM. Fetal and umbilical Doppler ultrasound in high-risk pregnancies. Cochrane Database Syst Rev 2010:CD007529.

d. OROS D, FIGUERAS F, CRUZ-MARTINEZ R, MELER E, MUNMANY M, GRATACOS E. Longitudinal changes in uterine, umbilical and fetal cerebral Doppler indices in late-onset small-for-gestational age fetuses. Ultrasound Obstet Gynecol 2011; 37:191-5

e. DOCTOR BA, O'RIORDAN MA, KIRCHNER HL, SHAH D, HACK M. Perinatal correlates and neonatal outcomes of small for gestational age infants born at term gestation. Am J Obstet Gynecol 2001; 185:652-9.

Reviewer #3

1. The Introduction provides outdated information and lacks references; i.e. the concepts that UA is the only vessel used for IUGR, or the classification for symmetric and asymmetric IUGR.

Authors: Dear reviewer the introduction is rewritten incorporating comments. We didn’t state UA as the only vessel, but we said its commonly used and studied. Special in low and middle-income countries umbilical artery is very commonly used for diagnosis and follow up of fetuses with growth restriction. Thanks for understanding us.

2. I am not sure the sample size calculation is adequate, since they claim it is 150, but usually this would be per study group. Since the proportion of IUGR with abnormal UA Doppler is rare, this would seem logical.

Authors: Thank you very much, that’s what we got by calculation as it stated it’s also a rare scenario too.

3. The definition of IUGR is never provided, the authors claim that the diagnosis was by attendings or ObGyn residents. This would be unacceptable due to the variability and lack of expertise, and this population would have to be confirmed or supervised

Authors: Dear reviewer the hospital protocol is included in the manuscript which has also definition of IUGR (Page 7, lines 135- 148)

4. The Methods section lacks the information for statistical analysis; Chi squared is only used for comparison of parametric proportions, however the authors present comparisons of medians(range), do not specify if they tested normality and do not describe their analysis adequately.

Authors: Dear reviewer we used chi square, cross tabulation and regression.

5. I would suggest the authors redefine their population because their results are very strange; for starters they have a high proportion of abnormal UA Doppler near term than preterm, which is not what commonly happens. Secondly, they do not provide basic information for delivery (Gestational age at delivery, birth weight, birth weight centile). Thirdly, they do not provide their criteria for diagnosis of the problem (IUGR) but rather assume it was previously diagnosed.

Authors: Dear reviewer thank you very much for the comment. We have included hospital protocol for the diagnosis and follow up of growth restriction (Page 7, lines 135-148). Regarding the gestational age of term and preterm it might because what is presented is gestational age at delivery. With gestational age at delivery almost 50% are preterm and 50% are term. There is no statistical significant difference in terms of birthweight between two groups as shown in table 2.

Submitted filename: Reviewer response May 10.docx

Click here for additional data file.

18 May 2020

PONE-D-20-03283R1

Perinatal Outcome of Growth Restricted Fetuses with Abnormal Umbilical Artery Doppler waveforms compared to Growth Restricted Fetuses with Normal Umbilical Artery Doppler Waveforms at a tertiary referral hospital in urban Ethiopia.

PLOS ONE

Dear Dr. Tolu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

The manuscript has been improved accordingly but it is still not suitable for publication in this Journal. It requires further corrections.

==============================

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Kind regards,

Rogelio Cruz-Martinez, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Firstly, the manuscript has multiple typographical and grammatical errors and thus, a more thorough editing process is necessary. Please replace “doppler” by Doppler in all the manuscript.

Normal umbilical artery Doppler should be considered as values below the 95th centile, values below the 10th centile should not be considered abnormal. An international consensus exist for definition of abnormal UA Doppler by including only the pulsatility index and therefore, UA Doppler indices such as S/D ratio and RI should be excluded.

Perinatal death should include also those cases with intrauterine fetal demise

In the abstract section, please include the p values between the study group comparisons.

“On the 7th neonatal day, 129(97%) of normal and 29(78.4%) of abnormal umbilical artery doppler were alive whereas 4(3%) of normal and 9(24.3%) of abnormal umbilical artery Doppler studies ended in early neonatal death”. Please replace this paragraph by the proportion of perinatal death between the study groups.

The frequency of adverse perinatal outcome (perinatal death, NICU admission, neonatal morbidity) should be adjusted by gestational age at birth) and all such outcomes (and not only NICU admission and neonatal death) should be also summarized in the abstract section and in the Results section.

Please specify in the Methods section how was the UA Doppler evaluated, site and angle of insonation, number of included waveforms and ultrasound settings, etc. Were all ultrasoud Doppler measurements performed at the day of delivery? Please specify.

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26 May 2020

May 26, 2020

To: PLOS ONE Editor in chief.

Dear Editor in chief.

We would like to thank the editor and reviewers for their thoughtful review of the manuscript. They raise important issues and their inputs are very helpful for improving the manuscript. We agree with almost all their comments and we have revised our manuscript accordingly. We respond below in detail to each of the editor comments. We hope that you find our responses satisfactory and that the manuscript is now acceptable for publication

Looking forward hearing from you soon

Sincerely,

Lemi B Tolu (MD, Assistant prof of obstetrics and gynecology).

Saint Paul’s Millennium Medical College(SPHMMC)

Department of Obstetrics and Gynecology

Addis Ababa, Ethiopia.

Email: lemi.belay@gmail.com

Dear editor

Thanks for thoughtful review of the manuscript. Below is point by point response to raised concerns and how we changed the manuscript according to the comments.

1. Firstly, the manuscript has multiple typographical and grammatical errors and thus, a more thorough editing process is necessary. Please replace “doppler” by Doppler in all the manuscript.

Authors: Dear editor thank you very much, two authors independently revised the typos and grammar of the manuscript and much is changed.

2. Normal umbilical artery Doppler should be considered as values below the 95th centile, values below the 10th centile should not be considered abnormal. An international consensus exists for definition of abnormal UA Doppler by including only the pulsatility index and therefore, UA Doppler indices such as S/D ratio and RI should be excluded.

Authors: Dear editor thank you very much we have corrected definition (page 7, line 135). On which indices to use, as you said PI is most recommended. But still raised S/D or absent or reversed doppler are abnormal that’s why we included in the operational definition.

3. Perinatal death should include also those cases with intrauterine fetal demise

Authors: Dear editor thank you very much, we have corrected with all appreciation, (Page 8, lines 151,152)

4. In the abstract section, please include the p values between the study group comparisons.

Authors: Dear editor thank you, corrected (abstract section)

5. “On the 7th neonatal day, 129(97%) of normal and 29(78.4%) of abnormal umbilical artery doppler were alive whereas 4(3%) of normal and 9(24.3%) of abnormal umbilical artery Doppler studies ended in early neonatal death”. Please replace this paragraph by the proportion of perinatal death between the study groups.

Authors: Dear editor thank you very much for the feedback, we have corrected (page 2, line 35, page 10 line 233)

6. The frequency of adverse perinatal outcome (perinatal death, NICU admission, neonatal morbidity) should be adjusted by gestational age at birth) and all such outcomes (and not only NICU admission and neonatal death) should be also summarized in the abstract section and in the Results section.

Authors: Dear editor that’s very true, thanks a lot. Upon multiple regression only NICU admission, respiratory distress and perinatal death is associated with gestational age, that’s why we did for them. We have included in the abstract section as limitation of the study.

7. Please specify in the Methods section how was the UA Doppler evaluated, site and angle of insonation, number of included waveforms and ultrasound settings, etc. Were all ultrasound Doppler measurements performed at the day of delivery? Please specify.

Authors: Dear editor thank a lot. We have included what we use in the method section (Page 6 lines 102-104,114)

Submitted filename: Reviewer response May 26.docx

Click here for additional data file.

3 Jun 2020

Perinatal Outcome of Growth Restricted Fetuses with Abnormal Umbilical Artery Doppler waveforms compared to Growth Restricted Fetuses with Normal Umbilical Artery Doppler Waveforms at a tertiary referral hospital in urban Ethiopia.

PONE-D-20-03283R2

Dear Dr. Tolu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Rogelio Cruz-Martinez, Ph.D.

Academic Editor

PLOS ONE

9 Jun 2020

PONE-D-20-03283R2

Perinatal Outcome of Growth Restricted Fetuses with Abnormal Umbilical Artery Doppler waveforms compared to Growth Restricted Fetuses with Normal Umbilical Artery Doppler Waveforms at a tertiary referral hospital in urban Ethiopia.

Dear Dr. Tolu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr Rogelio Cruz-Martinez

Academic Editor

PLOS ONE