Risk Factors associated with Fetal and Pregnancy Complications in Palestine

Background: Complications observed during pregnancy affect both mother and fetus, and are more commonly observed among pregnant women from developing countries. The study aims to identify the most common pregnancy and fetal complications during pregnancy, and associated risk factors with these complications. Methods: A longitudinal study was conducted from September 2017 to July 2018 among pregnant women attending and registering in primary health care clinics of the Palestinian Ministry of Health in Nablus city. Data were collected through interviews and by reviewing medical records. Women were followed up during their regular visits to the primary health care clinics. Any complication affecting either the fetus or the mother during the pregnancy period was recorded. Binary logistic regression was used to identify independent risk factors for pregnancy and fetal complications. Results: A total of 380 pregnant women were included in the study. The most common complications seen among women during pregnancy were preterm labor (PTL) (11.3%), followed by an equal number of gestational diabetes (GDM) and pregnancies induce hypertension (PIH), i.e. (7.9%). Large for gestational age (LGA) (11.6 %) and small for gestational age (SGA) (10.5%) were the most commonly observed fetal complications. Pregnant women living in camps (O.R 2.35, 95% [CI] 1.02- 5.45), nulliparity (O.R 14.9, 95% [CI] 1.09-202.5) and low parity women (O.R 16.8, 95% [CI] 1.47- 192.5) were at higher risk of having pregnancy complications. However, lower risk was noticed between women with gravida 4 (O.R 0.11, 95% [CI] 0.03-0.47) compared to women having more than 6 pregnancies. Age younger than 41 years was a protective factor against fetal complications, while parity ( ≤ 6 parities) especially 4 to 6 parities (OR 36.17; 95% CI 4.88-268) and active smoking mothers (OR 1.25; 95% CI 1.0-3.07) were identied as risk factors that are associated with an increased risk of fetal complications. Conclusions: Fetal and pregnancy-related

There are plenty of complications that arise during pregnancy ranging from mild to severe. Mild complications such as fatigue and discomfort reduce the quality of life of the women and are manageable if not treatable with either medication or lifestyle modi cation [1]. The severe ones are more complicated, require periodic but continuous monitoring, and are potentially life-threatening if left unattended or even with appropriate treatment. Among these, gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), preeclampsia, hyperemesis gravidarum are a few to name maternal complications [4][5][6]. Apart from these, some complications are also associated with the outcome of the pregnancy and include preterm labor (PTL) and miscarriage. Preterm labor is the most frequently observed complication which increases the risk of prenatal mortality and creates health issues among newborns [7,8]. Miscarriage, on the other hand, is another frequent complication of pregnancy and even results in 10-20% loss of pregnancy in healthy women [9]. Stillbirth is yet another entity and is an outcome of almost 1 in 160 pregnancies [10]. Interestingly, these complications are not only stand-alone but interrelated as well. For example, PIH can complicate 6-10% of pregnancies and it is considered a major cause of mother and infant mortality, maternal morbidity such as PTL, and fetal morbidity such as intrauterine growth retardation [11]. Contrarily, it also increases the risk of preeclampsia, which occurs in about 2-8% of pregnancies [12], and is considered a common and serious medical emergency leading to preterm delivery and death [12][13][14].
Gestational diabetes mellitus (GDM) is another common and serious pregnancy complications which is known to occur in about 7 % of all pregnancies (15). GDM can negatively affect the pregnancy, the fetus, and the long-term health of both the mother and her child such as obesity and the development of type 2 diabetes later on life [6,16].
The possible reported complications relating to the fetus during pregnancy include small for gestational age (SGA), large for gestational age (LGA), intrauterine growth restriction (IUGR), and intrauterine fetal death (IUFD) [11,17,18]. These fetal complications impose equal risk to the pregnant women and fetus.
As an example, LGA can cause major problems during labor and delivery such as prolonged labor, arrest of labor [19], and higher rates of caesarean section [20,21].
LGA is also associated with increased neonatal morbidity [19], postpartum hemorrhage, shoulder dystocia, neonatal hypoglycemia, and prolong hospitalization [20]. It is also associated with a long-term increased risk of developing overweight [22,23] and type 2 diabetes in the future [23]. Similarly, SGA is associated with a signi cant increase in mortality risk and minor neurological dysfunction [24]. Infants with SGA had signi cantly higher rates of hypothermia and symptomatic hypoglycemia when compared with appropriate for gestational age infants [25]. Other complications such as fetal intrauterine growth restriction (IUGR) is also a common risk of a frequent cause of perinatal morbidity, mortality, as well as impaired growth during childhood [26,27].
In Palestine, data on the prevalence of pregnancy and fetal related complications are lacking. Therefore, we intended to record baseline characteristics by identifying the commonly observed fetal and pregnancy complications among pregnant women and their fetuses in Palestine. Furthermore, the study also planned to identify the risk factors of having fetal and pregnancy complications during the pregnancy period.

Methodology
A multicenter prospective observational study was conducted at primary health care centers in the Nablus district of West Bank, Palestine, which include four major antenatal clinics. The clinics were run under the supervision of the Palestinian Ministry of Health. All pregnant women at the age of 17 years and more registering at Ministry of health (MOH) antenatal clinics during their rst trimester were included. The data was collected over the span of 10 months from the September 2017 to July, 2018.
Inclusion/Exclusion Criteria Pregnant women (age ≥ 17 years) at rst trimester of spontaneous pregnancy were included in the study.
Women with pre-existing chronic comorbidities such as hypertension and diabetes mellitus, or having a history of multi-fetuses' pregnancy, or refused to participate were excluded from the cohort. Also, women having induced pregnancy via intrauterine fertilization or intrauterine injection were excluded.

Data Collection/Acquisition
Acquired data were recorded on a developed structured questionnaire. It covered sociodemographic information including the education status of the mother, smoking status, and monthly income. For clinical information, women's current obstetric history such as the number of gravidities, parity, abortion, and last menstrual period was also recorded from medical les. Self-reported pre-pregnancy body mass index (BMI) at the rst antenatal visit were noted. Socioeconomic and baseline clinical data were collected at the beginning of the study. Included participants were followed during their regular visits to the antenatal clinics until delivery.
Face and content validity of the questionnaires was conducted by 2 independent researcher, 2 obstetrics and gynecology doctors, and 2 senior midwives. To ensure the reliability of the questionnaire, Cronbach alpha was calculated with a result of (0.90).

De ning the Outcomes
Maternal associated pregnancy complications were recorded as follows: 1. Gestational diabetes mellitus (GDM): any degree of glucose intolerance at the onset or rst recognition during pregnancy.
2. Pregnancy-induced hypertension (PIH): a blood pressure of 140/90 mmHg or above measured on 2 separate occasions and over 6 hours apart, without proteinuria, developed after 20 weeks of gestation.
3. Preterm labor (PTL): regular uterine contractions occurring at least once every 10 minutes and resulting in cervical dilatation or effacement before 37 weeks gestation.
4. Pre-eclampsia: PIH accompanied by proteinuria of >300 mg in a daily urine sample.
5. Abortion: a deliberate termination of a human pregnancy, performed during the rst 24 weeks of pregnancy.
. Stillbirth: a baby born with no sign of life at or after 28 weeks of gestation.
The outcomes related to fetal complications during pregnancy were de ned as follows: 1. Small for gestational age (SGA): a weight below 10th percentile for the gestational age.
2. Large for gestational age (LGA): a weight above 90th percentile for the gestational age.
3. Intrauterine growth restriction (IUGR): an unborn baby smaller than it should be secondary to abnormal growth rate inside the womb.
4. Intrauterine fetal death (IUFD): a fetal loss in pregnancy beyond 20 weeks of gestation or after a fetal weight of 500 g or more (in case of unknown gestational age).

Statistical Analysis
Any maternal or fetal complication was recorded as a dichotomous, i.e. yes or no. A negative response was only recorded when a respondent experienced no maternal or fetal complication. Age was recorded as a continuous variable and was later graded further into groups. For the purpose of the study, parity was categorized into four classes, i.e. nulliparity (did not give birth before), low multi-parity (history of previous 1 to 3 live births), grand multi-parity (history of previous 4 to 6 live births), and high parity (history of more than 6 live births).
Binary logistic regression was used to analyze the data. Odds ratio (OR) along with their respective 95% con dence intervals (CI) were recorded to compare the magnitude of different risk factors for both pregnancy and fetal complications. A p-value ≤ 0.05 was considered statistically signi cant. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS version 26), SPSS Inc., Chicago, IL, USA.
Ethical approval: The research method was performed in accordance with Declaration of Helsinki guidelines and regulations. Ethical approval for the study was obtained from the local institutional review boards (IRB) of An-Najah National University and the Palestinian MOH. A signed written informed consent form was obtained from all the study participants to ensure the prospective agreement for participating in the study.

Results
A total of 896 pregnant women registered at MOH antenatal clinics in Nablus during the study duration.
Only 380 pregnant women met the study inclusion criteria. The basic demographic characteristics of these participants are shown in Table 1. Among included cases in this study, more than half of the participants (n=209) were aged between 26 to 32 years originating from the city (50.2%) ( Table 1). Most women had at least one gravidity (28.7%) and 45.8% fell in the category of low multi-parity. There were 18 participants that had more than 6 parties as well. Similarly, more than half (52.1%) fell into the ideal BMI category while nearly every 2 out of ve women (38.2%) had a history of smoking. Anemia was observed as the most prevalent (36.9%) health problem at the rst visit followed by vitamin D de ciency (n=7). Among secondary sociodemographic characteristics, the family income of the majority of participants (65.5%) was between 1000 to 4000 NIS (middle monthly income) and a little less than a third (28.2%) had a bachelor degree.
Seventy-seven pregnant women (20.3%) had at least one (one or more) pregnancy complication, while 303 women continued their pregnancies without any complications. PTL was the most common type complication (11.3%) observed followed by GDM and PIH, i.e. 7.9% each. Table 2 shows the distribution of pregnant women complications during pregnancy. Among fetal complications, LGA and SGA were the most common fetal complications with a percentage of 11.6% and 10.5%, respectively (Table 2). Upon analyzing the data for the event of maternal complications associated with pregnancy (  In the case of fetal complications (  Dubai also reported PIH and GDM as the most identi ed complications [29]. Apart from that, PTL was the most commonly observed complication in a Jordan [30]. Results from the current study indicate that participants in our group depicted sort of similar complications that are prevalent in the region. Among fetal pregnancy complications, the current study identi ed SGA and LGA as the most common fetal complications during pregnancy (Table 2). This nding was consistent with previous studies identifying these complications as the most prevalent ones affecting fetuses during the pregnancy [31][32][33][34]. Moreover, the incidence rates for SGA and LGA in the current cohort of participants were similar to the rate of 16-20% of pregnant women reported previously [35,36].
Regarding risk factors of pregnancy complications, we found that both nulliparity and low parity (previous 1 to 3 live births) women had higher risk of having complications during pregnancy when compared to high parity (>6) women. This means, both naulliparity and low parity were risk factor of complications during pregnancy. Parity has an inconclusive effect on pregnancy complications. Some studies showed different results and somewhat discrepancies regarding parity and pregnancy complications. Parities of three and above are considered a risk factor for GDM (37), while PTL was reported in some studies among high multiparity (≥5) women [18,38]. On the other hand, nulliparous women are also reported to be at a greater risk of having pregnancy complications than women with other parities [31,38,39,40]. A signi cant association between different parity levels and pregnancy complications (including GDM, PIH, and PTL) was also reported by Bai et al study [41]. The study showed that the risk of any obstetric complications was higher among nulliparous women compared to parity one women. However, the study also revealed that multiparous women (>4) were also at a higher risk of pregnancy complication as compared to women with parity one. A recent meta-analysis of the Asian population identi ed only multiparity as a risk factor of GDM [42]. Moreover, Shechter-Maor et al (2020) reported that primiparous women (having 1 previous live birth) were at higher risk of having pregnancy complications than multiparous women [43]. The con icting results of parity in different studies pointed to the complexity of the association between possible risk factors of pregnancy complications. This means, there may be a possible in uence of further factors that contribute to a higher risk of these complications, such as ethnicity, socio-economic status, family history, and previous history of these complications.
An interesting result from the current study was gravida not having any adverse association with pregnancy complications. Instead, it depicted a statistically signi cant negative effect against pregnancy complications (O.R =0.11). The results identi ed pregnant women, mainly of gravida 4, being at lower risk of having pregnancy complications than higher gravida women. The degree of gravida or gravida status is rarely reported in previous studies as a risk factor or protective factor of pregnancy complications. In this context, Heaman and colleagues reported that being a primigravida is a risk factor of PTL [44]. However, the said study also showed that being a multigravida woman with a previous history of PTL was a common risk factor for PTL and eclampsia as well. Additionally, primigravid women are previously highlighted by another researcher from Australia as well in a way that primigravid women have much higher rates of maternal complications [41]. However, a recent study from South India showed that gravidity was not associated with high-risk pregnancy and included complications such as anemia, PIH and GDM [40].
The current study revealed that pregnant women living in camps had greater risk of having pregnancy complications (O.R=2.35) as compared to women living in cities. The possible explanation might be due to lagging pregnant women living in camps in getting health care services regularly due to social, educational and economic conditions which are known to be much lower in Palestinian camps than cities and towns.
Regression analysis of current study results missed the age as a common risk factor for having complications during pregnancy. It was contrary to the Jordanian study that identi ed older women (age > 40) to be at high risk of such adverse pregnancy complications [30]. Similarly, many other international studies have also reported that advancing age (women ≥40 years) is a potent risk factor of pregnancy complications [45][46][47][48]. Advanced age was also identi ed to be a risk factor for having speci c complications during pregnancy such as GDM [49,50], pre-eclampsia [39], and PIH [51]. However, the current study did not nd age as a risk factor for maternal pregnancy complications; this might be due to the small number of pregnant women with advanced age in our study sample.
Contrarily, the regression model for fetal pregnancy complications from current data managed to identify younger age (17-40 years) as a protective factor of fetal complications during pregnancy. This indicated that these complications were more common to be seen among mothers with older age (>41 years). This has previously been reported by some studies where fetuses of older-age women (≥40 years) are prone to endure complications such as IUFD [52] IUGR [48,53], LGA [54], and SGA [55]. Yet, some other studies reported age of 35 years and above as the cut-off for increased risk of complications such as LGA, but this cut-off point did not found age as a risk for SGA fetal complications [32].
However, both LGA and SGA have indecisive trend across the studies. As an example, LGA was more commonly reported among women aged 40 years old and more when compared to younger pregnant women aged 30-34 [56]. However, the result was insigni cant when comparing women aged women 35-39 years with the reference group pregnant women (30-34 years The results of the current study showed a relationship between parity status and fetal complications; fetal complications were more commonly seen among mothers with nulliparity, low multi-parity (1-3 previous live births) and high multi-parity (4-6 previous live births) compared to the reference group (Table  4), indicating women with high parities had a lower risk of fetal complications in our sample. Some studies reported that nulliparous women had signi cant associations with adverse fetal complications compared with multiparous women [31,60] where nulliparous women depict signi cant adverse association with SGA [61]. Additionally, the increased risk of fetal complications such as SGA [32,62] and IUGR [43] is also reported to be higher among primiparous mothers than multiparous mothers. Contrarily, there has been a study indicating LGA as more common to see among very high parity women (10-14 parities), but a lower risk of SGA was reported among this group [18]. However, since the study did not include nulliparous women in the analysis, it is di cult to compare our results with it. Moreover, a metaanalysis concluded that women who were both multiparous (≥3) and had their age ranging between 18-34 years had some protective effect against SGA [31]. Similarly, another study showed that only nulliparous women aged ≥ 30 years but not multiparous women were at higher risk of having SGA when compared with nulliparous women age 20 to 29 [58]. This may indicate that not only the level of parity may affect fetal complications, but the explanation of this could also be due to the existence of other in uencing factors such as maternal age or the existing relationship between speci c parity levels with speci c fetal complications.
The current study revealed that the continuation of smoking during pregnancy is quite common among Palestinian pregnant women. The high prevalence of smoking could be attributed to the increase in the Shish smoking practice among all Arab countries which itself is becoming an acceptable attitude among both men and women. Regression analysis showed that smoking women were at a higher risk of having fetal complications during pregnancy than non-smokers. This result con rmed previous ndings whereby smoking in pregnancy is an established risk factor for fetal complications such as SGA [17,25,44,62,63,64] and IUGR [65,66] in plenty of previous studies as a risk factor. It is well known that cigarette smoking during pregnancy decreases the carrying capacity of oxygen for both fetal and maternal blood, which in turn diminishes the oxygen available to the fetus at the tissue level and further effect fetal oxyhemoglobin dissociation [67]. Hence, the current study, once again, con rms the importance of smoking as a major risk factor for fetal complications during pregnancy.

Strengths and Limitations
This being one of the rst studies to report baseline data regarding maternal and fetal pregnancy complications among Palestinian pregnant women, also has some limitations need to be addressed.
There was no information collected about the history of previous pregnancy complications such as previous pre-eclampsia, abortion, PIH or GDM. Moreover, pregnant women who had pre-existing medical problems such as hypertension, diabetes, and epilepsy were not included in the study; this can underestimate the prevalence of complications during pregnancy. However, despite these limitations, we believe this study contributes to the literature related to the identi cation and evaluation of complications and risk factors of complications occurring during pregnancy.

Conclusion
Fetal and pregnancy complications are prevalent among Palestinian pregnant women.
LGA and SGA were mostly reported as fetal complications while pregnant women were more likely to suffer from GDM, PIH and PTL as pregnancy complications. Based on ndings, age younger than 41 years was a protective factor for fetal complications, but not the complications of pregnancy. Additionally, fetal complications were more prevalent among smoking mothers and women with ≤ 6 previous live births. In the further context of parity, parity of three and below, and living in camps were risk factors that increase the risk of pregnancy complications. However, it was equally interesting to note that gravida 4 was a protective factor for pregnancy complications. We strongly recommend better pregnancy monitoring and early screening of pregnant women to identify the risk for these complications which can help to either avoid or timely action against those risky situations.

Declarations
Ethics approval and consent to participate The study was approved by the Institutional review board (IRB) committee from An-Najah National University and by Palestinian Ministry of Health that permitted access to antenatal clinics and medical les. A signed written informed consent was obtained from all the study participants to ensure the prospective agreement of pregnant women participating in the study. The study methods were performed in accordance with the relevant guidelines and regulations of Helsinki Declaration.

Consent for publication
Not applicable Availability of data and materials: The data that support the ndings of this study are available from the corresponding author upon reasonable request.
All authors contributed to the study. NN, MT, SA conceived and designed the study. NN, MT contributed to data collection and assisted in completing the study. NN, SA analyzed the data. SA interpreted the data and wrote the nal draft of the manuscript. The authors have read and approved the manuscript.