Pregnancy: A Comprehensive Review

1.1 Cardiovascular diseases

Cardiovascular diseases are a group of heart and blood vessel disorders, mainly including congenital heart disease, rheumatic heart disease, and hypertension. It is a serious threat to human beings, especially to pregnant women, and is characterized by high prevalence, disability, and mortality.

Maternal deaths due to heart disease are currently on the rise and have become the most important cause of death in Western countries. In a subgroup of 5739 pregnant patients with prevalent diagnoses of congenital heart disease (57%) and valvular heart disease (29%), the highest mortality rate was in the pulmonary arterial hypertension (PAH) group (9%), with heart failure occurring in 11% and arrhythmia in 2% patients [7]. Another study also showed that women with congenital heart disease had a significantly higher frequency of stroke, heart failure, and arrhythmia during pregnancy. Neonatal mortality was significantly higher in the adult congenital heart disease group compared with the non-adult congenital heart disease group (0.83% vs. 0.22%; p = 0.001), and newborns of congenital heart disease pregnant women had low/very low or extremely immature birth weight (p < 0.001) or required more resuscitation and mechanical ventilation (both p < 0.001) [8]. The Norwegian Health Registry likewise registered all pregnant women in the country and studied whether chronic diseases were associated with miscarriage, and it found that women with cardiometabolic diseases had an increased risk of miscarriage (OR 1.25, 95% CI: 1.20–1.31; P < 0.001). And the risk was elevated for all diseases included in cardiometabolic diseases: atherosclerosis (OR 2.22; 95% CI: 1.42–3.49; p < 0.001), hypertensive disorders (OR 1.19; 95% CI: 1.13–1.26; p < 0.001), and type 2 diabetes mellitus (OR 1.38; 95% CI: 1.26–1.51; p < 0.001). In other categories, diseases such as hypoparathyroidism (OR 2.58; 95% CI: 1.35–4.92; p = 0.004), and Cushing’s syndrome (OR 1.97; 95% CI: 1.06–3.65; p = 0.03) had elevated risk [9].

Heart disease is a threat to the health of pregnant women in regions other than the West. At Madras Medical College in India, heart disease (HD) was diagnosed for the first time in 60.5% of pregnant women, with rheumatic HD being the most common (42%). The primary outcomes in pregnant women with heart disease were maternal mortality and maternal combined cardiac events (CE) (15.2%). The highest maternal mortality was in patients with prosthetic heart valves (PHV) (8.6%). The most common maternal combined cardiac event was heart failure (66.0%). So women with heart disease have a high mortality rate, the highest of which are PHV, pulmonary hypertension (PH), and left ventricular systolic dysfunction (LVSD) [10] (Table 1). Therefore, pregnant women with heart disease need intensive specialized care and preconception counseling, and women at high risk are advised not to become pregnant.

Another high prevalence of cardiovascular disease is hypertension. A specific group of hypertensive disorders of pregnancy is idiopathic noncirrhotic portal hypertension (INCPH). A study of 24 pregnancies in 16 patients with INCPH found that the overall prognosis for mothers and infants was favorable, despite complications associated with portal hypertension (e.g., miscarriage and preterm labor). Most fetuses at 20 weeks of gestation were healthy, and mothers were asymptomatic at a median follow-up of 27 months postpartum [11]. To minimize hypertensive disorders of pregnancy (HDP) complications, prompt identification and treatment including regular blood pressure monitoring and self-monitoring, combined with equity identification strategies and quality improvement measures, should be used to prevent serious complications and death.

Preeclampsia (PE) is a syndrome of hypertensive disorders of pregnancy that occurs most often after 20 weeks of gestation and is defined as new onset persistent hypertension with proteinuria or systemic involvement [12]. By comparing pregnant women in Sweden and China, a study found that the overall prevalence of preeclampsia was similar in both countries, with 16,068 (2.9%) and 1803 (2.3%) cases, but in terms of severity, there were 5222 (32.5%) cases in Sweden and 1228 (68.1%) cases in China. A higher risk factor for preeclampsia in China compared with Sweden was obesity (China: OR 5.12; 95% CI: 3.82–6.86; Sweden: OR 3.49; 95% CI: 3.31–3.67). In contrast, a higher risk factor for preeclampsia in Sweden compared with China was childlessness (Sweden: OR 3.91; 95% CI: 3.65–4.18; China: OR 1.65; 95% CI: 1.20–2.25) (Table 2). These suggest an association between obesity and childlessness and preeclampsia [13]. The impact of obesity on pregnancy complications in pregnant women with heart disease was further analyzed in a study, and it showed that pregnant women with a higher body mass index (BMI) (30 kg/m² and above) had a higher risk of experiencing an adverse CE in 790 pregnancies (23% vs. 14%; p = 0.006). In multivariate models, obesity (OR 1.7; 95% CI: 1.0–2.7) and higher Canadian Cardiac Disease in Pregnancy risk index (CARPREG II) (OR 1.7; 95% CI: 1.5–1.9) predicted CE. Preeclampsia was more common in obese women compared to normal weight women (8% vs. 2%; p = 0.001). Therefore, obesity is a modifiable risk factor that should be focused on during preconception counseling [14]. These results support the association of increased PE risk with factors such as obesity and childlessness.

1.2 Pestilences

Dengue infection during pregnancy almost doubles fetal death rate (OR 1.9, 95% CI: 1.6–2.2). Severe dengue infection increases the risk of fetal death approximately fivefold (OR 4.9, 95% CI: 2.3–10.2) [15]. Although the mechanism by which dengue infection leads to stillbirth is not clear, there are three main hypotheses: the symptoms of dengue infection in the mother have a direct effect on the fetus (severe dengue); dengue infection causes changes affecting the placenta, and the dengue virus has a direct effect on the fetus [16].

Pregnant women infected with hepatitis C virus (HCV) had higher odds of adverse perinatal outcomes (preterm labor, fetal dysplasia, fetal distress), but there were no differences in gestational diabetes, preeclampsia, eclampsia, or stillbirth. It is worthwhile to take precautions in advance, as pregnant women are recommended to be screened for HCV during pregnancy since they are still at risk for HCV infection during pregnancy [17].

Other infectious diseases, such as Q fever, also deserve public attention. The effect of Q fever (caused by Coxsackie bodies) on pregnancy is unknown, but available data suggest that it may increase the risk of early miscarriage, late preterm labor, or intrauterine fetal death. In addition, Q fever infection during pregnancy may increase the maternal risk of developing chronic Q fever. And Q fever is usually asymptomatic, so screening and treatment are recommended in high-endemic areas [18].

1.3 Autoimmune diseases

Autoimmune diseases are diseases in which an organism develops an immune response to its own antigens that results in damage to its own tissues. Pregnant women with autoimmune diseases such as systemic lupus erythematosus (SLE) and primary immunodeficiency disorders (PID) are at higher risk for obstetric complications and adverse pregnancy outcomes, including fetal loss, preterm labor, fetal growth restriction, and preeclampsia, and the women are at risk for recurrence and exacerbation of pre-existing autoimmune diseases during pregnancy.

SLE increases the risk of pregnancy complications such as preeclampsia and poor fetal prognosis. A previous study using blood transcriptome analysis and multicolor flow cytometry found that immune markers such as interferon and plasma cells were downregulated in healthy pregnancies, whereas these markers were significantly elevated in preeclampsia and lupus pregnancies with fetal complications [19].

In addition, neuromyelitis optica myelitis optica spectrum disease (NMOSD) is particularly common in women of childbearing age. Pregnancy may exacerbate NMOSD and affect the outcome of the pregnancy, and some treatments carry risks to the fetus [20]. A systematic review and meta-analysis examined 15 studies involving 443 patients with NMOSD. Immunosuppressive therapy during pregnancy and older age at conception was found to be associated with a lower risk of pregnancy-related seizures. The recurrence rate was highest in the first postpartum trimester, while Expanded Disability Status Scale scores worsened significantly during pregnancy and the postpartum period. This suggests that immunosuppressive therapy may help to reduce the risk of pregnancy-related seizures, but the increased risk of recurrence in the postpartum period needs to be further validated [21].

Autoimmune hemolytic anemia (AIHA), on the other hand, may flare up during pregnancy. Between 1997 and 2022, a study evaluated 33 women for recurrence or new onset of autoimmune hemolytic anemia (AIHA) in 45 pregnancies. Of the 20 women diagnosed with AIHA before pregnancy, 10 had recurrences, and 13 had new episodes of AIHA during pregnancy or in the puerperium (2 had recurrences during a second pregnancy). All these hemolytic events were severe and required treatment (e.g., steroids, intravenous human immunoglobulin, and blood transfusions), with complete remission in 65% of cases, maternal complications in 15% of cases, and adverse fetal events in 22% of cases. Despite the high risk of AIHA, a healthy pregnancy can be achieved with close monitoring and prompt treatment [22].

1.4 Endocrine diseases

During pregnancy, the endocrine system undergoes a series of physiologic changes to adapt to and support fetal development. Patients with endocrine disorders will also experience corresponding changes in their underlying diseases during pregnancy. Even some severe endocrine diseases can lead to infertility in patients.

Gestational diabetes (GD) is the most common endocrine disorder during pregnancy, and women with diabetes are at a higher risk of developing complications during pregnancy compared to those without. Hyperglycemia increases the prevalence of congenital malformations in infants before 8–10 weeks of gestation, when the fetus is forming its organs [23]. In addition, a retrospective cohort study investigated the association of history of spontaneous abortion (SAB) and induced abortion with the risk of GD in subsequent pregnancies. The study covered 102,259 pregnant women and showed that a history of SAB was significantly associated with the risk of GD and that this risk increased with the number of SABs.

Polycystic ovary syndrome (PCOS), which causes a range of symptoms in patients, has a prevalence of 5–13% in women [24]. It has been reported that women with PCOS have higher BMI after conception, greater weight gain during pregnancy, and higher chances of having adverse pregnancy outcomes such as miscarriage, gestational diabetes mellitus, gestational hypertension, preeclampsia, and cesarean delivery. Therefore, pregnant women should be screened for PCOS during prenatal checkups [25].

1.5 Hematologic diseases

The hematologic system is one of the most important systems and ensures the normal function of all kinds of blood cells in order to guarantee the health of the organism.

Sickle cell disease (SCD) is a classic inherited blood disorder. The use of hydroxyurea during pregnancy in pregnant women with SCD increases the likelihood of miscarriage and stillbirth due to the association of hydroxyurea with live births of full-term infants with a birth weight of <5.5 pounds for full-term infants in live births, but not with preterm births or serious medical problems at the time of the baby’s birth [26]. Meanwhile, a study analyzed the impact of SCD and prenatal anemia on severe maternal morbidity (SMM) and other adverse pregnancy outcomes (APOs) during pregnancy. The study found that the incidence of SMM was significantly higher in patients with SCD than in anemic patients and controls, especially in complications related to thrombosis or SCD-specific pathology. The results suggest that prenatal anemia may play a mediating role in pregnancy risk and that pregnancy risk associated with SCD is similar across many APOs [27].

In addition, a chronic hematologic malignancy, myeloproliferative neoplasms (MPNs), often cause true erythrocytosis, essential thrombocythemia (ET), primary myelofibrosis (PMF), and unclassifiable MPN (MPN-U) [28]. The live birth rate for pregnant women with MPN has been reported to be 65% in polycythemia vera (PV) and 70% in ET [29, 30, 31, 32]. In the study, there was a significant increase in preterm labor in MPN group pregnancies, 14% compared to 4% in control group pregnancies (p < 0.001). Correspondingly, low birth weight (<2500 g) was significantly increased in MPN pregnancies (p = 0.042). Maternal thrombotic complications occurred in three (1%) pregnancies in patients with MPN compared to none in controls. Pregnancy-related bleeding affected 14% of pregnancies in MPN compared with 9% in the control group (p < 0.110). Cesarean delivery was more common in MPN pregnancies. The incidence was 12.2 per 100,000 pregnancies. In conclusion, preterm labor is an important complication of MPN pregnancy, and maternal complications are less common than previously reported. Pregnant women with true erythrocytosis are at increased risk of fetal loss, and their high incidence of late miscarriage is associated with the presence of the JAK2v617F mutation, and therapeutically antithrombotic therapy appears to reduce the risk [4].

4.1 Drug delivery

One of the major challenges in the treatment of diseases during pregnancy is the transit of small molecule drugs through the placenta and their toxicity to the developing fetus. The placenta is responsible only for providing nutrients, removing waste products, and protecting the fetus from toxic substances in the maternal circulation. Thus, the placenta is a biological barrier between the mother and the fetus for drug delivery. The latest research in nanoparticle technology offers the opportunity for safe drug delivery during pregnancy by controlling the interaction of therapeutic drugs with placenta [40].

4.1.1 Diabetes mellitus

For patients with diabetes mellitus, there is currently no commercially available customized hybrid closed-loop insulin delivery system to achieve specific glycemic targets during pregnancy. A study was designed to evaluate the feasibility and performance of a customized closed-loop insulin delivery system (CLC-P) based on a regional model predictive controller for use at home by patients with gestational combined type 1 diabetes. Ten pregnant women with type 1 diabetes using insulin pumps in mid- or late-gestation (HbA1c 5.8 ± 0.6%) and with a mean gestational week on the system of 23.7 ± 3.5 weeks participated in the experiment. Compared with the break-in period (break-in 64.5 ± 16.3% vs. CLC-P 78.6 ± 9.2%; p = 0.002), the mean percentage of intervals increased by 14.1 percentage points, equivalent to 3.4 hours per day. Time above 140 mg/dL (p = 0.033) and time below 63 mg/dL and 54 mg/dL (both p = 0.037) were significantly reduced during CLC-P use (Table 3). Nine subjects exceeded the consensus goal of 70% or more of the time range during CLC-P use. The results suggest that extended use of CLC-P at home until delivery is feasible (Figure 2). This finding is helpful for pregnant women with diabetes, but larger randomized studies are needed to further evaluate systemic efficacy and pregnancy outcomes [41].

Variable	Run-in	CLC-P	Absolute difference (95% CI)	P value
Primary outcome
Time in 63–140 mg/dL, %	64.5 ± 16.3	78.6 ± 9.2	14.1 (6.6 to 21.7)	0.002
Secondary outcomes
Time < 63 mg/dL, % [IQR]	3.7 [1.5 to 6.4]	1.6 [1.4 to 2.1]	−2.8 (−8.3 to −0.3)	0.037
Time < 54 mg/dL, % [IQR]	1.0 [0.3 to 2.2]	0.4 [0.3 to 0.4]	−0.9 (−3.7 to −0.02)	0.037
Time > 140 mg/dL, %	29.8 ± 19.5	19.7 ± 9.5	−10.1 (−19.2 to −1.0)	0.033
Mean glucose, mg/dL	123.1 ± 24.1	115.1 ± 10.6	−8.0 (−19.1 to 3.1)	0.139

Table 3.

Continuous glucose monitoring outcomes for run-in versus CLC-P use.

Note: all p < 0.05 (data from At-Home Use of a Pregnancy-Specific Zone-MPC Closed-Loop System for Pregnancies Complicated by Type 1 Diabetes: A Single-Arm, Observational Multicenter Study. Diabetes Care [41].)

Furthermore, regarding medications for the treatment of type 2 diabetes mellitus (T2DM) in pregnant women, it has been suggested that women with T2DM who are treated with oral hypoglycemic agents, such as metformin and sulfonylureas, should be switched to insulin prior to conception or, at the latest, after the diagnosis of pregnancy. However, it needs to be noted that metformin crosses the placenta and interacts with fetal environmental factors to adversely affect the fetus [42] (Figure 3).

4.2 Genetic testing

Trisomy 21 is a group of chromosomal disorders that have an enormous impact on newborns and families, and many regions are now taking steps to prevent the occurrence of trisomy 21 in the early stages of pregnancy. Offering free deoxyribonucleic acid (cfDNA) testing in the first trimester of pregnancy to women at high risk for trisomy 21 may reduce invasive fetal karyotyping and the number of miscarriages. However, a randomized analysis of 2051 eligible women found that offering cfDNA screening but still requiring invasive testing in the event of a positive test did not significantly reduce the rate of miscarriage compared with invasive testing alone [46].

4.3 Complementary therapy

It is estimated that one in seven heterosexual couples are affected by infertility and therefore require the help of assisted reproductive therapy (ART) to conceive [47]. Interventions that may reduce the risk of miscarriage or increase the chances of a live birth include intrauterine injection of hCG at the time of embryo transfer at the stage of embryonic division, use of dehydroepiandrosterone and embryo culture media high in hyaluronic acid in women, and use of antioxidant therapy in men. Interventions that increase the potential risk of miscarriage or decrease the chance of live birth include the use of PGT-A fluorescence in situ hybridization and injection of embryo culture supernatant prior to embryo transfer in frozen cycles. When choosing an intervention, it is important to seek the advice of a medical professional and select the most appropriate one [48].

5.1 Miscarriage

Research shows that parental age affects the risk of miscarriage. The risk of miscarriage is low (10%) for women aged 25–29 years, which rising rapidly after the age of 30 years, and as high as 53% for those aged 45 years and over [49]. For fathers, men aged 25–29 years had the lowest risk of miscarriage, which then increased with age, e.g., 1.04 (95% CI: 0.90–1.21) in the 30–34 year old group versus the 25–29 year old group [50]. So the optimal age for both parents to have children is 25–29 years, after which the risk of miscarriage increases with age.

Moreover, most pregnant women choose to conceive again after a miscarriage, but the timing and number of intervals between pregnancies is also critical. Most mothers between the ages of 25 and 34 choose to have another child after an interval of six months. Pregnancy intervals of more than 24 months were more common among women who smoked and had lower levels of education. However, the length of the interval between pregnancies was not found to be associated with subsequent risk of miscarriage, preterm labor, or birth of a small-for-gestational-age child [51]. At the same time, if another miscarriage occurred after a second pregnancy, the higher the number of miscarriages, the higher the risk of recurrence, with age-adjusted ratio of 1.54 (95% CI: 1.48–1.60) after one miscarriage, 2.21 (95% CI: 2.03 to 2.41) after two miscarriages, and 3.97 (95% CI: 3.29 to 4.78) after three consecutive miscarriages [49].

5.2 Stillbirth

In full-term pregnancies (37–42 weeks), the risk of stillbirth increases with gestational age. The perinatal risk is lowest at 39 weeks of gestation, while delivery before or after this time increases the risk of adverse outcomes [52]. Besides, at 41 weeks, the risk of labor and stillbirth increased significantly, and neonatal mortality did not decrease compared to the previous period. And the risk of stillbirth increased even more markedly when labor was resumed after 41 weeks [53].

In addition, the lifestyle habits of pregnant women are also associated with stillbirth. The relative risk of late stillbirth in pregnant women with prenatal exposure to alcohol, smoking, or both was 2.22, 1.60, and 2.78, respectively, compared to pregnant women with no exposure to alcohol or smoking [37]. Adverse lifestyle habits significantly increase the risk of stillbirth.

5.3 Prematurity

Live birth at less than 37 weeks of gestation is called preterm labor, where the extremely preterm (<28 weeks) and very preterm (28–32 weeks) are accompanied by a high prevalence of neurologic and respiratory complications in the newborn [5]. There are three factors that contribute to preterm labor, the first of which is maternal age. Pregnant women aged 20–34 years have an increased risk of adverse fetal outcomes and an increased risk of spontaneous preterm labor compared to pregnant women aged 35 years and older. And for women of any age, the shorter the interval between pregnancies, the greater the likelihood of adverse outcomes [54].

Besides, the environment in which a pregnant woman lives can also affect pregnancy outcomes; for example, air pollutants (nitrogen oxides, particulate matter, and polycyclic aromatic hydrocarbons) have been associated with the risk of preterm labor and congenital malformations [55, 56, 57, 58].